3318.pdf

Surgical Excision of Keloid Combined with Post-operative Electron Beam Irradiation

Thesis

Submitted in partial fulfillment of Master Degree in

General Surgery

By

Mohamed Ashraf Abd El Moneim El Meleigy (M.B.B.Ch.)

Supervised by

Prof Dr Raafat Riyad Gohar Professor of General and Plastic Surgery Faculty of Medicine, Cairo University

Prof Dr Mostafa Ahmed Abolsaoud

Professor of General and Plastic Surgery Faculty of Medicine, Cairo University

Prof Dr Hamdy Mohamed Zawam

Professor of Oncology Faculty of Medicine, Cairo University

Faculty of Medicine

Cairo University 2010

Skin Anatomy

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Skin Anatomy

Introduction

The skin covers the entire external surface of the human body and

is the principal site of interaction with the surrounding world. It serves as

a protective barrier that prevents internal tissues from exposure to trauma,

ultraviolet radiation, temperature extremes, toxins, and bacteria. Other

important functions include sensory perception, immunologic

surveillance, thermoregulation, and control of insensible fluid loss.

The integument consists of two mutually dependent layers, the

epidermis and dermis, which rest on a fatty subcutaneous layer, the

panniculusadiposus. The epidermis is derived primarily from surface

ectoderm but is colonized by pigment-containing melanocytes of neural

crest origin, antigen-processing Langerhans cells of bone marrow origin,

and pressure-sensing Merkel cells of neural crest origin. The dermis is

derived primarily from mesoderm and contains collagen, elastic fibers,

blood vessels, sensory structures, and fibroblasts ( Carlson, 1994 ).

During the fourth week of embryologic development, the single cell thick

ectoderm and underlying mesoderm begin to proliferate and differentiate.

The specialized structures formed by the skin, including teeth, hair, hair

follicles, fingernails, toenails, sebaceous glands, sweat glands, apocrine

glands, and mammary glands also begin to appear during this period in

Skin Anatomy

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development. Teeth, hair, and hair follicles are formed by the epidermis

and dermis in concert, while fingernails and toenails are formed by the

epidermis alone. Hair follicles, sebaceous glands, sweat glands, apocrine

glands, and mammary glands are considered epidermal glands or

epidermal appendages, because they develop as downgrowths or

diverticula of the epidermis into the dermis ( Moore, 1998).

The definitive multi-layered skin is present at birth, but skin is a dynamic

organ that undergoes continuous changes throughout life as outer layers

are shed and replaced by inner layers. Skin also varies in thickness among

anatomic location, sex, and age of the individual. This varying thickness

primarily represents a difference in dermal thickness, as epidermal

thickness is rather constant throughout life and from one anatomic

location to another. Skin is thickest on the palms and soles of the feet (1.5

mm thick), while the thinnest skin is found on the eyelids and in the

postauricular region (0.05 mm thick). Male skin is characteristically

thicker than female skin in all anatomic locations. Children have

relatively thin skin, which progressively thickens until the fourth or fifth

decade of life when it begins to thin. This thinning is also primarily a

dermal change, with loss of elastic fibers, epithelial appendages, and

ground substance ( Burns, 2004 ).

Skin Anatomy

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Epidermis

The epidermis contains no blood vessels and is entirely dependent

on the underlying dermis for nutrient delivery and waste disposal via

diffusion through the dermoepidermal junction. The epidermis is a

stratified squamous epithelium that consists primarily of keratinocytes in

progressive stages of differentiation from deeper to more superficial

layers. The named layers of the epidermis include the stratum

germinativum, stratum spinosum, stratum granulosum, and stratum

corneum. The stratum germinativum or the basal layer is immediately

superficial to the dermoepidermal junction. This single cell layer of

keratinocytes is attached to the basement membrane via

hemidesmosomes.

As keratinocytes divide and differentiate, they move from this deeper

layer to the more superficial layers. Once they reach the stratum corneum,

they are fully differentiated keratinocytes devoid of nuclei and are

subsequently shed in the process of epidermal turnover. Cells of the

stratum corneum are the largest and most abundant of the epidermis. This

layer ranges in thickness from 15-100 or more cells depending on

anatomic location and is the primary protective barrier from the external

environment.

Melanocytes, derived from neural crest cells, primarily function to

produce a pigment, melanin, which absorbs radiant energy from the sun

and protects the skin from the harmful effects of ultraviolet radiation.

Melanin accumulates in organelles termed melanosomes that are

incorporated into dendrites anchoring the melanosome to the surrounding

Skin Anatomy

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keratinocytes. Ultimately, the melanosomes are transferred via

phagocytosis to the adjacent keratinocytes where they remain as granules.

Melanocytes are found in the basal layer of the epidermis as well as in

hair follicles, the retina, uveal tract, and leptomeninges. These cells are

the sites of origin of melanoma.

In areas exposed to the sun, the ratio of melanocytes to keratinocytes is

approximately 1:4. In areas not exposed to solar radiation, the ratio may

be as small as 1:30. Absolute numbers of melanosomes are the same

among the sexes and various races. Differing pigmentation among

individuals is related to melanosome size rather than cell number. Sun

exposure, melanocyte-stimulating hormone (MSH), adrenocorticotropic

hormone (ACTH), estrogens, and progesterones stimulate melanin

production. With aging, a decline is observed in the number of

melanocytes populating the skin of an individual. Since these cells are of

neural crest origin, they have no ability to reproduce.

Langerhans cells originate from the bone marrow and are found in the

basal, spinous, and granular layers of the epidermis. They serve as

antigen-presenting cells. They are capable of ingesting foreign antigens,

processing them into small peptide fragments, binding them with major

histocompatibility complexes, and subsequently presenting them to

lymphocytes for activation of the immune system. An example of

activation of this component of the immune system is contact

hypersensitivity.

Merkel cells, also derived from neural crest cells, are found on the volar

aspect of digits, in nail beds, on the genitalia, and in other areas of the

skin. These cells are specialized in the perception of light touch ( Burns,

2004).

Skin Anatomy

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Dermis

The primary function of the dermis is to sustain and support the

epidermis. The dermis is a more complex structure and is composed of 2

layers, the more superficial papillary dermis and the deeper reticular

dermis. The papillary dermis is thinner, consisting of loose connective

tissue containing capillaries, elastic fibers, reticular fibers, and some

collagen. The reticular dermis consists of a thicker layer of dense

connective tissue containing larger blood vessels, closely interlaced

elastic fibers, and coarse bundles of collagen fibers arranged in layers

parallel to the surface.

The reticular layer also contains fibroblasts, mast cells, nerve endings,

lymphatics, and epidermal appendages. Surrounding the components of

the dermis is the gel-like ground substance, composed of

mucopolysaccharides (primarily hyaluronic acid), chondroitin sulfates,

and glycoproteins. The deep surface of the dermis is highly irregular and

borders the subcutaneous layer, the panniculusadiposus, which

additionally cushions the skin.

The fibroblast is the major cell type of the dermis. These cells produce

and secrete procollagen and elastic fibers. Procollagen is terminally

cleaved by proteolytic enzymes into collagen that aggregates and

becomes cross-linked. These tightly cross-linked collagen fibers provide

tensile strength and resistance to shear and other mechanical forces.

Collagen makes up 70% of the weight of the dermis, primarily Type I

(85% of the total collagen) and Type III (15% of the total collagen).

Elastic fibers constitute less than 1% of the weight of the dermis, but they

Skin Anatomy

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play an enormous functional role by resisting deformational forces and

returning the skin to its resting shape ( Carlson, 1994 ).

Dermoepidermal Junction

The dermoepidermal junction is an undulating basement membrane

that adheres the epidermis to the dermis. It is composed of 2 layers, the

lamina lucida and lamina densa. The lamina lucida is thinner and lies

directly beneath the basal layer of epidermal keratinocytes. The thicker

lamina densa is in direct contact with the underlying dermis. These

structures are the target of immunologic injury in bullouspemphigoid and

epidermolysisbullosa.

Dermal papillae from the papillary dermis contain a plexus of capillaries

and lymphatics oriented perpendicular to the skin surface. These

fingerlike projections are surrounded by similar projections of the

epidermis. This highly irregular junction greatly increases the surface

area over which oxygen, nutrients, and waste products are exchanged

between the dermis and the avascular epidermis ( Carlson, 1994 ) .

Skin Anatomy

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Fig ( 1 ) : Anatomy of the Skin

Epidermal Appendages

Epidermal appendages are intradermal epithelial structures lined

with epithelial cells with the potential for division and differentiation.

These are important as a source of epithelial cells, which accomplish re-

epithelialization should the overlying epidermis be removed or destroyed

in situations such as partial thickness, burns, abrasions, or split-thickness

skin graft harvesting. Epidermal appendages include sebaceous glands,

Skin Anatomy

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sweat glands, apocrine glands, mammary glands, and hair follicles. They

often are found deep within the dermis, and in the face may even lie in

the subcutaneous fat beneath the dermis. This accounts for the remarkable

ability of the face to re-epithelialize even the deepest cutaneous wounds

(Carlson M, 1994).

Sebaceous glands

Sebaceous glands, or holocrine glands, are found over the entire surface

of the body except the palms, soles, and dorsum of the feet. They are

largest and most concentrated in the face and scalp where they are the

sites of origin of acne. The normal function of sebaceous glands is to

produce and secrete sebum, a group of complex oils including

triglycerides and fatty acid breakdown products, wax esters, squalene,

cholesterol esters, and cholesterol. Sebum lubricates the skin to protect

against friction and makes it more impervious to moisture.

Sweat glands

Sweat glands, or eccrine glands, are found over the entire surface of the

body except the vermillion border of the lips, external ear canal, the nail

beds, labia minora, the glans penis, and the inner aspect of the prepuce.

They are most concentrated in the palms and soles and the axillae. Each

gland consists of a coiled secretoryintradermal portion that connects to

the epidermis via a relatively straight distal duct. The normal function of

the sweat gland is to produce sweat, which cools the body by

evaporation. The thermoregulatory center in the hypothalamus controls

sweat gland activity through sympathetic nerve fibers that innervate the

sweat glands. Sweat excretion is triggered when core body temperature

reaches or exceeds a set point.

