Keloid Treatment Evaluation

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InDermatology and Venereology

q 3 ( 1 " Sawsan Omran Hashim A m '

( M . B . B . c l i ) Faculty of Medicine

Z a g a z i g University

K E L O I D S : TREATMENT

EVALUATION

Thesis

Submitted in partial fulfillment of Master Degree

c O n d e r Supervision of

Professor

AhmedA b d u l - f a d e r

SalemProfessor of Dermatology and V e n e r e o l o g y

Faculty of MedicineZagazig University

Professor

Mona Anwar El-HarrasProfessor of Dermatology and V e n e r e o l o g y


Dr.

A m r Nazir SaadawiAssistant Professor of Dermatology and V e n e r e o l o g y


Faculty of Medicine

Zagazig University

2004


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A C K N O W L E D G E M E N T

Above all and first of all praise and thanks must be to ALLAH.

I would like to express my deepest gratitude to

Professor Ahmed Abdul - Kader Salem, Professor of

Dermatology and Venereology, Faculty of Medicine, Zagazig

University, for his deep interest, sincere supervision, generous

assistance and continuous support during the progress of this work.

I am really grateful to Professor Mona Anwar El-Harras,

Professor of Dermatology and Venereology, Faculty of Medicine,

Zagazig University, for her kind advice, support, supervision and

sincere cooperation, in the accomplishment of this work.

I amhonoured to express my deep thanks to

Dr. Amr Nazir Saadawi, Assistant Professor of Dermatology and

Venereology, Faculty of Medicine, Zagazig University, who helped

me and gave me much of his valuable experience and sincere

directions to complete this work.


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LIST OF ABBREVIATION

a - SMA a - smooth muscle actin

BFGF Basic fibroblast growth factor

CO 2 Car bondi oxi de l aser CW Continues wave

ECU Extracellular matrix

EGF Epidermal growth factor

Er : YAG Erbium : YAG

FGF Fibroblast growth factor

FPDL Flash lamp pumped pulsed dye laser

HSC Hypertrophic scars

IFN - a Interferon - a

IFN - 13 Interferon - [ 3

IFN - y Interferon - yI G F 1 Insulin-like growth factor-1

KFs Keloid producing fibroblast

Nd : YAG Neodymium yttrium Aluminum Garnet

PDGF Platelets derived growth factor

TGF- beta I Transforming growth factor beta I

T G F - [ 3Transforming growth factor

TRT Thermal relaxation time


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CONTENTSPage

Introduction and Aim of the Work - - - - - - - - - - - - - 1Review of Literature - - - - - - - - - - - - - - - - - - - - - - 4

Chapter 1: Keloids - - - - - - - - - - - - - - - - - - - - - - - - - - - - 4- Historical background - - - - - - - - - - - - - - - - - - - - - - - - 4- Epidemiological factors - - - - - - - - - - - - - - - - - - - - - - - 4- Clinical features - - - - - - - - - - - - - - - - - - - - - - - - - - - - 5- Histopatholology of keloids - - - - - - - - - - - - - - - - - - - - 7- Physiology of wound healing - - - - - - - - - - - - - - - - - - 8

- Events in the process of wound healing - - - - - - - - - - - - 9

- Pathogenesis of keloids - - - - - - - - - - - - - - - - - - - - - - - 10- The role of cytokines - - - - - - - - - - - - - - - - - - - - 15

- The role of mast cells - - - - - - - - - - - - - - - - - - - - 18Chapter 2 : Treatment of keloids 191- Surgical therapy - - - - - - - - - - - - - - - - - - - - - - - - - - - 202- Physical therapy - - - - - - - - - - - - - - - - - - - - - - - - - - - 23

a- Laser in keloids - - - - - - - - - - - - - - - - - - - - - - - - 23b- Radiation therapy - - - - - - - - - - - - - - - - - - - - - 41

c- Cryotherapy - - - - - - - - - - - - - - - - - - - - - - - - - - 42d- Pressure therapy - - - - - - - - - - - - - - - - - - - - - - - 44

3- Pharmacological therapy - - - - - - - - - - - - - - - - - - - - - 46a- Intralesional corticosteroids - - - - - - - - - - - - - - - 46b- Silicon gel - - - - - - - - - - - - - - - - - - - - - - - - - - - 49c- Antihistamine - - - - - - - - - - - - - - - - - - - - - - - - - 50d- 5-Flurouracil - - - - - - - - - - - - - - - - - - - - - - - - - 51e- Calcium channel blockers - - - - - - - - - - - - - - - 53

4- Immunotherapy - - - - - - - - - - - - - - - - - - - - - - - - - - - 54Patients and Methods - - - - - - - - - - - - - - - - - - - - - 56Results - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 66Discussion - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 82Summary and Conclusion - - - - - - - - - - - - - - - - - - 89

References - - - - - - - - - - - - - - - - - - - - - - - - - - - - 92 Arabic Summary - - - - - - - - - - - - - - - - - - - - - - - -


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1

INTRODUCTION AND AIM OF THE WORK

Keloids are human dermal fibroproliferative disorders occurring

following trauma, inflammation, surgery and burns and possibly

spontaneously (Horn, 2001).

A Family history of keloids is frequently elicited. In familial

cases, the exact mode of inheritance is unclear. Both a u t o s o m a l

recessive and autosmal dominant patterns of inheritance are being

reported. A predisposition for keloids formation has been noted in

individuals with human leucocyte antigens ( H L A ) B 14, B W 1 6, andblood group A (Tredget, 1 9 9 7 ) .

Clinically, keloids are defined as over growth of dense, fibrous

tissue following healing of the skin injury that extends beyond the

border of the original cutaneous insult (when identifiable), does not

regress spontaneously and tends to recur after excisions (English and

Shenefelt, 1999).

Histologically, keloids are characterized by haphazard deposition

of collagen fibers within the dermis, surrounded by a mucinous

extracellular matrix with few macrophages and abundance of

eosinophils, mast cells, plasma cells and lymphocytes. The collagen

appears as thick hyalinized bands of eosinophilic nodules. These nodules

consist of a dense mass of fibroblasts within the collagen, encircled by

numerous small vessels (Horn, 2001).


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Pharmacological therapy includes ; i n t r a l e s i o n a l injection of

corticosteroids, silicone gel, antihistamine, 5- Flurouracil, and calcium

channel blockers. Intralasional injection of tramcinolone is used as a

first line of treatment modality. Corticosteroid injections alone willimprove but not eliminate keloids. Enhanced results may be achieved

when corticosteroids are combined with other treatment modalities.

Immunotherapy may have a role in the treatment of keloids,

Intralesional injection of interferon gamma ( I F N - 1 ) has been shown to

regulate collagen synthesis. The most dramatic results was achieved

when IFN- y was used after keloids excision (Shaffere et al. 2002).

The aim of this work was to search for a more satisfactory line

of treatment for keloids. Both intralesional steroid injection and

Nd:YAG laser were used for the treatment of keloids. Moreover,

a comparative clinical study between the results of both lines of

treatment was done.

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REVIEW OF LITERATURE

CHAPTER I

KELOIDS

Historical background :

Abnormal scaring was first described in the Smith Papyrus

between 2500 and 3000 BC. In 1817, Alibert proposed the word

cheloide (Keloids) to differentiate these lesions from malignant

neoplasms. The word is derived from the Greek word chele, meaning

crab claws, referring to the manner in which these lesions grow

laterally into normal tissue ( Y i l m a z et al., 2000).

Epidemiological factors :

Keloids occur in individuals with a familial predisposition,

enlarge, and extend beyond the margins of the original wounds and

rarely regress. Keloids may develop even after the most minor of skin

wounds, such as insect bites or acne. The time lag between injury and

keloids formation is variable, though a majority tend to form within

the first year after initiating the skin wound. Furthermore, keloids

rarely regress with time (Tredget et al., 1997 and Horn, 2001).

Patients with the highest incidence of keloids development are

between the ages of 10 and 30 years, although they occur in all age groups

and are rarely found in newborns or elderly (Appleton et al., 1996).

