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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

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
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Skin Anatomy

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 ).

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Skin Anatomy

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

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Skin Anatomy

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).
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Skin Anatomy

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
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Skin Anatomy

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 ) .

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Skin Anatomy

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 reepithelialization 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,
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Skin Anatomy

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.
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Skin Anatomy

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
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Skin Anatomy

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 ).

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Skin Anatomy

Fig ( 2 ): Anatomy of the Hair Follicle

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Skin Anatomy

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
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Skin Anatomy

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.
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Skin Anatomy

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 ).

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Skin Anatomy

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 ).
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Skin Anatomy

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

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

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
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Skin Anatomy

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).

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Chapter II
Physiology of
Wound Healing

Physiology of Wound Healing

Physiology of Wound Healing

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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Physiology of Wound Healing

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
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wound

formation,

release

Physiology of Wound Healing

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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Physiology of Wound Healing

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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Physiology of Wound Healing

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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Physiology of Wound Healing

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
OKane, 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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Physiology of Wound Healing

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

Production

Known Effects

1.

Platelets,

Stimulates fibroblasts to secrete collagenase to

Epidermal

macrophages

degrade the matrix during the remodeling

Factor

Growth

phase. Stimulates keratinocyte and fibroblast

Factor

proliferation. May reduce healing time when

(EGF)

applied topically.

2.

Platelets,

TGF-a:

Mitogenic

Transformi

macrophages,

keratinocytes and fibroblasts

ng Growth

lymphocytes,

TGF-b1 and TGF-b2: Promotes angiogenesis,

Factor

hepatocytes

up-regulates collagen production and inhibits


degradation,

and

promotes

chemotactic

for

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 cells

Promotes angiogenesis during tissue hypoxia.

Endothelial
Growth
Factor
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Physiology of Wound Healing

(VEGF)

4.

Macrophages,

Fibroblast

mast

Growth

lymphocytes

and keratinocyte migration, respectively.

5. Platelet-

Platelets,

Attracts macrophages and fibroblasts to zone of

Derived

macrophages, and

injury. Promotes collagen and proteoglycan

Growth

endothelial cells

synthesis.

6.

Macrophages,

IL-1:

Interleukins

keratinocytes,

neutrophils,

endothelial cells,

keratinocytes. Activates neutrophils

lymphocytes,

IL-4:

fibroblasts,

differentiation. Induces

osteoblasts,

proteoglycan synthesis.

cells,

Promotes
T-

angiogenesis,

granulation,

and

epithelialization via endothelial cell, fibroblast,

Factor
(FGF)

Factor
(PDGF)

basophils,

mast

cells

IL-8:

Proinflammatory,

chemotactic

fibroblasts,

and

Activates

Chemotactic

for

for

fibroblast
collagen

and

neutrophils

and

fibroblasts.

7. Colony-

Stromal

cells,

Granulocyte colony stimulating factor (G-

Stimulating

fibroblasts,

CSF): Stimulates granulocyte proliferation.

Factors

endothelial cells,

Granulocyte Macrophage Colony Stimulating

lymphocytes

Factor (GM-CSF): Stimulates granulocyte and


macrophage proliferation.

8.

Fibroblasts

Keratinocyt
e

Stimulates

keratinocyte

differentiation, and proliferation.

growth

factor

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migration,

Physiology of Wound Healing

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.
- 26 -

Physiology of Wound Healing

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.
- 27 -

Physiology of Wound Healing

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.

- 28 -

Physiology of Wound Healing

-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 .

- 29 -

Chapter III
Complications of
Wound Healing

Complications of Wound Healing

Complications of Wound Healing

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
- 30 -

Complications of Wound Healing

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


- 31 -

Complications of Wound Healing

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
- 32 -

Complications of Wound Healing

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

- 33 -

Complications of Wound Healing

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.
- 34 -

Complications of Wound Healing

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

- 35 -

Complications of Wound Healing

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 ).

- 36 -

Complications of Wound Healing

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.

- 37 -

Complications of Wound Healing

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.

- 38 -

Complications of Wound Healing

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.

- 39 -

Complications of Wound Healing

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
- 40 -

strength,

and,

although

Complications of Wound Healing

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
- 41 -

Complications of Wound Healing

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 3035, especially in areas where skin is less pliable and over convexities

Hypertrophic scars and keloids


chapters.

- 42 -

Discussed later in the following

Complications of Wound Healing

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).

- 43 -

Chapter IV
Defintion &
Historical
Background

Definition and Historical Background

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 ).

- 44 -

Definition and Historical Background

Figure ( 15 ):
Keloid

Figure ( 16 ):
Hypertrophic Scar

- 45 -

ChapterV
Epidemiology ,
Etiology & Genetics

Epidemilogy, Etiology & Genetics

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 ,

- 46 -

Epidemilogy, Etiology & Genetics

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

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).
- 47 -

Epidemilogy, Etiology & Genetics

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.

- 48 -

Chapter VI
Pathophysiology

Pathophysiology

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
- 49 -

Pathophysiology

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 alphasmooth
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 4sulfate, 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.

- 50 -

Pathophysiology

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.

- 51 -

Pathophysiology

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 ).

- 52 -

Chapter VII
Clinical
Presentation

Clinical Presentation

Clinical Presentation
Keloids appear as firm, mildly tender or pruritic, bosselated, welldemarcated 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 clawlike 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.

- 53 -

Clinical Presentation

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 ).

- 54 -

Clinical Presentation

Histology
Keloids

have

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 ).

- 55 -

Clinical Presentation

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.
- 56 -

Clinical Presentation

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


the wound

Spread outside the boundaries of the


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

- 57 -

Clinical Presentation

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 ).

- 58 -

Chapter VIII
Prevention &
Modalities of
Treatment

Prevention & Modalities of Treatment

Prevention & Modalities of Treatment

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
- 59 -

Prevention & Modalities of Treatment

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 downregulation 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 ).
- 60 -

Prevention & Modalities of Treatment

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 a2macroglobulin 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.

- 61 -

Prevention & Modalities of Treatment

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-SMAexpressing 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
- 62 -

Prevention & Modalities of Treatment

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
- 63 -

Prevention & Modalities of Treatment

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 reepithelialization 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


- 64 -

Prevention & Modalities of Treatment

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
- 65 -

Prevention & Modalities of Treatment

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, 78 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 ).

- 66 -

Prevention & Modalities of Treatment

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 proinflammatory 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
- 67 -

Prevention & Modalities of Treatment

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 (5FU) 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
- 68 -

Prevention & Modalities of Treatment

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
- 69 -

Prevention & Modalities of Treatment

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 interleukins, 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 )

- 70 -

Chapter IX
Electron Beam
Irradiation

Electron Beam Irradiation

Electron Beam Irradiation


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 333% 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 1020%. 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
- 71 -

Electron Beam Irradiation

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 Fishers 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 per- cent), 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 =
- 72 -

Electron Beam Irradiation

0.0017). The results suggested that keloid sites with a high risk of
recurrence should be treated with escalated radition doses and posttreatment 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. Keloidassociated 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 fol- lowing surgical excision, found a response rate of 93% at
24 months

( Durosinmi-Etti et al., 1994 ).


- 73 -

Electron Beam Irradiation

Researchers in Japan reported postoperative irradiation with a low megavoltage (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 ).
- 74 -

Electron Beam Irradiation

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 reac- tions 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,
- 75 -

Electron Beam Irradiation

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 ).

- 76 -

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