Skin Anatomy

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Apocrine glands

Apocrine glands are similar in structure but not identical to eccrine

glands. They are found in the axillae, in the anogenital region, and, as

modified glands, in the external ear canal (ceruminous glands), in the

eyelid (Moll's glands), and in the breast (mammary glands). They

produce odor and do not function prior to puberty, which means they

probably serve a vestigial function. The mammary gland is considered a

modified and highly specialized type of apocrine gland.

Hair follicles

Hair follicles are complex structures formed by the epidermis and dermis.

They are found over the entire surface of the body except the soles of the

feet, palms, glans penis, clitoris, labia minora, mucocutaneous junction,

and portions of the fingers and toes. Sebaceous glands often open into the

hair follicle rather than directly onto the skin surface, and the entire

complex is termed the pilosebaceous unit. Caucasian hair follicles are

oriented obliquely to the skin surface, whereas the hair follicles of black

persons are oriented almost parallel to the skin surface. Asian persons

have vertically oriented follicles that produce straight hairs. These

anatomic variations are an important consideration in avoiding alopecia

when making incisions in the scalp.

The base of the hair follicle, or hair bulb, lies deep within the dermis and,

in the face, may actually lie in the subcutaneous fat. This accounts for the

remarkable ability of the face to re-epithelialize even the deepest

cutaneous wounds. A band of smooth muscle, the arrectorpili, connects

the deep portion of the follicle to the superficial dermis. Contraction of

this muscle, under control of the sympathetic nervous system, causes the

Skin Anatomy

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follicle to assume a more vertical orientation.

Anatomy of hair follicle see fig ( 2 )

Hair growth exhibits a cyclical pattern. The anagen phase is the

growth phase, whereas the telogen phase is the resting state. The

transition between anagen and telogen is termed the catagen phase.

Phases vary in length according to anatomic location, and the length of

the anagen phase is proportional to the length of the hair produced. At

any one time at an anatomic location, follicles are found in all 3 phases of

hair growth. This is extremely important for laser hair removal, because

follicles in the anagen phase are susceptible to destruction, whereas

resting follicles are more resistant. This explains why multiple treatments

of an area may be necessary to ensure adequate hair removal (Carlson,

1994 ) ( Poblet et al., 2004 ) ( Prost-Squarcioni, 2006 ).

Skin Anatomy

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Fig ( 2 ): Anatomy of the Hair Follicle

Skin Anatomy

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Blood Supply of the Skin

Cutaneous vessels ultimately arise from underlying named source

vessels. Each source vessel supplies a 3-dimensional vascular territory

from bone to skin termed an angiosome. Adjacent angiosomes have

vascular connections via reduced caliber (choke) vessels or similar

caliber (true) anastomotic vessels. The cutaneous vessels originate either

directly from the source arteries (septocutaneous or fasciocutaneous

perforators) or as terminal branches of muscular vessels

(musculocutaneous perforators).

During their course to the skin, they travel within or adjacent to the

connective tissue framework and supply branches to each tissue with

which they come into close contact (bone, muscle, fascia, nerve, fat).

They emerge from the deep fascia in the vicinity of the intermuscular or

intramuscular septa or near tendons and travel toward the skin, where

they form extensive subdermal and dermal plexuses. The dermis contains

horizontally arranged superficial and deep plexuses, which are

interconnected via communicating vessels oriented perpendicular to the

skin surface. Cutaneous vessels ultimately anastomose with other

cutaneous vessels to form a continuous vascular network within the skin.

Clinically, this extensive horizontal network of vessels allows for random

skin flap survival.

In addition to the skin's natural heat conductivity and loss of heat from

the evaporation of sweat, convection from cutaneous vessels is a vital

component of thermoregulation. Cutaneous blood flow is 10-20 times

that required for essential oxygenation and metabolism, and large

Skin Anatomy

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amounts of heat can be exchanged through the regulation of cutaneous

blood flow. The thermoregulatory center in the hypothalamus controls

vasoconstriction and vasodilatation of cutaneous vessels through the

sympathetic nervous system ( McGregor, 1963 ) .

Lymphatics

Skin lymphatics parallel the blood supply and function to conserve

plasma proteins and scavenge foreign material, antigenic substances, and

bacteria. Blind-ended lymphatic capillaries arise within the interstitial

spaces of the dermal papillae. These unvalved superficial dermal vessels

drain into valved deep dermal and subdermal plexuses. These then

coalesce to form larger lymphatic channels, which course through

numerous filtering lymph nodes on their way to join the venous

circulation near the subclavian vein-internal jugular vein junction

bilaterally (Crockett, 1965 ).

Skin Innervation

Sensory perception is critically important in the avoidance of

pressure, mechanical or traumatic forces, and extremes of temperature.

Numerous specialized structures are present in the skin to detect various

stimuli. As previously mentioned, Merkel cells of the epidermis detect

light touch. Meissner corpuscles also detect light touch. These are found

in the dermal papillae and are most concentrated in the fingertips. Pacini

corpuscles are found deep within the dermis or even in the subcutaneous

tissue. These structures are specialized to detect pressure.

Skin Anatomy

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Pain is transmitted through naked nerve endings located in the basal layer

of the epidermis. Krause bulbs detect cold, whereas Raffini corpuscles

detect heat. Heat, cold, and proprioception also are located in the

superficial dermis. Cutaneous nerves follow the route of blood vessels to

the skin. The area supplied by a single spinal nerve, or single segment of

the spinal cord, is termed a dermatome. Adjacent dermatomes may

overlap considerably, of importance to note when performing field blocks

with local anesthesia ( Morris, 1997 ).

Surface Anatomy

Lines and creases are evident over major and minor joints. Skin

contraction produces wrinkles and creases that lie perpendicular to the

underlying muscular vector force. Relaxed skin tension lines (RSTL),

however, are formed during relaxation and often follow a different

direction than age and contracting wrinkles see fig (3). Relaxed skin

tension lines are created by the natural tension on the skin from

underlying structures ( Fongo, 1966 ).

Skin Anatomy

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Fig ( 3 ) : Four main facial lines show the direction of relaxed skin tension lines.

Papillary ridges on the tips of the digits of the hands and feet and the

surface of palms and soles are often used for personal identification.

These are also known as friction ridges, since they assist in the ability to

grasp. They are formed during fetal development and are unique to each

individual, including identical twins. This distinct pattern does not change

with aging. Stratum mucosum composes the outer surface of the ridges

with underlying dermal papillae. Sweat pores are usually located at the

top of the ridges ( Ashbaugh, 1999 ).

Skin Anatomy

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Skin Phototype

The amount of melanin pigment in the skin determines an

individual's skin color (skin phototype). Skin pigment can be inherited

genetically or acquired by various diseases. Hormonal changes during

pregnancy can also vary the amount of pigmentation.The Fitzpatrick

classification see table (1) is used to classify skin complexion and

response to ultraviolet exposure. This classification is based on a personal

history of sunburning and suntanning (Goldman et al., 2007 ). This

classification is used clinically for evaluation of facial skin pigmentation

before resurfacing procedures and is important for predicting outcomes

and adverse effects.

Table (1): Fitzpatrick Skin Classification (Fitzpatrick, 1988)

Type Color Reaction to sun exposure

I White Always burns/ never tans

II White Usually burns/ tans with difficulty

III White Sometimes mild burn/ average tan

IV Moderate Brown Rarely burns/ tans with ease

V Dark Brown Very rarely burns/ tans very easily

VI Black Never burns/ tans very easily

Anatomy of Aging Skin

Age-associated skin changes include thinning, skin laxity, fragility, and

wrinkles. Sun-exposed areas demonstrate additional aging changes,

including dyspigmentation, premature wrinkling, telangiectasia, and

actinic elastosis. Cutaneous aging is characterized by intrinsic and

Skin Anatomy

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extrinsic processes. Intrinsic or chronologic aging is a genetically

determined and inevitable process in skin, which also includes

photoprotected skin. Intrinsic aging naturally occurs and is exacerbated

by extrinsic aging, which is environmentally induced. Aging at the

cellular level is thought to be related to cellular senescence, specifically,

the shortening of telomeres (the terminal portions of chromosomes) with

each cell cycle. Telomere shortening ultimately results in cell-cycle arrest

or apoptosis once a critical length is reached. Preventable environmental

factors that amplify intrinsic aging include sun exposure and smoking.

Long-term UVA radiation exposure accelerates intrinsic aging via the

formation of reactive oxygen species (ROS). ROS lead to inflammatory

cytokines and the up-regulation of matrix metalloproteinases, which

result in the breakdown of collagen. UVB radiation can also contribute to

this aging process by causing direct DNA mutations. Histopathologically,

photoaging is manifest as flattening of the dermal-epidermal junction

resulting in decreased nutrient transfer between the layers, chronic

inflammation, elongated and collapsed fibroblasts, disorganized collagen

fibrils with overall decrease in collagen levels, and the accumulation of

abnormal elastin-containing material termed solar elastosis (Baumann,

2007).

Chapter II Physiology of

Wound Healing

Physiology of Wound Healing

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Introduction

Tremendous advancements have been made in understanding the

processes of wound healing. The cell types and the order in which they

appear in the wound have been established; many growth factors and

their functions have been elucidated ( Ueno et al., 2006 ). Despite the

advances in understanding the science of wound healing, many more

steps have yet to be discovered and elucidated. The frontier of this field

includes the prevention of hypertrophic and keloid scar formation and,

ultimately, any visual remnant of the wound.

An incision created by a scalpel, trauma resulting from a bullet, or tissue

death caused by a myocardial infarction all undergo a similar and

predictable reparative process. Understanding how the body repairs

damaged tissue and what factors influence the wound healing process

helps the surgeon ensure an acceptable outcome from surgery. Tissue

injury is common thread to every medical specialty. Wound healing in

any tissue follows a predictable sequence of events. A broad

understanding of the sequence of events, cells involved, relative time

table, and molecular signaling can allow for maximum optimization of

this important patient care issue. Although seemingly basic in concept,

advances in molecular science have allowed modern medicine to gain a

true appreciation of the complex interplay between the cells involved in

the phases of wound healing. As greater understanding of the growth

factors involved in wound healing emerges, future patient care may


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include scarless wound healing and transplant of tissues engineered from

stem cell progenitors.