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5

The exact prevalence of keloids is unknown. The male to female

ratio is approximately 1:1. Studies that report a higher female

incidence reflect greater cosmetic concern and more frequent ear lobe

piercing (Venugobal et al., 1999).

Cosman et al., (1996) in a review of three large series based on

clinical impression found an incidence between 4-5% and 16% in a

predominantly blacks. Blacks and Asians are affected more than

Caucasians, with comparable incidence ratios between 5:1 and 15:1.

There has been an estimated number of 300,000 patients per year

treated in the United States ( Y i l m a z et al., 2000).

Clinical features:

Certain anatomical locations have an increased susceptibility to

keloid formation, although no body area is immune. The p r e - s t e r n a l

area, upper back and posterior neck are the most susceptible regions of

the body (Urioste et al., 1999). The ears, deltoid regions, anterior

chest and beard area are moderately susceptible to keloids formation.

On the other hand, keloids rarely develop on the palms, soles, penis,

scrotum or upper eyelids (Alster and H a n d r i e k , 2000). Mucous

membranes tend to be spared, but corneal keloids formation has been

reported (Urioste et al., 1999).

The keloids appear as broad, e r y t h e m a t o u s firm papules, nodules

or plaques with numerous telangiectasias and a shiny atrophic surface.


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These extend in a claw-like fashion beyond the injury. Keloids tend to

have a more rope-like surface ( A l s t e r and Handrick, 2000). p

Although, keloids are clinically different from hypertrophic scars,

there is often a gray area between both pathologies where the differential

diagnosis become difficult. The difference between them is quantitative

rather than qualitative (Table 1) ( A l s t e r and Handrick, 2000).

Table (1) : The difference between keloids and hypertrophic scars

(Sherris et al., 1995 and Peled et al., 2000).

Clinical

characteristics

H y p e r t r o p h i c s c a r s , t i e l o i d s

Color - White, pink or red - Deep red or purple

Texture - Shiny, minimal markings - Shiny, no markings.

Morphology - Raised, firm within wound

borders.

- Raised, firm, extend beyond

wound borders.

Site - Usually occur on flexorsurfaces (Abdomen,

joints, etc).

- Presternal area, upper back and posterior neck are the

most susceptible regions.The ears,. deltoid region

and anterior chest aremoderately susceptible.

Response to

surgery- Improve with appropriate

surgery- Often worsen by surgery

Histological

characteristics

- Few thick collagen fibers

- Scanty mucoid matrix

- Thick hyalinized collagen

- Mucoid matrix

- Nodular configuration

- Disorganized arrangement

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The relation between keloids and carcinogenicity is a site of

controversy. H o m , (2001) stated that keloids are regarded as benign

tumour with a zero carcinogenicity rate. On the other hand, Alster and

Handrick (2000), reported that alanine transaminase activity isincreased in keloids but not in hypertrophic scars. Because absent or

depressed alanine transaminase activity is a feature of malignant tumors,

this may be a reason that keloids are resistant to malignant degradation.

Histopathology of keloids :

Keloids are dense and sharply defined new growth of the

myofibroblasts and collagen in the dermis with a whorl like

arrangement of hyalinized bundles of collagenous fibers. The

spherical collagen bundles lie parallel to the epidermis but those

lower down interlace in all directions. The ribbon like bundles are

more compact and prominent. In older lesions there is a paucity of

elastic tissue. By pressure the keloids cause thining of the normal

papillary dermis and atrophy of the adjacent appendages which is

pushes aside. Mucopolysaccharides are increased and often there are

numerous mast cells (Haverstock, 2001).

Electron microscopy of keloids :

Electron microscopy and scanning electron microscopy

demonstrate the presence of fibroblasts and myolibroblasts and a

haphazard arrangement of collagen bundles. These tend to be dense

and homogenous, showing the net like arrangement of normal

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collagen. The ground substance, as demonstrated by special stains, is

increased, with a fibrillar appearance instead of globular deposits

(Peled et al., 2000).

Physiology of wound healing :

Wound healing is a complex group of biochemical and cellular

events designed to achieve restoration of tissue integrity. A "partial

thickness" wound will heal rapidly by simple reepithelizatin while,

"full thickness wound" which extends to the dermis heal by primary or

secondary intention. The healing by "primary intention" occurs when

the wound is pulled together by sutures or adhesive so that the

epidermal edges are brought into-apposition (Akasaka et al., 2001).

Delayed primary intention occurs if the wound is infected.

Closure should be delayed until it has been cleared by the natural

defense mechanisms, with appropriate antibacterial treatment. This

delayed closure reduces morbidity but does not affect or delay the

development of wound strength (Beldon, 2000).

Healing by "secondary intention" occurs when there is a major

loss of skin. The wound may be allowed to heal from the base by the

formation of granulation tissue. In this process, there is deposition of

new collagen, but contraction of the wound is also important in

repairing the defect. This simple methods of wound management can

produce excellent cosmetic results, especially on concave surfaces(Beldon, 2000).

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Phases of wound healing :

Classically there are three phases for normal wound healing :

Inflammatory, fibroblastic and the maturation phases (Peled et al.,

2000 and Prathiba et al., 2001).

In the first "inflammatory phase", wounding is immediately

followed by classic inflammatory reaction. Capillaries dilate and pour-

out fluid into the wound, fibrin clots and seals the wound.

Biochemical substances are released that cause vasodilation and pain.

Inflammatory cells are mobilized and move into the wound area.

During this phase the epithelium grows across the sealed wound

(Prathiba et al., 2001).

In the second "fibroblastic phase", the main strength of the wound

is generated. Fibroblasts move into the fibrin clots and begin synthesizing

large amount of new collagen in structural framework. During this phase

the strength of wound rapidly increases (Peled et al., 2000).

In the third "maturation phase", the nodularity and redness of

the fibroblastic phase gradually soften and flatten. Biochemically,

there is ongoing simultaneous collagen synthesis and degradation.

There is continuing slow increase in wound strength up to a year

following injury (Peled et al., 2000 and P r a t h i b a et al., 2001).

Events in the process of wound healing :

Platelets degranulation results in the release and activation of

potent cytokines, including transforming growth f a c t o r - ( 3 ( T G F - ( 3 ) ,

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epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-1), and

platelets derived growth factor (PDGF). These growth factors function in

the recruitment and activation of neutrophils, epithelial cells, endothelial

cells, macrophage, mast cells and fibroblasts. A prolonged inflammatoryphase results in increase in cytokines activity. An increased risk of scar

formation has been correlated with this exaggerated cytokine activation

( I s h i l i a r a et al., 2000 and Shang et al., 2001).

Granulation tissue formation and scar maturation require a

balance between matrix degradation and collagen biosynthesis for

optimal wound healing (Niessen et al., 2001). Matrix degradation is

coordinated through the action of collagenases, proteoglycogenases

and other proteases. As well antifibrotic factors are released and

include interferon - a (IFN-a), i n t e r f e r o n - ( l ( I F N - P ) , and interferon -y

( I F N - y ) . These interferons inhibit fibroblast synthesis of collagen and

fibronectin and decrease fibroblast development (Niessen et al., 2001

and Shang et al., 2001).

Pathogenesis of keloids :

The basis for keloids formation has not been fully elucidated.

Although both an increased collagen synthesis and turnover is

observed, ultimately a disproportion at deposition of collagen has been

noted. Normal and elevated levels of type I and type III collagen have

been reported (Tredget et al., 1997 ; Naitoh et al., 2001): Keloids

derived fibroblasts produce increased amounts of collagen per cell in

comparison with normal fibroblasts. They appear to function

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autonomously, demonstrating continued collagen synthesis in vitro in

the absence of any h u m o r a l substances (Lim et al., 2001).

A ten-fold increase in c o l l a g e n a s e production has been shown

within keloids. Elevated levels of c o l l a g e n a s e inhibitors such as

alpha-1 antitrypsin and alpha-2 macroglobulin are present. As well as,

elevated levels of chondroitin 4-sulphate, which act to make collagen

fibers resistant to collagenase degradation, have been detected.

Slightly increased levels of IgG, 1gM and C3 have been reported,

while IgA and C4 levels remaining normal (Ishihara et al., 2000).

Alternations of growth factor levels in keloids have been reported.

