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International Surgery Journal | September 2019 | Vol 6 | Issue 9 Page 3341
International Surgery Journal
Joseph A et al. Int Surg J. 2019 Sep;6(9):3341-3346
http://www.ijsurgery.com
pISSN 2349-3305 | eISSN 2349-2902
Original Research Article
Recurrence of keloids after application of epidermal growth factor
Aneesh Joseph, Ajayakumar Kochunarayanan*, Fobin Varghese, Kalesh Sadasivan
INTRODUCTION
Scar following trauma and surgeries are a major problem
world-wide. Aberrations of normal physiologic wound
healing and may cause excessive scarring which may
develop after any insult to the deep dermis, including
burns, infections, trauma, vaccines, piercing and
surgeries. Patient’s quality of life is affected due to the
psychological trauma associated with excess scarring and
symptoms like pruritus, pain and contractures.
No treatment modality is uniformly successful for
keloids. Despite of high recurrence, patients demand for
intervention due to physical and psychological burden of
the disease. Pruritus and pain are the main symptoms.
Excision of a keloid and primary closure invariably result
in recurrence. Available adjuvant therapies are intra-
lesional steroid injection, radiation, cryotherapy, laser,
and immunomodulatory agents. Intralesional cortico-
steroid injection therapy is accepted as the first line in
treatment for keloids. It also has synergistic effects with
other modalities. Rapidly proliferating lesions respond
best to steroid injection than slowly growing, mature
lesions. In some studies, Intraoperative and postoperative
intralesional steroid therapy following excision has been
shown to reduce recurrence to around 50 %. Numerous
retrospective studies have shown that a short course of
ABSTRACT
Background:
Exact aetiology for keloid formation is yet unknown. The prime goal of the therapy is to decrease the
process of scarring. Many modalities of treatment are available for keloids. With current treatment modalities,
recurrence rates approaches 75%. This study was conducted to find out whether application of Epidermal growth
factor will reduce recurrence rates of keloids, after surgical excision.
Methods:
An observational study was conducted by collecting details of 40 patients who underwent surgical excision
of keloids followed by epidermal growth factor application over the wounds. The patients have been followed up to
6th months post excision and recurrence rates of keloids as well as overall scar quality were analysed.
Results:
Out of 45 patients included in the study, 16 (35.6 %) were males and rest females. The median age of the
study population was 18.0 (with an IQR 16.0; 26.0). Out of 45 patients, 12 patients had family history of keloids
(73%). Out of 45 patients, 8 had keloid tendency which amounts to 82%. Out of 45 patient who underwent treatment,
22 patient developed recurrence which is 48.9% Out of 45 patients included in the study, 16 (35.6 %) were males and
rest females. The median age of the study population was 18.0 (with an IQR 16.0; 26.0). Out of 45 patients, 12
patients had family history of keloids (73%). Out of 45 patients, 8 had keloid tendency which amounts to 82%. Out of
45 patient who underwent treatment, 22 patient developed recurrence which is 48.9%.
Conclusions:
There is a dearth of randomized controlled trials supporting the efficacy of epidermal Growth factor in
preventing keloid recurrence. The subjective improvements seen in some cases are encouraging. This study will be a
foundation for future studies and will highlight the breadth of knowledge yet to be explored by this therapy.
Keywords: Keloid, Excision, Epidermal growth factor, Recurrence rates
Department of Plastic and Reconstructive Surgery, Government Medical College Thiruvananthapuram, Kerala, India
Received: 21 May 2019
Revised: 06 August 2019
Accepted: 07 August 2019
*Correspondence:
Dr. Ajayakumar Kochunarayanan,
E-mail: drakmchtvm@gmail.com
Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial
use, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI: http://dx.doi.org/10.18203/2349-2902.isj20194076
Joseph A et al. Int Surg J. 2019 Sep;6(9):3341-3346
International Surgery Journal | September 2019 | Vol 6 | Issue 9 Page 3342
low-dose radiotherapy to the keloid excision wound
immediately after excision has been shown in to reduce
the rate of recurrence. The risks of ionizing radiations
including the potential for malignant transformation,
warrants caution and the need for further study. In adults
with lesions refractory to other modalities, radiation
therapy still offers a chance. Cryotherapy is now accepted
as a low-cost and effective method of treating keloid scar.
When treated with liquid nitrogen, complete flattening or
greater than 80% volume reduction occurred in 73–85%
of lesions are shown in multiple prospective studies.1, 2
The effect of lasers in keloids have been studies for years
but large multi-centric studies are lacking Though in
clinical practice laser is well accepted modality for
treating all types of scars, clinical studies quantifying its
effectiveness is still lacking. Availability of many
varieties of therapeutic lasers also complicates the
matter.3In summary, there is no single modality
completely effective in keloid management, multimo-
dality approaches offer some promise and treatment
should be individualized according to patients needs and
expectations. In current management protocols, first line
is corticosteroids, silicone sheeting, and compression
garments.4 Large, recalcitrant keloids can be managed by
surgery, steroids, radiation, or other modalities and may
best be performed.