Types of Wound Healing

The three categories of wound closure are primary, secondary, and

tertiary. Primary healing involves closure of a wound within hours of its

creation. Secondary healing involves no formal wound closure; the

wound closes spontaneously by contraction and re-epithelialization.

Tertiary wound closure, also known as delayed primary closure, involves

initial debridement of the wound for an extended period and then formal

closure with suturing or by another mechanism.

Phases of Wound Healing

Knowledge of the phases of wound healing allows the practitioner

to counsel patients effectively and treat wounds appropriately. The

typical wound, after primary closure, may take over a year to fully

mature; the appearance of the scar may dramatically change during this

time. Thus, all wounds should be at least 1 year old before scar revision is

considered. The wound healing process has 3 phases. They are the

inflammatory phase, the proliferative phase, and the remodeling phase

( Komarcevic, 2000 ). The inflammatory phase is characterized by

hemostasis and inflammation. Collagen exposed during wound formation

activates the clotting cascade (both the intrinsic and extrinsic pathways),

initiating the inflammatory phase. After injury to tissue occurs, the cell

membranes, damaged from the wound formation, release


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thromboxane A2 and prostaglandin 2-alpha, potent vasoconstrictors. This

initial response helps to limit hemorrhage. After a short period, capillary

vasodilatation occurs secondary to local histamine release, and the cells

of inflammation are able to migrate to the wound bed. The timeline for

cell migration in a normal wound healing process is predictable.

Wound healing and growth factors. Cells involved in wound healing. The cells

appearing in a wound are depicted in sequence from left to right, and the color bars

represent the range of days each cell type is in the wound.

Fig ( 4 ): Cells involved in wound healing


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Inflammatory phase

The inflammatory phase begins at the time of injury and lasts 2-4

days. The phase begins with hemostasis and formation of the platelet

plug. Platelets release platelet-derived growth factor (PDGF) and

transforming growth factor beta (TGF-b) from their alpha granules to

attract neutrophils and macrophages. Neutrophils scavenge for bacteria

and foreign debris. Macrophages are the most important mediators of

wound healing. Macrophages continue to emit growth factors to attract

fibroblasts and usher in the next phase of wound healing .

Proliferative phase

The proliferative phase begins on approximately day 3; it overlaps

with the inflammatory phase. The most important cell is the fibroblast.

Fibroblasts peak approximately day 7 from injury and are responsible for

initiating angiogenesis, epithelialization, and collagen formation.

Epithelialization is from the basement membrane if the basement

membrane remains intact (eg, first-degree burn). If the basement

membrane is not intact, the epithelialization is from the wound edges.

Fibroblasts produce mainly type III collagen during this phase.

Granulation tissue, formed in this phase, is particularly important in

wounds healing by secondary intention. When collagen synthesis and

breakdown become equal, the next phase of wound healing has begun.


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Remodeling phase

Increased collagen production and breakdown continue for 6

months to 1 year after injury. The initial type III collagen is replaced by

type I collagen until a type I:type II ratio of 4:1 is reached, which is equal

to normal skin. Also, fibroblasts differentiate into myofibroblasts, causing

tissue contraction during this phase of wound healing. Collagen

reorganizes along lines of tension and crosslinks, giving added strength.

Strength eventually approaches 80% of the strength of uninjured tissue.

Vascularity decreases, producing a less hyperemic and more cosmetically

appealing wound as this phase progresses.

The timetable for wound healing can be quite variable. Chronic wounds

can stall in the inflammatory phase because of poor perfusion, poor

nutrition, or a myriad of other factors causing excessive buildup of

exudates in the wound base. These wounds tend to remain unhealed

unless active and aggressive means are undertaken to correct the

underlying comorbidities while providing proper wound care.

Healing may also become exaggerated in keloid and hypertrophic scar

formation. Excessive type III collagen formation in the proliferative

phase causes an overgrowth of scar tissue in these wounds. The etiology

is multidimensional. Individuals with darkly pigmented skin are

genetically prone to keloid formation. Certain areas of the body, such as

the sternum and shoulder, are more prone to hypertrophic scar formation.

Phases can also be blunted as in the fetus, which has a decreased

inflammatory phase and heals without scar. Experiments evaluating fetus


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wound healing have found a higher level of TGF-b3 than in adults.3This

is thought to antagonize the effects of TGF-b2 and TGF-b1 found to be

upregulated in keloids and hypertrophic scars. Thus, a greater

understanding of the growth factors in fetus healing may lead to novel

therapy for scarless wound healing and treatment of keloid and

hypertrophic scars. Human trials are currently underway ( Ferguson and

O’Kane, 2004 ).

Collagen types and locations are as follows:

• Type I - Located in all connective tissue except hyaline cartilage and

basement membranes

• Type II - Located in hyaline cartilage

• Type III - Located in distensible connective tissue (blood vessels)

• Type IV - Located in basement membranes

• Type V - Located in all tissues

• Type VI - Located in all tissues

• Type VII - Located in the dermal-epidermal junction

• Type VIII - Located in the Descemet membrane

• Type IX - Located in hyaline cartilage

• Type X - Located in hypertrophic cartilage and hyaline cartilage.


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Local cytokines

Growth factors represent the intercellular signaling that orchestrates the

complex sequence of cell migration, division, differentiation, and protein

expression during wound healing. The 8 major families of growth factors

are expressed in varying levels by the cells involved with healing.

Table ( 2 ): Growth Factors

Growth

Factor

Production Known Effects

1.

Epidermal

Growth

Factor

(EGF)

Platelets,

macrophages

Stimulates fibroblasts to secrete collagenase to

degrade the matrix during the remodeling

phase. Stimulates keratinocyte and fibroblast

proliferation. May reduce healing time when

applied topically.

2.

Transformi

ng Growth

Factor

Platelets,

macrophages,

lymphocytes,

hepatocytes

TGF-a: Mitogenic and chemotactic for

keratinocytes and fibroblasts

TGF-b1 and TGF-b2: Promotes angiogenesis,

up-regulates collagen production and inhibits

degradation, promotes chemoattraction of

inflammatory cells.

TGF-b3 (antagonist to TGF-b1 and b2): Has

been found in high levels in fetal scarless

wound healing and has promoted scarless

healing in adults experimentally when TGF-b1

and TGF-b2 are suppressed.

3. Vascular

Endothelial

Growth

Factor

Endothelial cells Promotes angiogenesis during tissue hypoxia.


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(VEGF)

4.

Fibroblast

Growth

Factor

(FGF)

Macrophages,

mast cells, T-

lymphocytes

Promotes angiogenesis, granulation, and

epithelialization via endothelial cell, fibroblast,

and keratinocyte migration, respectively.

5. Platelet-

Derived

Growth

Factor

(PDGF)

Platelets,

macrophages, and

endothelial cells

Attracts macrophages and fibroblasts to zone of

injury. Promotes collagen and proteoglycan

synthesis.

6.

Interleukins

Macrophages,

keratinocytes,

endothelial cells,

lymphocytes,

fibroblasts,

osteoblasts,

basophils, mast

cells

IL-1: Proinflammatory, chemotactic for

neutrophils, fibroblasts, and

keratinocytes. Activates neutrophils

IL-4: Activates fibroblast

differentiation. Induces collagen and

proteoglycan synthesis.

IL-8: Chemotactic for neutrophils and

fibroblasts.

7. Colony-

Stimulating

Factors

Stromal cells,

fibroblasts,

endothelial cells,

lymphocytes

Granulocyte colony stimulating factor (G-

CSF): Stimulates granulocyte proliferation.

Granulocyte Macrophage Colony Stimulating

Factor (GM-CSF): Stimulates granulocyte and

macrophage proliferation.

8.

Keratinocyt

e growth

factor

Fibroblasts Stimulates keratinocyte migration,

differentiation, and proliferation.


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Wound optimization

Creating conditions that allow for proper wound healing can make

all the difference in various wounds, from an inconspicuous wound after

plastic surgery to an amputation or even death in a patient with severe

vascular disease or burn. When approaching an injured patient, the

following list can guide the thought process of the physician or caretaker

in optimizing healing conditions.

• Perfusion: Tissues cannot heal without the cells, oxygen, and nutrients

that the cardiovascular system delivers ( Jonsson et al., 1991 ). This is

particularly important in the wound healing of patients with diabetes or

paraplegia, patients who smoke, and patients who have been exposed to

radiation. Patients with severe vascular disease may experience enhanced

wound healing via increased perfusion after a vascular bypass or related

procedure. Patients who smoke should cease smoking immediately in the

event of major surgery or injury. Nicotine causes severe vasoconstriction,

and the toxins in cigarette smoke can greatly decrease the ability of

tissues to heal. Paraplegics and diabetics with neuropathy must cease all

substance abuse and be continually educated and reinforced on the need

for pressure relief to avoid pressure ulcers. In the event of pressure sore

discovery, absolute pressure relief to increase perfusion is paramount.

• Infection: Infection is defined as having quantitative bacterial counts of

105colony forming units per gram of tissue. Infected wounds do not heal

because of decreased epithelialization and increased collagen breakdown.

These wounds should be appropriately cleared of infection by drainage,

debridement, and the administration of appropriate antibiotics.


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• Nutrition: When assessing nutritional status, certain serum nutritional

markers can be helpful. Albumin is a good marker of overall long-term

nutritional status over the last month; ideally, it should be at least 3.5

g/dL to optimize wound healing. Prealbumin can offer a more recent

nutritional status picture and should be maintained above 17 g/dL.

Caloric needs of the severely injured patient can exceed 35 kcal/kg/d and

0.8-2 g/kg/d of protein and should be continually assessed and adjusted

according to the stage of healing and injury. This is particularly true for

burn patients who require multiple debridements and grafting. Vitamin

supplementation has not been proven to increase wound healing unless a

specific deficiency exists ( Thomas, 1997 ). Vitamin A is an exception to

this rule and is detailed below ( Langemo et al., 2006 ).