Some of these agents promote collagen accumulation. One of the growth

factors is TGF-13, which induce fibroblast, collagen, fibronectin and

proteoglycan (Urioste et al., 1999 and Shang et al., 2001).

The difference between normal wound healing and with keloids

lie not only in length of time over which new collagen is formed, but

also in the arrangement of the newly formed collagen. In keloids, theformation of new collagen following the inflammatory stage extends

much longer time than in normally healing wound. Even in the early

periods of fibroblastic phase, one can see that collagen fibers in the

granulation tissue are arranged in nodular pattern. The nodules

gradually increase in size and show thick, highly hyalinized bands of

collagen lying in a concentric arrangement (Chin et al., 2000).


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Immediately following wounding, platelet degranulation and

activation of the complement and clotting cascade form a fibrin clot

for haemostasis, which acts as a scaffold for wound repair (Lim et al.,

2001). Platelet degranulation is responsible for the release andactivation of an array of potent cytokines, including epidermal growth

factor ( E G F ) , insulin like growth factor-1 ( I G F - 1 ) , platelet derived

growth factor (PDGF), and transforming growth f a c t o r - 1 3 ( T G F - ( 3 )

which function as chemotactic agents for the recruitment of

neutrophils, macrophages, epithelial cells, mast cells, endothelial cells,

and fibroblasts (Shang et al., 2001 and Niessen et al., 2001).

Proliferation and differentiation of inflammatory cells are

required for phagocytosis, release of cytokines, and the formation of

granulation tissue. Prolongation of the inflammatory stage in large

wounds such as burn or following an infection exaggerates the

inflammatory phase of healing and hence increase the activity of

fibrogenic cytokines such as TGF-f3 and I G F - 1 , thus increasing the

risk of keloids development (Boyce et al., 2001).

The transformation of a wound clot into granulation tissue

requires matrix degradation and biosynthesis that are balanced to

achieve optimal wound healing. The degradation of extracellular

matrix is through the action of collagenase, proteoglycogenases, and

other proteases, which are released by mast cells, macrophages,

endothelial cells, and fibroblasts. Importantly, either excessivesynthesis of collagens, fibronectin, and proteoglycans by fibroblasts or

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deficient matrix degradation and remodeling may lead to abnormal

lesions such as keloids and hypertrophic scars (Nirodi et al., 2000).

Histologically, keloids and hypertrophic scars differ from

normal skin by an increase in thickness of the epidermis and dermis,

lack of epithelial ridges, minimal amounts of distinct collagen fibers

and fiber bundles, and the presence of nodules (Tredget et al., 1997

and Beldon, 2000).

Immunohistochemical examination has revealed that

hypertrophic scars contain whorls of connective tissue in nodular

structures containing a-smooth muscle actin (a-SMA)-positive

fibroblasts with small blood vessels and fine, randomly oriented

collagen fibrils, whereas keloids have few if any a-SMA-positive

fibroblasts and large, thick collagen fibers (Tredget et al., 1997 and

Beldon, 2000).

Although the predominant cell present in keloids and

hypertrophic scars is the fibroblast, Chin et a l . ; ( 2 0 0 0 ) described afour fold increase in the numbers of mast cells over those in normal

skin. Clinically the release of histamine by these cells likely

contributes to the common patient complaint of itchness. In addition,

the vasodilatory effect of histamine may promote erythema, and leakage

of plasma proteins into the regional tissues (Beer et al., 1998).

Comparisons of the rate of proliferation of fibroblasts form keloids or

hypertrophic scars and normal skin generally show no significant

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difference, although several studies report a faster rate of proliferation

for normal cells (Beldon, 2000).

Excessive biosynthesis of extra cellular matrix (ECM) proteins

by fibroblasts has been proposed as one of the potential contributing

factors to the accumulation of excessive matrix. Using

p r o p y l h y d r o x y l a s e activity as an index of collagen synthesis, it has

been demonstrated that keloids have increased p r o p y l hydroxylase

activity. However, other have used C proline to trace collagen

biosynthesis and found that keloids fibroblasts produced similar

quantities of collagen relative to normal controls (Lim et al., 2001).

Excessive matrix accumulation can occur not only by increased

synthesis of ECM proteins but also by a reduction in matrix

degradation, either intracellularly or e x t r a c e ' l l u l a r l y .

I n t r a c e l l u l a r

degradation of collagen by hypertrophic scars compared to patient-

matched normal skin fibroblasts using 02 labeling was not

significantly different (Peled et al., 2000). However, many

hypertrophic scars and keloids fibroblast cell stains have demonstrated

reduced mRNA for collagenase as well as net reductions in the ability to

digest soluble collagen commpared with their normal fibroblast pairs.

Other unique feature of keloids and hypertrophic scars

fibroblasts include a reduced ability of synthesize nitric oxide as an

important mediator of growth factor signaling, which likely functions

in wound healing through its antiproliferative and antimicrobial

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1 5

effects It was found to be important in collagenase regulation also

(Cobbold, 2001).

Taken together, the undesirable physical properties of

hypertrophic scars and keloids appear not to be a simple matter of

excessive extracellular matrix protein production. Activated

fibroblasts in hypertrophic scars and keloids are unable to degrade

collagen which may inhibit their ability to remodle the pre-existing,

randomly oriented collagen into a more uniform, organized matrix.

Increased verscian, a proteoglycan with long hydrophilic chondroitin

sulphate sugar chains, may contribute to tissue rigidity and bulk

through its propensity to attract water, interfering with the assembly

collagen fibrils into fibers and fiber bundles. Conversely, the smaller

proteoglycan, decorin, "decorates" the surface of collagen fibrils and

promtes the lateral association of fibrils to form smaller fibers and fiber

bundles as well as inhibits TGF-f3 activity (Kossi and Laato, 2000).

The role of Cytokines or growth factors in

fibroproliferative disorders:

The release and activation of growth factors during the

inflammatory phase of healing are prerequisties for subsequent

processes, including angiogenesis, re-epithelization, recruitment and

proliferation. Angiogenesis is stimulated by endothelial c h e m o -

a t t r a c t a n t s and mitogens such as heparin, released by mast cells,

fibroblast growth factor (FGF) IL-8, released by neutrophils,


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macrophages and kerationcytes and IGF-1, released by macrophages

(Niessen et al., 2001 and Ohtsura et al., 2000).

Wound reepithelization occurs following the migration of

epithelial cells from the wound margin and epidermal appendages

within the wound bed and has been shown to be enhanced by EGF,

TGF-a, vaccinia growth factor, and I G F - 1 (Chodon et al., 2000).

Fibroblast recruitment, proliferation, and production of ECM are

influenced predominantly by the fibrogenic growth factors PDGF,

I G F - 1 , and T G F -1 3 , as well as basic fibroblast growth factor (Ohtsura

et al., 2000). These fibrogenic growth factors upregulate ECM protein

production, increase the rate of proliferation and/or migration of

fibroblasts, and inhibit the production of proteases required to

maintain the balance between production and degradation. Of the

many fibrogenic growth factors that have been identified, three have

thus far been implicated in the development of hypertrophic scars and

keloids : T G f - 1 3 , PDGF, and I D G F - 1 (Niessen et al., 2001).

Transforming growth factor-13 was initially isolated from human

platelets but has been shown to be produced at the wound site by

infiltrating lymphocytes, macrophages and fibroblasts (Niessen et al.,

2001). Many of the biologic actions of T G F - 1 3 contribute to the normal

wound healing process and have been implicated in wide variety of

fibrotic disorders (Chodon et al., 2000). The release of T G F - 1 3 byplatelets localizes it in the wound environment very soon after injury,

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where it acts as a chemo-attractant for neutrophils, T - I y m p h o c y t e s ,

m o n o c y t e s , and fibroblasts (Shang et al., 2001). In vivo, stimulation of

granulation tissue formation and enhanced connective tissue response

support the role of TGF-f3 in normal wound healing. However, theprolonged and excessive presence of

T G F - 1 3 likely contributes to the

development of keloids and hypertrophic scars ( G h a h a r y et al., 1995 ;

Shang et al., 2001).