• Steroids: Corticosteroids can blunt the response of macrophages, the

most essential cell in wound healing.Vitamin A, insulinlike growth factor

(IGF), and oxandrolone (anabolic steroid) can be given to reverse the

effects of corticosteroids on wound healing ( Komarcevik, 2000 ).

• Dressing: Numerous dressings are available on the market. Many claim

that they need to be changed less often than other dressings. This may be

true for a clean wound. However, there is no substitute for frequent

dressing changes in a grossly contaminated or recently debrided infected

wound. Other basic principles apply. The wound should be kept moist

(but not wet) at all times. Desiccated tissue is dead tissue and must be

sharply debrided. With the advent of negative pressure wound dressing,

wound healing for even chronic wounds can be greatly increased. Again,

great prudence should be used; apply negative pressure wound dressing

only when indicated.


- 28 -

Currently, cytokines have a limited role in clinical practice. The only

currently available commercial product proven to be efficacious in

randomized, double-blind studies is platelet-derived growth factor

(PDGF), available as recombinant human PDGF-BB. In multiple studies,

recombinant human PDGF-BB has been demonstrated to reduce healing

time and improve the incidence of complete wound healing in stage III

and IV ulcers. Many other cytokines currently under study in vitro

include transforming growth factor beta (TGF-b), epidermal growth

factor (EGF), and IGF-1.

Proper wound healing involves a complex interaction of cells and

cytokines working in concert. In recent years, more chemical mediators

integral to this process have been identified. The sequential steps and

specific processes have not been fully differentiated. When examining the

process of wound healing, one should identify the major steps and know

the important mediators ( Koveker, 2000 ).

Wound Healing Terms

-Primary closure: A wound closed surgically with sutures or by

other means soon after creation is considered a primary closure.

-Secondary closure: This type of closure is appropriate for infected

or contaminated wounds in areas of poor blood supply. The wound fills

with granulation tissue, contracts, and reepithelializes. This leads to a

worse scar from a prolonged inflammatory phase.


- 29 -

-Tertiary closure (delayed primary closure): This type of closure

allows for a superior cosmetic appearance to the closure of a

contaminated wound. The wound is allowed to stay open and undergo

repeat dressing changes for a few days. This decreases the bioburden of

the wound and allows for a decreased infection rate after surgical closure

a few days later.

Acute wound: A wound is acute if it occurred in the last 4-6 weeks.

Chronic wound: A wound is chronic if it has been present for longer than

4-6 weeks .

Chapter III Complications of Wound Healing

Complications of Wound Healing

- 30 -


Prevention of Complications

Preoperative evaluation

Surgical complications must be anticipated and addressed as soon as surgical

treatment is determined to be necessary, usually during the preoperative

consultation. Appropriate patient selection involves the detection of both

physical and psychiatric conditions, which may interfere with a desirable

outcome.

Medical risk factors are identified during the initial patient encounter. An

effective strategy is to combine the use of a questionnaire form, which may

be reviewed by the physician, and direct questioning to clarify and confirm

identified risks See fig (6).

Risk factors for intraoperative and postoperative bleeding include both

medication use (eg, aspirin, warfarin, herbal remedies, vitamins) and active

medical problems (eg, blood dyscrasias, liver or kidney disease). Allergies to

medications, anesthetics, topical antibiotics, latex, and bandage adhesives

need to be ascertained. Immunosuppression, whether related to underlying

disease or secondary to medication, should be recognized. Tobacco and


- 31 -

heavy alcohol use may affect wound healing and hemostasis.

Viral illness, such as recurrent herpes labialis, may require prophylactic

treatment for a procedure in the perioral region. Cardiac valve disease,

recent cardiac stenting, or internal prosthetic placement may require

preoperative antibiotics. The presence of a pacemaker/defibrillator may

require that bipolar electrocautery be used.

Figure ( 6 ): Preoperative evaluation questionare


- 32 -

Proper surgical technique

Perhaps the single most important contribution the surgeon can make

to ensure a desirable outcome is to adhere to proper surgical technique. At

the time of surgery, the patient's evaluation should be reviewed, and the

patient's vital signs should be taken. A strategy should be planned to

accommodate for risk factors that were previously identified.

Strict aseptic technique and universal precautions are mandatory; hair should

be secure, and a face mask, eye protection, scrubs, gloves, and gown should

be worn, if necessary. Proper patient positioning is required for accessibility

and immobility. Skin should be widely prepared with povidone-iodine

solution (avoid in the periorbital area to prevent corneal irritation ) and

properly draped. The patient's eyes should be protected when operating on

the head or the neck ( Mac Rae et al., 1984 ).

Postoperative care and follow-up care

Postoperatively, patients should be prepared to follow wound care

instructions and to watch for warning signs of complications. Instructions

should be provided in both verbal and written forms. Patients should be

informed of the expected appearance of edema and ecchymosis in areas

seemingly distant to the operative site. For example, periorbital edema and


- 33 -

ecchymosis are frequent sequelae of surgical procedures performed on the

forehead, but they may be unexpected and alarming to the patient. Similarly,

surgery on the cheek may result in ecchymosis appearing on the neck,

or even intra-orally due to tracking of blood in naturally occurring tissue

planes (See figs 7-9 ).

Figure ( 7 ):

Ecchymosis on the neck

due to tracking of blood in

naturally occurring tissue

planes.

Figure ( 8 ):

Periorbital ecchymosis


- 34 -

Figure ( 9 ):

Extensive ecchymosis in a

patient on anticoagulant

medication.

Bleeding Complications

Bleeding is the most common complication in surgery. Bleeding from

the smaller caliber vessels encountered in cutaneous surgery is unlikely to

pose a life-threatening immediate risk. Postoperative bleeding may eventuate

in the terrible tetrad of hematoma, infection, dehiscence, and necrosis. A

normal hemostatic response to vascular injury involves the initial formation

of a platelet plug followed by a fibrin-platelet clot, and it depends on the

adequate quantity and function of coagulation factors and platelets

The most commonly used medications known to affect hemostasis include

warfarin, aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), and

antiplatelet agents

Postoperative bleeding usually arises within the first 24 hours after surgery.


- 35 -

Minor postoperative bleeding from wound edges is not uncommon, and it

usually results from excessive activity on the patient's part; from trauma to

the area of the wound; or from the increase in blood flow, which occurs

when the vasoconstrictive effect of epinephrine diminishes.

Bleeding under the suture line results in hematoma formation, which

presents with sudden pain and a tender, often bluish area of swelling at the

wound site. A hematoma can have deleterious consequences as it exerts

pressure on the wound edges; it may lead to ischemia, tissue necrosis, and

dehiscence. The collection of blood is also an excellent medium for bacterial

growth and places the wound at increased risk of infection. If discovered in

the acute postoperative period (within the first few days), the hematoma is

still gel-like and may be expressed from the wound through the suture line or

by partial takedown of the repair. (See figs 10-12).

Figure ( 10 ):

Early hematoma under full-thickness

skin graft repair


- 36 -

Figure ( 11 ):

Expression of early hematoma

Figure ( 12 ):

Expression of the hematoma in this

patient did not require takedown of

the graft

Seroma, a collection of serous fluid under the suture line, may occur

in areas of extensive undermining or dead space. Seromas may be drained to

alleviate pain and tension on the wound by using a large-bore needle and

syringe to withdraw the fluid. See figure (13) ( Leese et al., 2000 ) ( Waner

et al., 1993 ).


- 37 -

Figure ( 13 ): Aspiration of seroma

Infection

The postoperative wound infection rate in skin surgery is low.

Reported rates are 0.7-2.29%. Most skin surgical procedures fall into either

the clean category or the clean-contaminated category in the classification

scheme, which predicts the infection rate as a function of wound

contamination.

• Clean wounds (Class I): Imply total adherence to aseptic

technique have an expected infection rate of 1-4%.

• Clean-contaminated wounds (class II): Include wounds in

which a minor break in technique has occurred or when a non-infected, has

an expected infection risk of 5-15%.

• Class III and IV wounds: Include grossly contaminated and

acutely infected wounds that are generally not encountered in skin surgery.


- 38 -

This classification scheme was devised as a guide to prophylactic

antibiotic administration. In general, clean wounds do not require

prophylactic antibiotics, clean-contaminated wounds may require them, and

contaminated and infected wounds definitely require antibiotic treatment

( Rappaport et al., 1990 ).

Sutures are foreign bodies, and they incite a local immune response, which

compromises the local ability to fight infection ( Katz et al., 1981 ).

Other factors associated with an increased risk of infection include lengthy

procedures (2 h or more), inflamed operative sites (eg, ulcerated tumor,

irritated lesion, inflamed cyst, re-excision of recent biopsy site), and the

presence of drains. Patient characteristics, such as advanced age,

immunocompromised state, malnourishment, and obesity, also predispose to

infection ( Dixon et al., 2006 ).

Signs and symptoms of wound infection usually present in an

escalating manner from postoperative days 4-6 and include tenderness,

erythema, warmth, and swelling at the wound site ( Elston, 2007 ).

Purulent exudate, frank cellulitis, lymphangitis, and fever may be

present.


- 39 -

Suture Reactions and Contact Dermatitis and

Hypersensitivity

Suture reactions

Sutures are foreign bodies; as such, they cause a local,

immunologically mediated tissue response, clinically evident as erythema. .

The longer the sutures are in, the more reactivity occurs. The larger the

caliber of the suture, the more reactivity; the increase of one suture size

results in a 2- to 3-fold increase in tissue reactivity. Synthetic or wire sutures

are much less reactive than natural sutures (eg, silk, cotton, catgut); a

monofilament suture is less reactive than a braided suture.

Suture tracking results from the sutures being tied too tightly or being

left in place too long. Puncture scars on either side of the wound connected

by a linear scar in the area where sutures were placed give a railroad track

appearance ( See Fig 14 ).

Figure ( 14 ):

Typical railroad track

appearance of suture

tracking caused by sutures

that were tied too tightly.