Platelets derived growth factor is initially released into the wound

by platelets, with later production by infiltrating macrophages,

endothelial cells, epithelial cells and fibroblasts. In turn, PDGF alsofunctions as a chemo-attractant and mitogenic factor for fibroblasts

and endothelial cells. Although the abnormal persistence of PDGF has

not been correlated with the development of hypertrophic scars and

keloids, the ability of this cytokine to modulate the production of I G F - 1 by fibroblasts and endothelial cells may indirectly contribute to

fibrosis (Niessen et al., 2001).

The critical role that macrophages play in wound healing is based

partially on their release of growth factors, including I G F - 1 . Detailed

studies of cell growth control have divided growth factors into two

types: competency and progression. Competency factors such as PDGF

and FGF allow cells to enter the GI phase of the cell cycle, and

progression factors such as IGF-1 and EGF facilitate the progression of

PDGF- induced competent cells into the S phase of the cell cycle,ultimately resulting in increased proliferation rate (Beldon, 2000).

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The role of mast cells in pathogenesis of keloids :

In most keloids, hypertrophic scars and surgical scars there are

approximately twice as many mast cells in apparently normal dermis

surrounding the scar as in the lesion itself (Mckee et al., 1996). It has

been previously suggested that mast cell number increase in connective

tissue as healing progresses, but there is some evidence to indicate that

mast cell number decrease in aging keloids. Finding mast cells in greater

number in dermis surrounding scars suggests that as the surgical scars

progress, their mast cell component approaches that of normal dermis

(Yamamoto et al., 1995 ; Urioste et al., 1999 and Haverstock, 2001).

Beer et al. (1998) stated that, it would be valuable to quantify

mast cells in perilesional and entirely normal dermis from another skin

site to ascertain if any increase in dermal mast cells occur surrounding

scars even when lesional mast cells are not increased.

Mast cell numbers are not of value to distinguish between

keloids and hypertrophic scars histologically. The precise role of mast

cells in cutaneous scar reactions remains undetermined, but absolute

mast cell numbers may not accurately reflect tissue concentrations for

active mast cell products (Beer et al. 1998 and Kim, 2000).

Clinically, the release of histamine by these cells likely to

contribute to the common patient complaint of itching. In addition, the

vasodilator effect of histamine may promote erythema and leakage of plasma proteins into the regional tissues (Kim, 2000).

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CHAPTER II

Treatment of keloids

Currently, treatment of keloids, remains time consuming and hasfew consistently successful approaches. The result is that many

methods of care have been proposed but few regimens have been

standardized (Shaffer et al., 2002). The following scheme shows the

treatment modalities used in keloids (Porter, 2002) :

I- Surgical therapy II- Physical therapy

A- Laser therapy CO, laser Ultrapulsed CO, laser Argon laser Argon-pumped dye laser Flash lamp-pumped-pulsed dye laser (FPDL) Neodymium-Yttrium-Aluminum-Garnet (Nd-YAG)

B- Radiation therapy X-ray therapy 1 3 - r a d i a t i o n therapy

C- Cryotherapy

D- Pressure therapy

III- Pharmacological therapy Intralesional injection of corticosteroids Silicon gel Antihistamine 5-flurouracil Calcium channel blockers (verapamil)

IV- Immunotherapy

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I- Surgical therapy

Surgical excision of keloids is the most long-standing form of

treatment (Gloster, 2000).

Recurrence rates for simple surgical excision of keloids alone

vary from 50% to 80%. Surgery has been largely relegated to a second

line therapy for lesions unresponsive to other treatments and large

lesions requiring debulking before the use of other modalities

(Kuwahara and Rasberry, 2000).

Several surgical approaches are available. Care must be taken to

remove all sources of residual inflammation, including trapped hair

follicles, epithelial cysts, and sinus tracts, which may act as potential

sources of fibrogenic growth stimuli (Lee et al, 2001). Surgical

reconstruction should be designed to minimize tissue trauma and

wound tension while avoiding dead space, h a e m a t o m a formation and

infection (Field, 2001).

Reorientation of scars to parallel lines of skin tension are vital(Field, 2001). If the surrounding tissue is not under excessive tension,

smaller keloids may be excised and closed primarily. If primary

closure is not possible and asking graft is necessary, full-thickness

excision of the keloids retaining a rim to which the skin graft is

attached, is thought to decrease recurrence (Haverstock, 2001). The

rim is thought to act as a splint to decrease the central tensile forces. A

full thickness graft that permits primary closure of the donor site is

preferred to a split thickness graft that leaves an open donor site,

because the donor site has a lower incidence of abnormal scar


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1formation (Shaffer et al., 2002). As well, a full thickness graft may

provide a sufficient micro vasculature to allow for anastomosis with

the host micro vasculature, thus resulting in decreased angiogenesis

and fibroblast proliferation (Urioste et al, 1999).

Contracted scars may benefit from the use of z-plasty or

w-plasty, in which the contractile bands of the keloid are served and

rearranged. This must be performed with great caution because of the

risk of generating new keloids (Haverstoke, 2001).

Excisional surgery of keloids, in the absence of adjunctive therapy,

results in 45-100% recurrence rates (Berman and Bieley 1996).

Excisional surgery combined with intraoperative and

postoperative intradermal corticosteroids injections are the most

common mode of therapy for the treatment of keloids. Recurrence

rates following excisional surgery combined with corticosteroids

range from 0-100% but the majority of studies report < 50%

recurrence. The concentration of postoperative t r i a m c i n o l o n e

acetonide was vary from 10 to 40 m g / m l (Porter, 2002).

The use of pressure as a surgical adjunct for treating ear lobule

keloids most commonly occurring after ear piercing resulted in no

recurrences in several studies with small number of patients. Button

compression therapy, using two shirt buttons sutured together to

s a n d w i t c h the ear lobe after excision of the keloids and sutured

together led to no recurrence at 8 months to 4 years, after the buttons

were left in situ from 3weeks to 6 months (Horn, 2001).

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Excisional surgery of keloids followed by radiation give

excellent results. In a study of 124 keloid patients underwent surgery

followed by post operative x-ray radiation (600 rad/day for three

consecutive days), and were followed up at 6 and 24 months. Good to

excellent results were obtained in 92% at 24 months ( H o m , 2001).

Excisional surgery combined with preoperative hyaluronidase

solution (150U in 1 ml of sodium chloride solution) followed by

external radiation of 720-1080 rad in 8-12 fractions had 0%

recurrence. In general, reports of surgery with adjunctive radiation

therapy included large numbers of keloid patients, long follow-up

periods, and obtained more favorable results than radiation therapyalone (Porter, 2002).

Injection of IFN-a 2b into the surgical excision site immediately

following keloids excision limited keloids recurrence only in the areas

injected. Berman and Bieley (1996), have used 1 F N - a 2b for treating

keloids after surgical excision in 11 patients with 12 head and neck

keloids. 10 million units mixed with 1mm of diluent with injections of

0.1 ml per linear cm of excised tissue (up to 5 cm) was injected into

the suture line after surgical excision of the keloids. Patients had a

repeat injection at the same site and same concentration at one week.

One patient (8.3%) had recurrence. This patient had only one-half of

her excision site injected. Follow up ranged from 3 to 31 months with

an average of 14.7 months. Most of these referral patients had a

history of prior recurrence following initial surgical excision (Niessen

et al., 2001).

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II- Physical therapy

This includes,

A- Laser therapy.

B- Radiation therapy either x-ray or [3- radiation.

C- Cryotherapy.

D- Pressure.

A- Laser in k e l o i d S

The word laser is an acronym for Light Amplification by

Stimulated Emission of Radiation.

Laser radiation properties :

Laser light has several unique properties making it different from

standard light e.g. sunlight.

Monochromaticity :

Monochromaticity means that laser light from a given source is

all of one wavelength. Whereas standard light is polychromatic, often

covering the entire visible spectrum. This property is important for

targeting of specific chromophores in the skin, such as

oxyhaemoglobin, melanin, tattoo ink and water where each has a

characteristic absorption spectrum.

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Coherence :

Coherence means that the waves of energy are in phase with each

other, both in space and time.