- 40 -

This complication is best prevented by tying the suture just tightly

enough to approximate the tissue. Additionally, the use of a suture with

stretch, such as Prolene, and the use of loop sutures (eg, loose first knot,

secured second and third square knots) may be helpful, allowing some suture

"give" as the wound evolves. Once suture tracking has occurred, the normal

contour of the skin may be restored by using laserbrasion or dermabrasion.

Contact dermatitis and hypersensitivity

Contact dermatitis must be differentiated from wound infection and

suture reaction, both of which cause erythema around the wound. Typically,

contact dermatitis is readily recognized by the characteristic shape of the

erythematous area.

Irritant contact dermatitis that results from adhesive bandage use is common;

however, true allergic contact dermatitis is rare ( Norris, 1990 ).Paper tape

may be used as an alternative in patients who experience dermatitis caused

by bandage adhesive. Allergic contact dermatitis to povidone-iodine solution

and chlorhexidine has been reported but is rare.Delayed-type

hypersensitivity has been reported with the use of topical lidocaine ( Marks,

1982 ).

Dehiscence, Necrosis, and Surface Contour Irregularity

Dehiscence

Dehiscence results when a wound fails to heal in apposition. The

healing wound has minimal tensile strength, and, although


- 41 -

re-epithelialization occurs rapidly within 2 days, fibroplasia and subsequent

collagen production are initiated after a delay of approximately 5 days. The

deposition and remodeling of collagen gradually increase the tensile strength

of the wound. The wound regains 3-5% of its original strength at 2 weeks;

15%, at 3 weeks; 35%, at 1 month; and increases to a final strength of 80%,

after several months.

Both systemic and local factors can cause wound dehiscence; however, the

most common cause involves surgical error. Excessive tension on the wound

resulting from inadequate undermining .

Dehiscence may result when sutures are removed too early, especially in

wounds that do not have adequate buried absorbable sutures to provide

tensile strength .

Systemic factors increase a patient's risk of wound dehiscence. Age older

than 65 years, hypoalbuminemia, obesity, uremia, malignancy, systemic

infection, hypertension, Cushing disease, thyroid disease, liver disease, and

congestive heart failure can predispose to wound dehiscence. Additionally,

tobacco use have adverse effects on wound healing and increase the risk of

dehiscence.

Necrosis

Necrosis of tissue occurs secondary to tissue ischemia. Any condition

that results in a decrease of oxygenated blood flow to the wound has the

potential to cause necrosis. Damage to tissue during surgery is the most

common cause. Excessive tension on wound edges, excessive suturing and


- 42 -

undermining, and superficial undermining all decrease blood flow to the

distal wound margins. Random pattern flaps and grafts with a length-to-base

ratio of greater than 4:1 are at high risk of necrosis because of the precarious

nature of the circulation at the wound edges .

Other complications can contribute to tissue necrosis. An expanding

hematoma may cause excessive tension on the wound, leading to

compromised blood supply and tissue death.

Cigarette smoking has a deleterious effect on the survival of reconstructive

flaps and grafts ( Aker et al., 1997).

Surface contour irregularity

Surface contour irregularity is to be expected in the healing wound.

Spread scars occur on high-tension and high-use areas (eg, shoulders, back,

chest), and they occur as a result of complications, such as infection or

dehiscence

Depressed scars and trapdoor defects most commonly occur in sebaceous

areas, typically on the nose.

Dog ears may result when the angle at the apex of the ellipse exceeds 30-

35°, especially in areas where skin is less pliable and over convexities

Hypertrophic scars and keloids Discussed later in the following

chapters.


- 43 -

Nerve Injury and Other Complications

Nerve injury

Inadvertent nerve damage is one of the most dreaded complications of

skin surgery. Patients should always be warned of the possibility of nerve

injury during discussion of informed consent. Nerve injury may be transient

and reversible or permanent.

Transection of small cutaneous sensory nerves is common, resulting in a

patch of anesthesia at the surgical site. This type of injury is reversible;

sensation typically returns within several months.

Other complications

Milia are essentially tiny epidermal inclusion cysts. they may appear

after excisional surgery at the suture line because of implantation of

epidermal components into the dermis ( Mandy, 1986).

Telangiectases may appear after surgery around the sutured area, and

they are often associated with wound tension or a personal tendency.

Pruritus within scars is a relatively common occurrence ( Field et al.,

2000).

Chapter IV Defintion & Historical

Background

Definition and Historical Background

- 44 -

Defintion and Historical Background

A keloid is an abnormal proliferation of scar tissue that forms at

the site of cutaneous injury (eg, on the site of a surgical incision or

trauma); it does not regress and grows beyond the original margins of the

scar. Keloids should not be confused with hypertrophic scars, which are

raised scars that do not grow beyond the boundaries of the original

wound and may reduce over time ( Atiyeh et al., 2005 ).

Keloid and hypertrophic scars are benging fibrous grwoths that show

abnormal wound-healing responses in predisposed individuals from

certain ethnic groups ( Kose and Waseem, 2008 ).

The first description of abnormal scar formation in the form of keloids

was recorded in the Smith papyrus regarding surgical techniques in Egypt

around 1700 BC ( Berman et al., 1999 ). The term keloid, meaning "crab

claw," was first coined by Alibert in 1806, in an attempt to illustrate the

way the lesions expand laterally from the original scar into normal tissue.

( Alibert, 1817 ). Since that time, physicians have attempted to

characterize normal scars, hypertrophic scars and keloids (see figs 15 &

16 ) ( Atiyeh et al., 2005 ) ( Lee et al., 2004 ).

Definition and Historical Background

- 45 -

Figure ( 15 ):

Keloid

Figure ( 16 ):

Hypertrophic Scar

ChapterV Epidemiology ,

Etiology & Genetics

Epidemilogy, Etiology & Genetics

- 46 -

Epidemiology , Etiology & Genetics

Epidemiology and Etiology

It is known that keloids affect only humans, and the black African is

particularly susceptible while Caucasians and albinos are least affected

( Datubo-Brown, 1990 ). Individuals with darker pigmentation, black

persons and Asians, are more likely to develop keloids (Newsome et al.,

2003). The exact incidence of keloids remains unknown ( Brissette et al.,

2001).

Comparable incidence ratios for the races vary from 5.1 to 15.1;5the male

to female ratio is approximately equal. An incidence of 6.2% was found

in a study of 4877 people in a rural African community ( Oluwasanmijo,

1974 ).

Most of the aetiologies proposed for keloid formation are without

scientific basis. These include: oestrogen imbalance, thyroid hormone

alteration, ingrown hairs, melanocyte-stimulating hormone and

pregnancy, to name a few ( Cohen and McCoy, 1980 ). There is a clear

familial predilection for keloid formation that may follow an autosomal

dominant or recessive inheritance pattern ( Omo-dare, 1975 ).

A keloid may occur anywhere on the body, although certain areas of the

body show increased susceptibility; morphologies are specific to each

anatomic site. With the exception of the newborn, keloids have been

noted in all age groups though they tend to occur in younger patients,

most commonly in the second to fourth decades of life ( Newsome et al.,

2003 ), we have noticed however, that in older patients with keloids ,


- 47 -

the scar had developed even at a younger age. A possible explanation for

the greater incidence in the younger age group could be their increased

predisposition to trauma because of their adventurous habit, apart from

the subtle difference in the healing property. Keloids may follow wounds

from diverse aetiology.

The most important risk factor for the development of abnormal scars,

such as keloids, is a wound healing by secondary intention, especially if

healing time is greater than 3 weeks ( Newsome et al., 2003). Sharquie

and Al-Dhalimi found spontaneous keloids in about one-third (34%) of

their Iraqi patients ( Sharquie and Al-Dhalimi, 2003 ).A proportion of

our patients gave no history of trauma; in such patients some trivial,

unnoticed or overlooked injury such as insect bite or razor cut had been

the precursor of such keloids. Other uncommon injuries include

circumcision (especially females), feet burning for post-febrile

convulsions in children and vaccination scars.

Research efforts are hampered by the fact that there is no reliable animal

model because keloids do not occur in animals ( Kelly, 2004).

Genetic predisposition

Some evidence supports a relationship between genetic

predisposition and an individual's propensity to form keloid scars.

Genetic associations for the development of abnormal scars have been

found for HLA-B14, HLA-B21, HLA-BW16, HLA-BW35, HLA-DR5,

HLA-DQW3, and blood group A. Regions of the human genome highly

correlated with keloid formation in 2 pedigrees with familial keloids have

been recently identified. The regions identified were in 2 separate,

unrelated locations on the human genome, underscoring the complex and

multivariable pathogenesis of this disease ( Marneros et al., 2004).


- 48 -

Figure ( 17 ): Development of raised dermal scarring. Individuals without keloid genetic predisposition are more likely to develop normal or temporarily raised scars (hypertrophic scars) that remain within the confines of the original lesion. However, for individuals with keloid genetic predisposition, keloids may be developed, where

the raised scar continually grows beyond the confines of the original lesion and invades into surrounding normal skin.

Fig ( 18 ): Etiology of Keloids.

Chapter VI Pathophysiology

Pathophysiology

- 49 -

Pathophysiology

Keloids are dermal fibrotic lesions that are a variation of the

normal wound healing process. They usually occur during the healing of

a deep skin wound. Hypertrophic scars and keloids are both included in

the spectrum of fibroproliferative disorders. These abnormal scars result

from the loss of the control mechanisms that normally regulate the fine

balance of tissue repair and regeneration.

The excessive proliferation of normal tissue healing processes results in

both hypertrophic scars and keloids. The production of extracellular

matrix proteins, collagen, elastin, and proteoglycans presumably is due to

a prolonged inflammatory process in the wound. Hypertrophic scars are

raised, erythematous, fibrotic lesions that usually remain confined within

the borders of the original wound. These scars occur within months of the

initial trauma and have a tendency to remain stable or regress with time.

Keloid formation can occur within a year after injury, and keloids enlarge

well beyond the original scar margin. The most frequently involved sites

of keloids are areas of the body that are constantly subjected to high skin

tension. Wounds on the anterior chest, shoulders, flexor surfaces of the

extremities (eg, deltoid region), and anterior neck and wounds that cross

skin tension lines are more susceptible to abnormal scar formation.