Collimation:

Collimation means that the laser beam component waves are

highly parallel, producing a narrow beam allowing them to be

propagated for long distances with minimal convergence or

divergence and focused into very small spot sizes.

These previous three properties of laser light allow high-energyradiation of a specific wavelength to be delivered to a small area.

The wavelengths of lasers used in dermatology can range from

ultraviolet (100 nm) through the visible range into the infrared

(10.600 nm).

Laser construction :

A laser consists essentially of a power source, a lasing medium,

a resonating cavity and delivery system. It is necessary to supply

energy into a lasing medium to elevate electrons to an excited state

and produce a population inversion (Lanigan, 2000).

The lasing medium will determine the characteristics of the laser

light emitted. The lasing medium can be solid (e.g. crystals such as

ruby), liquid (e.g. rhodamine dye) or gaseous (e.g. carbon dioxide).

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The resonating cavity contains the lasing material and has mirrors at

either end to reflect back released photons (Urioste et al., 1999).

The light emerging from a laser cavity can be delivered to tissue

either via an optical fiber or using an articulating arm with mirrors to

deflect the beam. The hand piece delivers the laser beam onto the skin

(Connell and Harland, 2000).

Laser beam can be delivered as a continuous, pulsed or pseudo-

continuous beam. Continuos wave lasers, e.g. carbon dioxide and

argon lasers, produce a steady beam of radiation although this can be

mechanically shuttered into pulses of light. The pulses thus produced

are usually tens milliseconds or longer. Pulsed lasers, e.g., flash lamp

pumped pulsed dye lasers, emit a single pulse or a train of pulses.

Extremely short pulses of light can be delivered by Q. switched as Q.

switched Nd : YAG laser (Alster and Handrick, 2000).

Laser light interaction with tissue :

Laser light when it interacts with tissue can be reflected,

scattered, transmitted or absorbed. The important effect

therapeutically is absorption. The absorbing molecule within tissue,

which in the skin could be haemoglobin, melanin, collagen or water, is

termed the chromophore (Porter, 2002).

The penetration of light into skin is governed by the

combination of absorption and scattering. In general, as the

wavelength of light increases the penetration into skin also increases.


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The outcome of laser-tissue interactions can be grouped as follows :

photothermal, photochemical plasma induced ablation, photo-ablation

and photodisruption. By far the most important interaction in

dermatology is photothermal (Shaffer et al., 2002).

P h o t o t h e r e m a l interactions :

In p h o t o t h e r e m a l laser interactions, the absorbed photons are

converted to heat. The local increase in temperature is the most

significant influencing factor. The effect of heat on biological tissue

depends on the duration and the peak value of tissue temperature

achieved. The effect of heating can be seen as coagulation, which can

proceed to necrosis and vaporization, resulting in tissue ablation and

carbonization (Lanigan, 2000).

As tissue is heated, structural changes occur in complex

molecules such as proteins, DNA and RNA. These structural changes

result in impairment of function (denaturation). In addition to

denaturations there is grosser structural disorder with enlargement of

molecules termed coagulation. Denaturation and coagulation generally

proceed as tissue temperature rises above 60 C (Porter, 2002).

Thermal coagulation causes cell necrosis. Heating tissue above

1 0 0 C causes evaporation of water and vaporization of tissue. Tissue

vaporization is used therapeutically in resurfacing lasers such as the

CO, laser ( Driscoll, 2001).

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Selective photothermolysis :

The theory of selective photothermolysis suggests that selective

tissue absorption of laser light leads to selective destruction of the

absorbing tissue. Skin lesions can, therefore, be treated with a laser

emitting a wavelength corresponding to the absorption peak of the

chromophore contained in the lesion (Brissett and Sherris, 2001).

The mechanism of selective thermolysis is based upon the

thermal relaxation time of the tissue to be irradiated. Thermal

relaxation time is defined as the time required for an object to

decrease its temperature by 50% after being exposed to laser energy

without increasing the temperature of the surrounding tissue (Brissett

and Sherris, 2001). Table (2) shows the classification of sun reactive

skin type (Fitzpatrick, 1999).

Table (2): Fitzpatrick's classification of sun-reactive skin types

(Fitzpatrick, 1999).

Skin type Colour Reaction to first summer exposureI White Always burns, never tans

I I White Usually burns, tans with difficulty

III White Some times mild burns, tans average

IV Moderate brown Rarely burns, tans with ease

V Dark brown Very rarely burns, tans very easily

VI Black No burns, tans very easily

2 7

0 - 0


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Clinical lasers used in treatment of keloids

Carbon dioxide laser (CO2)

The carbon dioxide laser was one of the first laser to be used in

keloids management. In 1982, the continuous wave CO, laser was

successfully employed in the excision of keloids. Its advantage were

attributed to its non traumatic and anti-inflammatory properties

(Urisote et al., 1999).

The carbon dioxide laser emits a continuous wave invisible

beam of 10.600 nm, which is in the mid infrared or heat part of theelectromagnetic spectrum. The Co, laser is a gas laser that uses a

mixture of carbon dioxide, nitrogen, and helium as the lasing medium.

Excitation of the lasing medium is most commonly achieved by high

voltage electrical current. To obtain adequate energy transfer, an

intermediary nitrogen atom is first excited with the energy

subsequently transferred to carbon dioxide atoms. After the carbon

dioxide atom decays with the emission of infrared energy, the

molecule is brought down to the ground state through collisions with

the helium atom (Shaffer et al., 2002).

The mid-infrared photons produced by the Co, laser cannot be

transmitted through conventional fiber optics. Articulated arms direct

laser energy from the laser cavity to the desired location through a

series of hollow, rigid tubes with reflecting mirrors at eachconnection. The arms can be attached to micromanipulators and

28

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microscopes, expanding the utility of laser. The hand piece at the end

of the articulated arm contains a lens that focuses the beam to various

spot size of 0.1 to 2.0 mm. The hand piece is held from the skin

surface, so that the spot size is small, it is said to be focused. Whenfocused, the laser imports much energy to a small area, thereby

allowing it to be used as a cutting tool. If, in contrast, the spot size is

made larger by increasing the distance of the focal point from the skin,

the laser beam is said to be defocused. This reduces the power density

allowing ablation of the superficial skin without damage to the deeper

structures (Driscoll, 2000).

There is nonselective absorption of the laser light by

intracellular and extracellular water producing thermal tissue damage

to a depth of 0.6mm. Any tissue with high water content will absorb

the Co-, laser energy and will vaporize as the water reaches boiling

point. Care must be taken to protect surrounding tissues from this heat

( M a n u s k i a t t i et al., 2001).

A retrospective study by Norris in 1991, evaluating the

effectiveness of the continuous wave Co, laser as a primary modality

in the treatment of keloids concluded that laser excision of keloids

with healing by secondary intent alone failed to suppress keloid

growths and recurrence. These findings have been supported by

studies performed by Apfelberg et al., (1996) ; O l h r i c h t and Arndt

(1997) as they reported that higher recurrence rates were observed

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1

after laser excision of keloids using continuous wave

CO, laser.

It is common practice at present to reserve Co, laser keloids

excision to special situations such as the debulking of large keloids

before initiation of another treatment modality (Yilmaz et al., 2000).

Surgical removal of keloids with the Co e laser alone has reported

recurrence rates of 37.5-92%, but when combined with postoperative

corticosteroids and hyaluronidase ( 4 0 m g / m l of triamcinolone

acetonide and 150 mg of hyaluronidase), the recurrence at one or more

years follow up was 16% (Berman and Bieley, 1996).

In (1994) Gold, stated in a study that silicone gel sheeting was

topically applied post operatively after eight keliods were removed by

a carbon dioxide laser, 12.5% had recurrence at 12 week, compared

with a 37.5% recurrence of keloids excised by carbon dioxide lasers

without postoperative treatment with silicone gel sheeting.