The most important risk factor for the development of abnormal scars

such as keloids is a wound healing by secondary intention, especially if

healing time is greater than 3 weeks. Wounds subjected to a prolonged

inflammation, whether due to a foreign body, infection, burn, or

inadequate wound closure, are at risk of abnormal scar formation. Areas

Pathophysiology

- 50 -

of chronic inflammation, such as an earring site or a site of repeated

trauma, are also more likely to develop keloids. Occasionally,

spontaneous keloids occur without a history of trauma.

After the initial insult to the skin and the formation of a wound clot, the

balance between granulation tissue degradation and biosynthesis becomes

essential to adequate healing. Extensive studies of the biochemical and

cellular composition of keloids compared to mature scar tissue

demonstrate significant differences. Keloids have an increased blood

vessel density, higher mesenchymal cell density, a thickened epidermal

layer, and increased mucinous ground substance. The alpha–smooth

muscle actin fibroblasts, myofibroblasts important for contractile

situations, are few, if present at all.

The collagen fibrils in keloids are more irregular, abnormally thick, and

have unidirectional fibers arranged in a highly stressed orientation.

Biochemical differences in collagen content in normal hypertrophic scars

and keloids have been examined in numerous studies. Collagenase

activity, ie, prolylhydroxylase, has been found to be 14 times greater in

keloids than in both hypertrophic scars and normal scars. Collagen

synthesis in keloids is 3 times greater than in hypertrophic scars and 20

times greater than in normal scars. Type III collagen, chondroitin 4-

sulfate, and glycosaminoglycan content are higher in keloids than in both

hypertrophic and normal scars. Collagen cross-linking is greater in

normal scars, while keloids have immature cross-links that do not form

normal scar stability.

Pathophysiology

- 51 -

The increased numbers of fibroblasts, recruited to the site of tissue

damage, synthesize an overabundance of fibronectin, and receptor

expression is increased in keloids. Mast cell population within keloid

scars is also increased, and, subsequently, histamine production increases.

Figure ( 19 ): Keloid wound healing. A hypertrophic scar is a nodule consisting of

proliferation of fibroblasts embedded in dense collagen bundles. Often, mild chronic

inflammation and focal hemorrhage are present. Vasculature may be prominent and is

usually perpendicular to the skin surface. No cytologicatypicality of the fibroblasts is

present.

Figure ( 20 ): A keloid is a nodule consisting of a proliferation of fibroblasts

embedded in the dense collagen bundles. Keloidal fibers are present, which are

characterized by the thickened eosinophilic collagen bundles. Mild chronic

inflammation may be observed.

Pathophysiology

- 52 -

Growth factors and cytokines are intimately involved in the cycle of

wound healing. Immunohistochemical studies of keloids demonstrate an

amplified production of tumor necrosis factor (TNF)–alpha, interferon

(INF)–beta, and interleukin-6. Production of INF-alpha, INF-gamma, and

TNF-beta is diminished. INF-alpha, INF-beta, and INF-gamma reduce

fibroblast synthesis of collagen types I, III, and, possibly, VI. A

relationship appears to exist between immunoglobulins and keloid

formation; while levels of immunoglobulin G and immunoglobulin M are

normal in the serum of patients with keloids, the concentration of

immunoglobulin G in the scar tissue is elevated when compared to

hypertrophic and normal scar tissue. Note that no animal model exists for

experimental investigation of keloids ( Butler et. al, 2008 ).

Chapter VII Clinical

Presentation

Clinical Presentation

- 53 -


Keloids appear as firm, mildly tender or pruritic, bosselated, well-

demarcated tumours occurring more frequently on shoulders, chest, neck,

upper arms, earlobes and cheeks. Keloids are variable in size from 2 to 3

mm papules to large pendulous tumours. Shapes vary from evenly

contoured symmetric protrusions with regular margins to irregular claw-

like projections. The colour of keloid is also variable, mildly

erythematous in new lesions while dull red or more pale in older lesions.

Keloids may occur on eyelids, genitalia, palms, soles, cornea or mucous

membranes rarely.

Keloids develop rapidly over weeks or months following trauma or other

precipitating factors. The lesions may continue to grow or remain stable

for long periods of time. Sometimes, keloids may undergo central

suppurative necrosis. This change is thought to be due to ischemic

necrosis from vascular compromise secondary to keloid overgrowth.

Dark skinned individuals are more susceptible to keloid formation,

especially on the face. Growth of keloid may be stimulated by pregnancy.

Surgically resected keloid is followed by regrowth of a larger tumour and

if skin graft has been used, keloid may occur in donor site as well.


- 54 -

Differences between Hypertrophic Scars and Keloidal Scars

Clinical

Keloidal scar is a lesion that persists for more than 12 months. It

extends beyond the original wound and spreads by invasion rather than

expansion. These scars can occur in other animal species besides human

beings i.e. horses, cows and dogs. Small injury may produce a large

lesion. They are independent of areas of motion and worsened by surgery.

Areas of high predilection are chest, shoulders, back, earlobes, neck etc.

The disease is likely to recur.

Hypertrophic scar is a lesion that may regress with time and occur earlier

after injury and limited to the boundary and are more responsive to

surgical excision. Its size is directly proportional to that of injury. They

occur in areas of motion and occur across flexor surfaces like joints and

abdomen.

Some researchers suggest that because the keloids and hypertrophic scars

are so similar, they should be considered together while others feel

opinion that the different behaviour of these scars invalidates this

approachbeen found but their biologic effect is different.

Hypertrophic scars have nodules containing cells and collagen within the

mid-to deep part of scar. Within these nodules, there are -smooth muscle

actin staining myofibroblasts which are absent from normal dermis,

normal scars and keloidal scars ( See table 1 ) ( Ajab khan kakar 2006 ).


- 55 -

Histology

Keloids have a normal epidermal layer; abundant

vasculature; increased mesenchymal density, as manifested by a

thickened dermis; and increased inflammatory-cell infiltrate when

compared with normal scar tissue. The reticular layer of the dermis

consists mainly of collagen and fibroblasts, and injury to this layer is

thought to contribute to formation of keloids. Collagen bundles in the

dermis of normal skin appear relaxed and in an unordered arrangement;

collagen bundles are thicker and more abundant in keloids, yielding

acellular, nodelike structures in the deep dermal region. The most

consistent histologic distinguishing characteristic of keloids is the

presence of large, broad, closely arranged collagen fibers composed of

numerous fibrils. In addition to collagen, proteoglycans are another major

extracellular matrix (ECM) component deposited in excess amounts in

keloid scars.

There are four histologic features that are consistently found in keloid

specimens that are deemed pathognomonic for their diagnosis. They are

1) the presence of keloidal hyalinized collagen.

2) a tonguelike advancing edge underneath normal-appearing epidermis

and papillary dermis.

3) horizontal cellular fibrous bands in the upper reticular dermis.

4) prominent fascialike fibrous bands. ( Lee et al., 2004 ).


- 56 -

Metabolic activity

Keloidal scars have higher levels of adenosine triphosphate and

fibroblasts than hypertrophic scars. There is a higher density of

fibroblasts in both types of scars but keloidal scars have a higher

expression of proliferating cell nuclear antigen. This may explain the

tendency of keloidal scars to grow beyond the boundary of the original

injury or trauma.

Other differences

Antinuclear antibodies against fibroblasts, epithelial and

endothelial cells have been found in patients with keloids but not in

hypertrophic scars.

Differential diagnosis

Keloids can be differentiated from hypertrophic scars, as described

earlier. Hypertrophic scars remain within the boundary of initial injury.

They are not claw-like and often regress spontaneously.

Keloids can be distinguished histologically from dermatofibrosarcoma

protuberans, clinical picture of which may be similar to keloids.

Allergic contact dermatitis secondary to gold earrings may produce

keloidal lesions on the earlobes but histopathologic study of these lesions

shows a dense infiltration of lymphocytes and formation of lymphoid

follicles rather than dense collagen tissue.


- 57 -

Keloids can be differentiated from lobomycosis (keloidal blastomycosis).

In lobomycosis, on histopathology there are abundant fungi and giant

cells in the lesions which are granulomatous and devoid of collagenous

fibrosis ( Ajab Khan Kakar, 2006 ).

Table ( 3 ): CLINICAL FEATURES OF HYPERTROPHIC SCARS AND KELOIDS

HYPERTROPHIC SCARS KELOIDS

Develop soon after surgery May develop months after the trauma

Usually improve with time Rarely improve with time

Remain within the confines of Spread outside the boundaries of the

the wound original lesion

Occur when scars cross joints Occur predominantly on the earlobe,

Or skin creases at right angle shoulders, sternal notch and rarely

develop across joints

Improve with appropriate su- Are often worsened by surgery

rgery

Are of freaquent incidence Are of rare inidence

Have no association with Are asscociated with dark skin color

skin color


- 58 -

Work up of a patient of keloid

Diagnosis is usually based on clinical findings. Biopsy helps confirm the diagnosis in case of uncertainty ( Ajab Khan Kakar 2006 ).

Chapter VIII Prevention & Modalities of

Treatment

Prevention & Modalities of Treatment

- 59 -


Prevention

The most important factor in hypertrophic scar and keloid

formation is prevention. Avoiding all unnecessary wounds, especially in

keloid-prone patients, remains an obvious but imperfect solution ( Slemp

et al., 2006 ). All surgical wounds should be closed with minimal tension,

incisions should not cross joint spaces, midchest incisions should be

avoided, and incisions should follow skin creases whenever possible

( Slemp et al., 2006 )( Rudolph, 1987 )( Lanza et al., 1992 ). Especially

in head and neck surgery, the esthetic subunits of the face must be

considered for incision sites (Baisch et al., 2006 ). An atraumatic

operation technique should be used, followed by efficient hemostasis, and

wound closure should include eversion of the wound edges. It is also

crucial to properly debride contaminated wounds and limit foreign bodies

in the form of polyfilamentous sutures ( Slemp et al., 2006 ). Particularly

in the face, subcutaneous sutures should be used only when necessary.

Furthermore, wound healing and the esthetic outcome of scar formation

can be improved with massage or greasing ointments ( Baisch et al.,

2006 ).

Plan for prophylaxis of keloids and hypertrophic scars in a

keloid prone patient:

-Post traumatic wound care for preventing infection

-Proper surgical planning and Immediate post operative care to


- 60 -

prevent wound dehiscence

1. Pressure garment plus

2. Contractubex© cream or

3. Post operative injection interferon B alpha I/L or

4. Injection triamcinolone acetonide I/L and /or

5. Silicon gel dressing for 3 months ( Sharad, 2005 )

Treatment

Surgery for Keloids

Simple total excision of a keloid stimulates additional collagen

synthesis, thus sometimes prompting quick recurrence of a keloid even

larger than the initial one. For this reason, intra-marginal surgical

excision of keloid tissue is recommended in order not to stimulate

additional collagen synthesis. Surgical excision of a keloid alone is

associated with a high recurrence rate. Thus, surgical therapy should be

combined with adjuvant treatment such as pressure, corticosteroids, and

radiotherapy. Kauh and colleagues demonstrated that surgical excision

combined with steroid injection into the wound bed causes down-

regulation of type I collagen gene expression without compromising

wound healing. If intralesional steroids are used post-op eratively, we

recommend leaving the sutures 3 to 5 days longer to prevent wound

dehiscence. Never the less, surgical therapy for the treatment of keloids

has been relegated mainly to second-line therapy for lesions unresponsive

to steroids or pressure ( Rockwell et al., 1989 ).


- 61 -

Pressure

The use of pressure to treat keloids was initially described in

1835,50 although compression therapy was not popularized until the

1970s, when physicians noted that pressure stockings used on lower

extremity burns resulted in scars that matured more rapidly, with less

erythema and thickness. The compression phenomenon is not well

understood, but theories include the following:

(1) a decrease in blood flow with a resultant decrease in a2-

macroglobulin and a subsequent increase in collagenase-mediated

collagen breakdown, normally inhibited by a2-macroglobulin.

(2) hypoxia leading to fibroblast degeneration and collagen

degradation.

(3) lower levels of chondroitin 4-sulfate, with a subsequent increase

in collagen degradation.

(4) decreased scar hydration, resulting in mast cell stabilization and

a subsequent decrease in neo-vascularization and matrix production.


- 62 -

Figure ( 21 ):

compression garment

for the forearm

Histologic examination showed that pressure therapy in hypertrophic

scars partly restores the extracellular matrix organization, like that

observed in normal scar tissue, and induces the disappearance of a-SMA-

expressing myofibroblasts, probably by apoptosis. Recent studies have

investigated presence of epilysin (MMP-28), a proteolytic enzyme

expressed by keratinocytes in response to injury, in normal and

hypertrophic scars and evaluated the effect of in vitro compression on its

expression. Immunohistochemistry revealed a slight protein presence in

normotrophic scar keratinocytes and strong positivity in hypertrophic scar

keratinocytes, whereas compression therapy induced a significant

reduction in this protein in hypertrophic scars. Other experimental studies

were able to show that tumor necrosis factor-a (TNF-a) release, which is

significantly enhanced in hypertrophic scars, can be diminished with

compression therapy, whereas the apoptosis rate can be strongly

increased in hypertrophic scars with pressure. The part of the face most

amenable to the use of pressure dressings is the ear lobe, and pressure


- 63 -

clips are in common use for patients with ear lobe keloids. Pressure

therapy should be started immediately after reepithelialization of the

wound, and patients should wear these pressure devices for continuous 8

to 24 hours a day for the first 6 months of scar healing. The success rate

depends largely on patient compliance ( English and Shenefilt, 1999 ).

Fig ( 22 ):

Compression garment for the face

Topical Silicone Gel

Topical silicone gel sheeting has enjoyed much popularity in the

treatment of abnormal scars. First reported in the early 1980s, silicone

therapy has recently been marketed for at-home use to improve the

appearance of any scar. It is recommended that these silicone sheets be

worn at least 12 hours a day for a minimum of 2 months. The mechanism

of action is unknown, but it has been suggested that the greater wound


- 64 -

hydration achieved using occlusive therapy (silicone and non-silicone

based) affects local keratinocytes to alter growth factor secretion and,

secondarily, influences fibroblast regulation. It is also believed that

hydration decreases capillary permeability, inflammatory and mitogenic

mediaors, and collagen synthesis. In patients who are known to be

hypertrophic scar formers, topical silicone gel sheeting has a distinct

effect in impeding the formation of abnormal scars in surgical incisions.

Application of silicone gel sheets should begin as soon as re-

epithelialization is finished, and daily application for at least 12 hours is

recommended, although the exact duration needed for maximum benefit

is unknown and requires further investigation (See fig 23)( Urioste et al.,

1999 ).

Figure ( 23 ): Silicon Sheet


- 65 -

Radiation

Debeurmann and Gougerot first described the use of X-rays for the

treatment of keloids in 1906. Later evidence showed that radiation

therapy alone is inadequate for the treatment of keloids; therefore,

Cosman and colleagues introduced the use of post-excision radiation

therapy as an adjunct to surgical excision. The reported efficacy rate

varied between.

65% and 99% compared with excision alone. It is suggested that radiation

directly affects fibroblast proliferation by inducing apoptosis. The total

dose recommended for the treatment of keloids varies from 15 to 20 Gy

fractionated over five to six treatments. The main drawback of radiation

therapy, aside from hyperpigmentation, is the risk of radiation-induced

malignancy, although only a few cases have been described, and large

treatment cohorts with extensive follow-up have provided no evidence to

substantiate the risk of carcinogenesis. Nevertheless, radiation therapy is

contraindicated in children, as well as in areas of high carcinogenic

potential, namely the breast and thyroid ( Malaker et al., 2004 ).

Laser Therapy

Many laser types, including the carbon dioxide laser and the pulsed

dye laser (PDL), have been tested for treatment of hypertrophic scars and

keloids, with varied results. The carbon dioxide laser, which is commonly

used for skin resurfacing, has not been proven to be more effective in


- 66 -

treating problem scars than are other methods. The PDL is considered to

be the criterion standard for vascular lesions, such as port wine stains,

initial hemangiomas, and facial telangiectasias. Additionally, this laser

type is often successfully used for non-vascular indications, such as

keloids or hypertrophic scars. Currently, the PDL wavelengths 585 and

595 nm are most frequently used for therapeutic purposes. Alster reported

an average improvement of 57% after the first treatment and 83% after

the second treatment with PDL for hypertrophic surgical and traumatic

scars. In addition to a reduction in erythema, flatening, a clear reduction

in itching and pain, and optimization of the skin texture have been

observed. The entire scar in each patient was exposed to PDL at a

wavelength of 585 nm, a pulse duration of 0.45 ms, and a fluence of 6.5

to 7.25 J/cm2. Recent biochemical studies suggest that 585-nm PDL

treatment alters signaling pathways to favor collagen degradation and

fibroblast apoptosis. In contrast to the above-cited results, Chan and

colleagues failed to show any clinical improvement using PDL for

hypertrophic scars. In 27 hypertrophic scars, one side of each of which

was treated (585 nm, 7–8 J/cm2, 2.5 ms, 5 mm), the authors documented

no superiority of the treated half after three to six treatments regarding

thickness and elasticity, although pain and touch sensitivity were far

better on the treated side. Several reports have shown a trend toward

better clinical improvement using low to moderate fluences, although

laser therapy has not shown a clear advantage over cold scalpel excision,

especially in keloids (See fig 24)( Norris, 1999 ).


- 67 -

Figure ( 24 ): Ear keloid treated with catbon dioxide laser pre and immediately post

Corticosteroids

Intralesional corticosteroid injections have become a mainstay in the

treatment of hypertrophic scar and keloids, alone or in combination with

other therapeutic procedures. Corticosteroid application can soften and

flatten keloids but cannot narrow hypertrophic scars or eliminate keloids.

Intralesional corticosteroid injection decreases fibroblast proliferation,

collagen synthesis, and glycosaminoglycan synthesis and suppresses pro-

inflammatory mediators. We recommend beginning with direct serial

intralesional corticosteroid injections in an already- developing keloid or

hypertrophic scar. The most commonly used drug for steroid injection is

triamcinolone acetonide (TA) at a dose of 5 to10 mg/mL, which should

be injected with a 25- to 27-gauge needle into the upper dermis of a


- 68 -

developing hypertrophic scar every 3 to 6 weeks. Injections are

discontinued when the scar is stable, when surgical intervention is

indispensable, or if side effects such as tissue atrophy, hypopigmentation

or telangiectasia develop. The treatment of preexisting keloids should

begin with three monthly, intralesional injections of TA at a dose of 40

mg/mL mixed with equal parts of 2% lidocaine. Some authors also

recommend the addition of hyaluronidase, which helps to disperse the

injection. Because tissue absorption through intact or sutured skin is poor,

the use of topical steroids is indicated only for superficial lesions, such as

those occurring from dermabrasion ( Brissett and Sherris, 2001).

Other Pharmacologic Therapies

5-Fluorouracil

Intralesional injection of the pyrimidine analog 5-fluorouracil (5-

FU) has been investigated for the regression of keloids and hypertrophic

scars. 5-FU targets rapidly proliferating fibroblasts in dermal wounds

responsible for excessive collagen production. 5-FU has been shown to

be effective in the treatment of hypertrophic scars, whereas studies of

intralesional 5-FU application have provided mixed results in keloids.3

The injection can be painful, and purpura and ulcers have been

documented. 5-FU can also be combined with corticosteroids; Fitzpatrick

was the first to report improved efficacy and less painful injections by

mixing corticosteroids (triamcinolone acetonide) with 5-FU. Apikian and

Goodman found that the combination of 5-FU with corticosteroids has


- 69 -

fewer undesirable side effects than intralesional corticosteroid injection

alone. This combined therapy provides also more rapid response.