High energy, pulsed CO, laser d e - e p i t h e l i a l i z a t i o n of keloids

and hypertrophic scars followed by immediately by 585-nm pulsed dye

laser irradiation has been shown to provide excellent clinical results. One

or two passes of the CO, laser are performed at 500 mJ energy/pulse and

5 W of power using a 3 mm collimated hand piece to d e - e p i t h e l i a l i z e

and produce collagen shrinkage within keloids. A 585- nm pulsed dye

laser is then used at an energy density of 6 . 5 . 1 / c m 2

to deliver non

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overlapping 5 to 7 mm pulses over the de-epithelialized keloids

(Driscoll, 2001).

Ultrapulsed Co 2 laser:

Modification in laser technology have produced two groups of

Co, lasers. The first are high-energy, short pulsed Co, lasers that

produce individual, high energy pulses (up to 500 mJ) with pulse

durations of less than 900 microseconds ( p . ^ ) . The second group are

scanned continuous wave Co, lasers, which use a computer controlled

o p t i c o - m e c h a n i c a l scanner to direct a focused, continuous wave laser

beam in a special pattern, resulting in less than milliseconds (ms)

tissue exposure time (Lanigan, 2000).

Bernstien et al. (1998), evaluated the high energy short pulsed

Co, laser and the scanned Co, laser in the treatment of 24 post surgical

keloidal scars. Scar improvement was evaluated by photographic

analysis of all cases before and after treatment. A11 24 keloids had

greater than 50% improvement, with 20 of the 24 showing a greaterthan 75% improvement. They concluded that the short pulsed and

scanned Co, lasers appear to be very effective in the surgical

managements of keloids.

The continuous-wave effect of carbon dioxide laser produced

unwanted scarring by thermal damage to the dermis. By mechanically

"pulsing" the beam to short burst that approached the thermalrelaxation time (TRT) of the skin (about 700 msec), destruction

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V O W

without scarring can be achieved. Pulse durations of 250 msec to one

sec are delivered by ultrapulsed carbon dioxide laser. This allows

thermal destruction of the epidermis and papillary dermis without

thermal diffusion to the surrounding tissue (Driscoll, 2001). Outcomeis improved by using the ultrapulsed laser in conjunction with an

o p t o m e c h a n i c a l scanner. This scanner provides uniform ablation of

the epidermis and papillary d e r m i s by rapidly moving the beam across

the targeted area allowing little or no diffusion to surrounding tissue.

The zone of thermal damage produced by the ultrapulsed laser is less

than 100 i L t m , as opposed to the 400 j . . t m produced by continuous-wave

carbon dioxide laser (Manuskiatti et al., 2001).

In their study Lupton and Alster (2002), stated a variety of

lasers can be used to treat scars and keloids effectively. It is of

paramount importance that the type of scar be probably classified on

initial examination so that the most appropriate method of treatment

can be chosen. They concluded that the 5 8 5 - 1 1 1 1 1 pulsed dye laser is the

most appropriate system for treating hypertrophic scars, keloids,

erythematous scars, and striae. The PDL carries a low risk of side

effects and complications when operated and appropriate treatment

parameters and time intervals. Atrophic scars are best treated with

ablative CO, and Er : YAG lasers.

A serum-free in vitro model was used to determine the effect of

combined carbon dioxide (CO") and erbium (Er) : YAG laser irradiationon keloid-producing fibroblasts (KFs) from two distinct facial sites.

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T G F - b e t a I and bFGF play an integral part in wound healing and were

assayed using this model. At 48 hours after seeding, 20% of each well

was exposed to 1.7 J / p u l s e of Er: YAG laser energy and CO, delivered

at 3 or 5 W and at a duty cycle of 25%, 50% or 100% using aquantitative enzyme-linked immunosorbent assay. The results showed

that laser treated ear lobule KFs demonstrated decreased T G F - b e t a 1

production when compared with preauricular KFs. Statistical

significance (P < 0.005) was seen in the 3-w C O 2 25% duty cycle ; a

trend was seen in the 3-w CO, 50% duty cycle (P < 0.08). Preauricular

KFs secreted increased bFGF when compared with lobule KFs.

Significance was seen in the 3-w CO, 25% and 50% duty cycles

(P < 0.05). Laser treated preauricular KFs had increased bFGF

secretion when compared with non laser treated preauricular KFs in the

3-w CO 2 25%, 50% and 100% duty cycles ( C h o n g et al., 2001).

In Happak et al. (1996) study ; 13 h y p e r t r o p h i c scars and

keloids were studied and he stated that keloids recurred after an initial

improvement. The attempts to remove hypertrophic scars did not bring

the desired results.

In a prospective analysis, Stern and L u c e n t e (1989), noted no

significant advantage to excision of ear lobule keloids with the CO,

laser versus simple excision with a scalpel. In this study, 23 keloids

were excised by laser and only 4 by scalple. The authors used a 20-w

CO, laser at an average intensity of 12 w. Adjuvant treatment with aseries of triamcinolone injections were administrated only when the

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first sign of recurrence was noted. Results were unsatisfactory with an

overall 70% recurrence rate.

Argon laser :

The argon laser emits blue-green light at six different wave-

lengths ranging form 457 to 514 nm with 80% of the energy being

contained in the 488- and 514 nm peaks with a skin penetration of one

to 2 mm (Lanigan, 2000).

The argon laser was one of the first lasers used in the treatment

of keloids. It was thought to work by coagulation of the capillary

plexus leading to an area of local anoxia. With the production of lactic

acid by glycolysis, pH decreases, and as a result collagenases are

released. The resulting increase in collagenases will cause increased

collagenolysis (Yilmaz et al., 2000).

Although absorption is selective, the subsequent tissue effects

may or may not be equally selective depending on the pulse duration

of the laser exposure. If the duration is long, the laser energy absorbed

by haemoglobin and melanin produces heat, which non-specifically

damages surrounding dermal and epidermal structures. The degree of

damage produced by the laser on the skin depends on power density,

measurement specified by power output, spot size, and duration of

exposure. Very short exposures may limit non-specific damage to

adjacent structures maximizing the potential selectivity of the device.However, currently available argon lasers have pulse exposures

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greater than that required for a truly specific tissue effect (Spicer and

Goldberg, 1996).

Henning et al., (1986) failed to show overall improvement in 13

keloids treated with the argon laser. Apfelberg et al., (1989), found

similar results as they reported a recurrence rate varied from 45 to 93%.

Argon-pumped dye laser:

The argon-pumped dye laser contains fluorescent organic dye as

the active mediumwith an argon laser as a power source.

A rhodamine 6 G may be used to emit a wide range of wavelengths,

from 488 to 638-nm. The argon pumped dye laser emit a continuous-

wave beam that can be mechanically shuttered to produce pulse

durations of 20 msec (Lanigan, 2000).

Flash lamp-pumped pulsed dye laser (FPDL):

The FPDL, unlike the argon-pumped dye laser, uses a high-

power flash lamp to produce a true pulsed beam. The active mediumof the FPDL is a rhodamine dye that produces yellow light. Much of

the original FPDL research was done on yellow light at a wavelength

of 577-nm. This wavelength coincides with the longest absorption

peak wavelength of oxyhaemoglobin. At 577-nm the FPDL penetrates

the skin to a depth 0.5 mm, 2 mm below the d e r m o e p i d e r m a l junction.

Penetration can be further increased to 1.2 mm if the wavelength is

changed to 585-nm (Connell and Harland, 2000).

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Over the past ten years great studies have been made with use of the

585-nm vascular-specific flash lamp-pumped pulsed dye laser in the

treatment of hypertrophic scars and keloids. The first study demonstrating

a success in scar treatment come from A l s t e r and Colleagues in 1993.They treated keloids at 6.5-7.5 J / c m

2 with a 5 mm spot or 6-6.75 J / c m 2

with a 7 mm spot and repeated at 6 to 8 weekly intervals depending on

clinical response.

A l s t e r ' s work became confirmed by Dierick et al. (1995), who

treated 15 patients with keloids and obtained an average improvement

of 77%. After an average of 1.8 treatments. Goldman andFitzpatrick (1995), also treated 48 patients with similar laser

parameters. Keloids less than one year old did better than those more

than one year. Similar results were also seen by Alster and

McMeekin 1996. Combination of CO 2 and FPDL in treatment of

keloids have also shown additional benefit of the compared to CO,

laser alone ( A l s t e r , 1997).

Using the principle of selective photothermolysis, Paquet et al.,

(2001) concluded that using the 585-nm pulsed dye laser, for the

treatment of keloids, yielded only minimal effects if any, on the erythema

of keloids. While Manuskiatti et al. (2001), reported that, the clinical

improvement of keloids after PDL treatment demonstrated no statistically

significant fluence dependence in the study, but a trend toward better

response with lower fluences was seen. In addition, multiple treatmentssessions were suggested for achieving greater response.


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considered as available choice only after all other methods failed. It is

now generally recognized as an excellent first line treatment option.

Early scar treatment with pulsed dye laser irradiation effectively

prevents scar formation or worsening and yields a better and more

prolonged clinical improvement. The concomitant use of

corticosteroids, 5-flurouracil, or other treatments is proving to be of

particular importance in reducing scar bulk and symptoms of more

proliferative scars (Alster and H a n d r i c k , 2000).

Alster and Williams (1995), treated sixteen adult patients who

developed keloidal or hypertrophic sternotomy scars after cardiac

surgery, one-half of their keloids treated by a 585-nm flash lamp-pumped pulsed dye laser with pulse duration of 450 microseconds,

spot size of 5 mm, and fluences of 6.5-7.25 J / c m 2 (mean, 7.0 J / c m

2

) .

The two treatments (which occurred 6-8 weeks apart) resulted in

statistically significant improvement of keloids symptoms including

pruritus and erythema, decreased scar height and improved skin

surface texture in the laser treated portion compared with the untreated

sites at 6 months post-therapy.

It was found that, a 585-nm flash lamp pumped pulsed dye laser

is preferred for the treatment of hypertrophic scars and keloids. C O 2

laser vaporization of scars that are proliferative, such as hypertrophic

scars and keloids, is not advised due to the high rate of recurrence or

worsening (Alster, 1997).

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Neodymium-Yttrium-Aluminum-Garnet (Nd:YAG) laser:

The Nd: YAG is a solid state laser containing a crystal of

Yttrium-Aluminum-Garnet (YAG) doped with neodymium (Nd) ions.

The primary wavelength of this laser is in the near infrared at 1064 n m

with a pulse duration of 10 nsec (Lanigan, 2000). The Nd : YAG lasers

produce continuos wave (CW) or pulsed (Q-switched) radiation. The

Q-switched laser produces high fluence infrared light with pulse

duration of 10-20 ns and has repetition rates (.10 Hz). By insertion of a

frequency doubling crystal into the laser beam the wavelength is halved

to green light at 532-nm (Landthaler and Hohenleutner, 1997).

The penetration is advantageous in the treatment of dermal

lesions but fraught with complications in other due to the deeper

thermal injury. In addition the energy tends to scatter more than CO-,

laser (Lanigan, 2000).

The Nd : YAG laser energy is delivered to the skin by flexible

fiber optics. The distal end of the fiber is coupled to a focusing handpiece. Solid sapphire crystal probes fixed to the end of the fiber have

expanded the versatility of Nd:YAG laser. These contact fibers serve

as thermal scalpels that can incise tissues haemostatically. The

Q-switched Nd:YAG lasers deliver nanosecond pulses that result in

less depth of penetration and subsequently, less complications of

scarring and hypopigmentation (Ries and Speyer, 1996).

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Because of the extensive penetration of the Nd:YAG laser into

the skin it can not be used to ablate superficial skin lesions but used to

treat large haemangiomas, thick nodular portwine stains and highly

vascular tumour as Kaposi's sarcoma due to powerful coagulation andhaemostatic effects. Common warts and planter warts can be

coagulated by means of Nd:YAG laser (Pfau et al., 1994).

The Nd:YAG laser seems to be suitable for tissue welding

because it can destroy tissue by heat without direct contact, bleeding

or smoke. Laser welding may have advantages over suturing because

it provide better cosmetic results (Spicer and Goldberg, 1996).

The Nd:YAG laser has been shown to exert an effect on collagen

metabolism. Collagen production was shown to be selectively inhibited

by a direct photobiological effect while DNA replication and cell

viability of fibroblasts were unchanged (Yilmaz et al., 2000).

In their study Berman and Flores (1998a), concluded that

radiation therapy, using various protocols, has been a safe andefficacious modality in reducing recurrence. The C O 2 , Nd: YAG, and

Argon lasers have been used as destructive modalities for the

treatment of proliferative scarring. The pulsed dye laser offers

symptomatic improvement and reduces the erythema associated with

these scars.

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B- Radiation Therapy :

X-ray therapy :

Cosman et al. (1996), found that the most advantageous timefor radiation to prevent recurrence of keloids was early postoperative.

The mechanism of radiotherapy involves the destruction of

proliferative fibroblasts and neovascular bed.

Total doses range between 1500 and 2000 rads. The treatment

begins immediately after surgery; several repeated doses may follow

for few days. Radiation therapy alone is not recommended because itis poorly effective with recurrence rate between 50% and 100%

(Porter, 2002).

Postoperative interstitial radiotherapy with iridium 192 has been

employed in multiple studies, with a dose variation from 14 to 20 Gy,

at a point from 2.5 to 5mm to the wire. Keloid recurrence rates ranged

from 20% to 36.8%. Advantages to this treatment include easy

application, irradiation of limited volume, and comparable efficacy to

external radiotherapy. The most important side effect of radiation

therapy is malignancy. For this reason many clinicians reserve

radiotherapy for keloids resistant to any other modalities (Devita 2001).

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Beta-radiation (Strontium-98) :

Beta-radiation alone was effective in the eradication of

symptoms (55%), while the results in the reduction of size were poor.

Pre-operative radiation was found to be of no advantage. Excision

followed by radiation therapy is a useful and effective methods of

keloid eradication. No malignant transformation occurred ( K l u m p a r

et al., 1994).

C- Cryotherapy :

The therapeutic effect of cryotherapy are related to direct celldamage as well as changes in micro-circulation provoked by freezing.

These extremely low temperatures cause vascular damage and blood

stasis within the keloids tissue lead to cell anoxia. As blood flow

becomes more and more sluggish, white thrombi form, occluding the

lumens of the smaller vessels and leading to tissue necrosis and

sloughing. Keloids that have a greater blood flow by Doppler and

those that are more erythematous, respond better to cryotherapy

(Porter, 2002).

During each treatment session, the entire lesion should be

treated with two to three freeze thaw cycles of 30 seconds each. The

healing process lasts about a month. At that time the patient can be

evaluated for further treatment. The age of the lesion is an important

factor in predicting the success of the treatment regardless of thepatient's age. The younger keloids seem to respond better to


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cryosurgery than the older ones do. Generally two to 10 sessions,

separated by 30 days are required (Urioste et al., 1999).

Cryotherapy alone has resulted in complete keloids flattening in

51% to 74% of patients treated, but when used in combination with

intralesional steroids, 84% response rate was seen with follow-up

periods up to 1-5 years (English and Shenefelt, 1999).

The efficacy of intralesional cryosurgery in treatment of large,

bulky keloids unresponsive to intralesional steroids, was evaluated by

Gupta and Kumar (2001), they found that, 7 out of 12 patients

showed more than 75% flattening. Depigmentation was observed

along the tracks of the needles in all the patients, which improved

during follow up due to pigment spread from the normally pigmented

areas inbetween.

Jaros et al. (1999), stated that cryosurgery has used as a simple

and effective method prior to intralesional steroids injections to

facilitate the injection. This step may work by inducing tissue oedemawith subsequent cellular and collagen disruption. The liquid nitrogen

is applied very briefly for 5-15 seconds until the skin frosts. After 10-

15 minutes the keloids are then injected until the skin begins to

blanch. This technique allows better dispersal of the steroids

preparation through out the keloidal tissue, and it minimizes its

deposition into the subcutaneous or surrounding normal tissue.

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The pain caused by application of liquid nitrogen; although

generally not sever, is a drawback for some patients, especially when

the keloids to be treated are fairly large. A certain degree of atrophy

and hypopigmentation is also inevitable with this approach. Thehypopigmantation is due to sensitivity of melanocytes to low

temperatures and is fairly permanent. This characteristic makes

cryotherapy less desirable in dark patients (Porter, 2002).