Imiquimod 5% Cream

Imiquimod 5% cream, a topical immune response modifier, is

approved for the treatment of genital warts, basal cell carcinoma, and

actinic keratoses. Imiquimod stimulates interferon a, a proinflammatory

cytokine, which increases collagen breakdown. Additionally, imiquimod

alters the expression of apoptosis-associated genes. Therefore, it has been

used in an attempt to reduce keloid recurrence after excision. Berman and

Kaufman reported positive effects on the recurrence rate of keloids after

post-operative application in patients. By contrast, Malhotra and

colleagues showed a complete recurrence of presternal keloids after

keloid excision

and after imiquimod therapy. The role of imiquimod in the prevention of

hypertrophic scars is under evaluation

Onion Extract

Allium cepa, or onion extract, is found in numerous scar treatment

products.83 This ‘‘botanical’’ ingredient exhibited anti-inflammatory,

bacteriostatic, and collagen down-regulatory properties86 and improves

collagen organization in a rabbit ear model, but three major clinical

studies in the United States evaluating the effects of onion extract on

human wound healing showed no evidence that this extract could be


- 70 -

beneficial in improving hypertrophic scars. Products containing onion

extract did not improve scar cosmesis or symptomatology any more than

a petrolatum-based ointment.

Interferons

Interferons are cytokines secreted by T-helper cells that, apart from

other functions, suppress fibrosis. All interferon isoforms (a, b, g) have

been shown to reduce collagen and extracellular matrix production while

increasing collagenase level but have been applied only experimentally

and predominantly in small numbers of patients. Furthermore, the use of

interferons is also associated with severe side effects, including fever,

chills, night sweats, fatigue, myalgia, and headache.

Immunotherapy

Immune modulators and antibody therapies are new in the context

of problem scars. Commercial drugs like tacrolimus and sirolimus are

known to affect cytokine activation, TNF-a, interferons, and inter-

leukins, with wide-ranging effects on inflammation and cell-cycle

regulation. Topically used, these drugs may suppress fibroblast activity

and increase the apoptosis rate in keloids.84 Anti-TGF-b antibody

application use in animal models decreased scar hypertrophy and

collagen contraction.90 Further molecular investigations will yield more

specific, probably gene-based, therapies that are designed not only to

treat, but also to prevent problem scars. ( Dolore et al., 2009 )

Chapter IX Electron Beam

Irradiation

Electron Beam Irradiation

- 71 -


Ionizing radiation have been used for many decades to treat a

variety of benign tumors and tumor-like conditions with different degree

of success. However, there is no general consensus among radiotherapists

regarding the indications of radiation therapy, dose per fraction,

fractionation. Total dose and technique (Hussein, 1998).

Keloid

Irradiation of keloids which was first described in the early 1900s

by Freund is a well-accepted procedure. It can reduce the recurrence

rates to 3–33% according to the literature without any complications. The

main resrvation against this modality, the carcinogenic effect, has not

definitely been proven in a single case. The radiation protocols used in

the clinical setting include X-ray therapy, afterloading brachytherapy

with iridium-192 (192Ir) wires, electrons from linear accelerator, and

stron- tium-90-yttrium-90 (90Sr-90Y) contact brachytherapy. All

techniques are applied with varying dose and fractionation schedules (

Ingeborg et al., 2005 ).

Radiation therapy is infrequently used as monotherapy. When combined

with surgical excision, the recurrence rate following radiation treatment

has been reported between 10–20%. A dose of at least 1500Gy, delivered

in fractions within 10 days of surgery, is recommended by some

investigators. Inhibition of fibroblast proliferation and angiogenesis

during the exaggerated wound-healing process is the proposed


- 72 -

mechanism of action. The use of a potentially carcinogenic treatment for

the treatment of a benign process such as keloid scaring is controversial.

Although a large study found no increased risk of malignancy following

radiation therapy for keloids, case reports have outlined the development

of carcinoma (two breast, one thyroid) in three patients. It is, therefore,

prudent to exercise caution when considering radiation therapy as an

adjunct to other modalities for the treatment of keloid or hypertrophic

scars in young children and in radiosensitive areas such as the breast or

thyroid ( Tina et al., 2003 ).

Between 1988 and 2000, 378 cases of keloids were treated by Ogawa,

and 147 keloids in 129 patients were selected for this study. Keloids that

occurred at a different site in the same patient and keloids that recurred

later at the same site were deemed to be different keloids. Those keloids

were surgically removed, and the patients were treated postoperatively

with 15-Gy electron beam irradiation and followed for more than 18

months. The therapeutic outcomes were evaluated. Statistical analysis

was performed using Fisher’s exact probability test or chi-square test.

Recurrence occurred in two sites on 14 earlobes (14.3 percent), in two

sites on 12 necks (16.7 percent), in 22 sites on 51 anterior chest walls

(43.1 percent), in 13 sites in 33 scapular regions (39.4 percent), in four

sites on 15 upper limbs (26.7 percent), in four sites in 11 suprapubic

regions (36.4 percent), and in one site on 11 lower limbs (9.1 percent).

The overall recurrence rate was 32.7 percent. Analysis of the therapeutic

outcomes showed that the recurrence rates in the sites with high stretch

tension, such as the chest wall, and the scapular and suprapubic regions

were statistically higher than in sites without high tension, such as the

neck, earlobes, and lower limbs (41.1 percent versus 13.5 percent, p =


- 73 -

0.0017). The results suggested that keloid sites with a high risk of

recurrence should be treated with escalated radition doses and post-

treatment self-management ( Ogawa et al., 2003 ).

Forty-seven patients with a combined total of 60 keloids were treated

with 6-MeV electron beam radiotherapy after surgical excision of the

keloids. Mean daily fractions of 4 Gy (range, 3-5 Gy) were administered

up to a total dose of 16 Gy (range, 12-18 Gy). The median follow-up was

70 months. Patients were asked to complete a questionnaire addressing

their satisfaction with the treatment results. This self-assessment was

compared with the clinical outcome ; Four keloids (7%) relapsed

completely, and five recurrences (8%) were classified as limited relapses.

All recurrences were observed at sites of high stretch-tension. Keloid-

associated symptoms, e.g. itching and pain, were improved in 81%.

Hypopigmentation was observed in 29 patients (62%), a mild redness of

the scar in eight patients (17%), and grade 1 telangiectasias in two

patients (4%). No severe complications or secondary malignancies were

observed. Self-assessments did not fully correspond to the clinical

examination and recurrence status. Twelve patients were not satisfied

with the treatment result, but only two of these relapsed completely.

Three relapsed patients described the result of therapy as excellent or

good (Bischof et al., 2007 ).

The most advantageous time for radiation to prevent recurrence of

keloids is the early postoperative period. Durosinmi-Etti et al.,

evaluating 454 keloidal scars treated with superficial X-ray therapy

within 72 h following surgical excision, found a response rate of 93% at

24 months ( Durosinmi-Etti et al., 1994 ).


- 74 -

Researchers in Japan reported postoperative irradiation with a low mega-

voltage (4MeV) electron beam. Keloid sites were irradiated within 1 or 2

days after surgery for three consecutive days. The advantages of the use

of an electron beam are that the peak of dose is delivered to the layer of

the occurrence of keloid, and the depth of penetration of radiation is

limited, without appreciable effect on deeper structures.

External radiation following excision, often combined with other

therapies, has been associated with recurrence rates of less than 10%

(Berman and Bieley, 1996 ).

Between October 1985 and June 1992 Postoperative keloids of 125

Patients were treated with superficial X-ray (100--140 Kv) and electron

beam (6 and 9 MeV ), in an attempt to prevent their recurrence, 100

patients with 129 sites received a dose of 1200--4000 cGy at 200--300

cGy per fraction within one to four weeks and at intervals of one to three

weeks between excision and irradiation. Rate in the prevention of keloid

was only 28.6~ (37/ 129 ). However, 25 patients with 25 sites received

a total dose of 1500 cGy at 500 cGy per fraction starting within one week

after excision and at intervals of 96 hours. The success rate was 84%

(21/25) (Sun, 1993 ).

Cosman and colleagues introduced the use of post-excision radiation

therapy as an adjunct to surgical excision. The reported efficacy rate

varied between 65% and 99% compared with excision alone. It is

suggested that radiation directly affects fibroblast proliferation by

inducing apoptosis. The total dose recommended for the treatment of

keloids varies from 15 to 20 Gy fractionated over five to six treatments (

Slemp and Kirscner, 2006 ).


- 75 -

Ogawa located five cases of carcinogenesis (i.e., fibrosarcoma, basal cell

carcinoma, thyroid carcinoma, and breast carcinoma) that were associated

with radiation therapy for keloids. However, it was unclear whether an

appropriate dose of radiation was used and whether sufficient protection

of surrounding tissues was provided. Moreover, a questionnaire study of

radiation oncologists around the world revealed that approximately 80

percent considered radiation to be acceptable for treating keloids ( Ogawa

et al., 2009 ).

Acute and Chronic Side Effects of electron beam irradiation In general, the relatively low total radiation doses applied do not

stimulate skin and soft tissue reactions beyond the common toxicity

criteria (CTC) level of grade 1-2. Within the first weeks and months after

irradiation using total doses of 10-20 Gy, the skin around the irradiated

scar becomes darker; usually this hyperpigmentation lasts for about 1

year and slowly disappears spontaneously without any further therapeutic

action. Moreover, a dry desquamation can be observed, which fades away

in between 2-4 weeks. To improve and accelerate the skin regeneration

process, it is convenient to instruct the patient to apply hydrating products

locally over the lesion after the post-surgical dressing has been removed

for example, aloe vera or glycerol for several weeks.

Chronic skin and soft tissue reactions may involve skin depigmentation,

some dryness and thinning of the skin and sometimes sensitivity loss;

however, these reactions have to be seen in the context of various

previous treatments and the post-surgical repair processes. In summary,

not all possible treatment side effects can be addressed to radiotherapy,


- 76 -

and quite often the surgical and other non-surgical therapies produce their

own pattern of side effects that cannot attributed to radiotherapy

( Seegenscmiedt et al., 2008 ).

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