D-Pressure therapy:

The mechanism by which pressure alters keloids include a

decrease in blood flow with resultant decrease in alpha-macroglobulin,

lower level of chondroitin sulphate with subsequent increase in collagen

degradation, decreased scar hydration resulting in mast call stabilization

and subsequent decrease in neovascularization and extracellular matrix

production or excessive hypoxia resulting in fibroblast degeneration and

collagen degradation ( A l s t e r and W est, 1997).

The pressure exerted must exceed the inherent capillary pressure

of 24mm Hg, and the treatment should be maintained day and night

for 6 to 12 months. Daily discontinuation of pressure should not

exceed 30 minutes. Materials used include compression wraps (carbon

bandage), tubular support bandages (Jobskin), presized garments

(Jobst), adhesive plasters, pressure earrings and self-adhering

polyurethane sponges (Urioste et al., 1999).

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Russell et al. (2001), assessed 30 patients, between 1989 and

1999, who had been fitted with pressure devices made from zimmer

splints. There was a 50% or greater reduction in the size of each

keloid when assessed at one year. Zimmer splints are cheap, readilyavailable, easily moulded to fit the patients and can be decorated so

that they can be worn as earrings.


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III- Pharmacological therapy

Many pharmacological agents have been used in the treatment

of keloids, these agents include:

a- Intralesional injection of corticosteroids.

Hansen (1956), was the first to use hydrocortisone injections at

the site of lesions for the treatment of keloids with success. Conway

et al. (1960), reported the use of decadron, a cortisone analogue with

success. In 1963, Murray advocated injecting steroids into the

excised scar wound edges at the time of surgery to prevent recurrence.

Ketchum et al. (1966), reported the successful intralesinoal

treatment of patients with triamcinolone. The triamcinolone is now a

mainstay of keloid therapy.

Berman and Bieley (1996), reported a response rate between

50% to 100% to triamcinolone acetonide injection (10 to 40 m g / m 1 ) ,

when used alone, with recurrence rate of 9% to 50% in 5 years.

Dexamethasone-21 phosphate (1 m g / m l ) may be used with a response

rate of 76.5 %. When combined with surgery, the recurrence rate in

the majority of studies falls below 50% (Berman and Bieley 1996).

Although the various guidelines exist for preparation, dosage,

and administration, one approach employs varying concentrations (10,

20, 30, and 40 m g / m l ) in different lesions or areas of the same lesion

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47

to establish the minimal effective dosage for subsequent treatments,

usually at 3- to 4- weeks intervals (Tredget et al., 1997).

Frequent initial injections (once to thrice weekly) were found to

be more efficacious with decreasing frequency (weekly to monthly)

during a period of stabilization and resolution of keloids. The addition

of the pulsed dye laser treatments simultaneous with injection therapy

was found to be most effective (Fitzpatrick, 1999).

Enhanced results may be achieved when corticosteroids are

combined with other treatment modalities (i.e., Laser or cryosurgery).

Injections need to be administered at intervals of 4 to 6 weeks for

several months or until the keloid is flattened (Shaffer et al., 2002).

Various delivery systems exist including spring or C O , -

p o w e r e d devices, but most commonly L u e r - l o k syringes with 25 to 30

gauge needles are used to place the injections 0.5 cm apart and into

the bulk of the lesion (Tredget et al., 1997 and Horn, 2001).

Intralesional injection of t r i a m c i n o l e n e acetonide for the

treatment of keloid is painful, and lidocaine-mixed preparations are

much the same. The speed of injection is an important determinant of

pain in intralesional therapy. The injection should be extremely slow

and lidocaine should be added for sensitive patients (Ono, 1999).

The effect of corticosteroids may be explained in part by

interruption of the inflammatory response. The specific mechanism of

action of corticosteroids is related to both suppression of collagen


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possible, and that was probably responsible for the greater effect that

they have observed. After cleaning the area, triamcinolone acetonide

at a concentration of 10 m g / m l was injected into the keloids.

Cryotherapy is applied for 1 and 2.5 minutes. Once the frozen tissuethaws, a further injection of triamcinolone was administrated to blanch

then to edematous and hyperaemic tissue, for better and longer lasting

action. This cycle was repeated every 4-6 weeks as necessary.

1 ) - Silicone gel:

Silicone gel was used by Quinn et al. (1985), as a line of topical

therapy for keloids. They found that the gel softened and reduced

keloids in a shorter period of time than pressure therapy. Sawada and

Sone (1992), used silicone cream in the treatment of keloids with

occlusion. They named this process hydration and occlusion.

Gold (1994), used silicone gel sheets topically on keloids with

success. The silicone oil has been used as silicone cream or silicone

gel in the treatment of keloids. Topical application of silicone gel tokeloids for at least 12 hours daily for about months has been showed

to be effective (Dockery and Nilson 1994).

Suetak et al., (2000), evaluated the efficacy of treatment with

topical silicone gel sheet for keloids, by comparing it with simple film

occlusion. They found that occlusion with silicone gel sheet or plastic

film induced hydration of the skin surface which was followed by aninitial quick and later slow process of dehydration when the skin was

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exposed to the ambient atmosphere. The magnitude of the increase in

hydration induced by silicon gel sheet was always smaller than of the

plastic film occlusion and, unlike the latter treatment, hydration

become less with repetition of silicone gel sheet treatment.

The mechanism of action is still unclear, however hydration and

occlusion are found to play an important role by increasing the

temperature of the scar 1 or 2 F of the body temperature thereby

enhancing the activity of collagenase (Berman and Belly, 1996).

Chin et al. (2000), found elevated level of metalloproteinases in

wound fluid collected under occlusive dressing. In normal woundhealing, the proteinases are important in degrading the extracellular

matrix and thus in controlling scar formation. The most common side

effect of silicon gel is contact dermatitis (Tredget et al., 1997).

In their study, De Oliverira et al., (2001), concluded that,

silicone and non-silicone gel dressings are equally effective in the

treatment of keloids and hypertophic scars.

c- Antihistamine therapy:

Antihistamines have been used in keloids treatment to stabilize

mast cells and reduce histamine level (Urioste et al., 1999).

Venugopal et al. (1999), investigated the effect of avil

(pheniramine maleate) on fibroblasts cultured from abnormal scars in

comparison to normal skin. They observed a decrease in the

proliferation rate in cells from normal skin (39%), hypertrophic scars


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5 1

(44%) keloids (63%). They also reported a decrease in the rate of DNA

synthesis in cells from normal skin (50%), hypertrophic scars (55%)

and keloids (63%) treated with 8 mg avil (72h). The rate of decrease in

collagen synthesis in normal skin (44%), hypertrophic scar (74 %) andkeloids fibroblast (73%) correlated with change in DNA synthesis.

d - 5- t b r o u r a c i l therapy :

Five-flurouracil, a pyrimidine analogue with antimetabolite

activity, it was investigated as an adjunct to glaucoma filtering

surgery, a procedure in which inhibition of wound healing is desirable

to achieve surgical success. This drug has been 'shown to inhibit

fibroblast to reduce postoperative scaring by decreasing fibroblast

proliferation. The safety and efficacy of this agent in surgery was

demonstrated in long term follow-up with a multi-center study of

5-flurouracil (Fitzpatrick, 1999).

In 1989, Fitzpatrik began clinical investigation of the use of

intralesional injections of 5--flurouracil for treatment and preventionof hypertrophic scars and keloids and he concluded that the use of

5-flurouracil intralesionally for treatment of hypertrophic scars and

keloids appears to be both effective and safe.

Uppal et al. (2001), evaluated the effects of a single dose of

5-flurouracil on keloids and the possibility of altering the

pathophysiology of keloids using a single application of 5 - f l u r o u r a c i lsolution for 5 minutes after extra lesional excision. They found a


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perceived improvement in conditions for those treated with

5-flurouracil, compared to the control specimens with a significant

reduction in all the markers assayed.

The injection of 5-flurouracil was performed as frequently as

3 times per week, and as the keloids began to respond, the injection

was reduced to twice per week, once per week, and then every other

w

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Keloid Treatment Evaluation