Epidermal growth factor (EGF) is a 6045 Da protein with
53 amino acid residues and three intra-molecular
disulfide bonds. The discovery led to the Nobel Prize for
Stanley Cohen.5 It is synthesized by platelets and
macrophages and stimulates collagenase secretion by
fibroblasts to remodel matrix.6 This growth factor is
important in initiating cell migration in normal wound
healing.7 It is found to be involved in positive regulation
of cell proliferation, angiogenesis, ECM biosynthesis,
and cell motility enhancing proper wound healing. EGF
might be useful to treat keloid scars, especially to prevent
occurrence rather than treatment of keloids already in
place.8 Recombinant human EGF is approved to be used
in humans for treating diabetic foots and superficial burns
and is found to be safe for local application. Local
application of recombinant Human epidermal growth
factor in keloid excision wound site may promote proper
epithelial and fibroblast proliferation and fast remodelling
of wound leading to a healthier scar.
Objectives
The objective of this study is to find out the recurrence
rates of keloids with application of epidermal growth
factor after excision and to find out if there is
improvement in scar quality in terms of POSAS score,
with application of epidermal growth factor in post-
excision keloids.
METHODS
Prospective study design was used to conduct a study in
Department of Plastic and Reconstructive Surgery of
Government Medical College, Thiruvananthapuram, from
July 2017 to December 2018. Sample size was calculated
as followed.
The recurrence rates of keloids after excision and closure
ranges from 45-100 %.4,5
Sample size is calculated by the following formula
where P=reference recurrence rate 70%, Q=(1-P), η
(Relative precision)=20%, Confidence interval=95%,
substituting all values, n=45.
Data collection tool: Data was collected from patients
using a semi structured questionnaire.
Data analysis
Appropriate statistical software (SSPS trial version) was
used for analysis of data. All quantitative variables were
expressed as mean (SD) and all categorical variables as
proportions. Paired t-test was used for determining
associations. A p value less than 0.05 will be considered
as statistically significant. Scar quality assessment was
done using patient and observer scar assessment scale
(POSAS).
Data collection process
All patients undergoing elective keloid surgery who was
in age group between 10-60 years, who gave informed
written consent and who didn’t undergo any other
modality of treatment for last two months were included
in the study. Patients with wound infection, diabetes,
immune compromised status like AIDS/HIV infections
and malignancy chemo-radiation were excluded from the
study. Skin conditions like eczema, psoriasis and other
autoimmune diseases were excluded. Patients with
conditions affecting proper wound healing like smoking,
scurvy, and collagen vascular diseases were also
excluded. Patients who were pregnant were excluded.
Keloids younger than 3 months were excluded, no upper
limit for duration of occurrence. The merits and demerits
of each available modality of treatment are explained
based on current norms of managing keloids. Those who
opt in were included in the study. A detailed history of
each patient obtained starting with history of keloid
formation, recurrence, previous treatments any
coexisting, co-morbid conditions like; diabetes mellitus,
hypertension and jaundice, family history of keloid were
asked. Both physical measurement and photographic
documentation of keloid were done. Preoperatively all
patients should undergo routine lab tests were done
before any surgery. No preoperative hair clipping or
shaving were done in the area. After painting with 5%
povidone iodine, local anaesthesia was given with 1%
lignocaine with adrenaline if not contraindicated. Keloid
Joseph A et al. Int Surg J. 2019 Sep;6(9):3341-3346
International Surgery Journal | September 2019 | Vol 6 | Issue 9 Page 3343
lesions were excised completely through the junction of
keloid and normal skin, not leaving behind any keloid
tissue. Perfect haemostasis attained. 1 ml/cm² of
epidermal growth factor gel containing recombinant
human epidermal growth factor was applied over the
entire raw area. Wound was closed with 4-0/6-0
nonabsorbable suturing of skin. No subcutaneous sutures
were placed. The treatment of wound with rEGF will be
continued for 1 week after the surgery by applying gel
over the wound every alternate day. No other treatment
modality was followed during this treatment. Wounds
were inspected by a senior plastic surgeon after 3 months
and 6 months post excision. Treatment outcome was
recorded as recurrence or no recurrence. Complications if
any were also recorded. No recurrence was defined as
scar without elevation and extension, although slight
scarring or redness present was accepted as no
recurrence. Recurrence was defined as any elevation of
the scar above normal skin or extension beyond the
original surgical wound. No major complications were
observed from the study.
RESULTS
Out of 45 patients included in the study, 16 (35.6) were
males and rest females (Figure 1). The median age of the
study population was 18.0 (with an IQR 16.0; 26.0)
(Table 1). Of these patients, keloids were caused by ear
piercing in 22 patients, following surgery in 11 patients
and rest due to trauma. 62 patients had associated wound
complications leading to keloid formation (Figure 2).
Median duration of keloids were 2 years (with an IQR
1.00; 4.00). Out of 45 patients, 12 patients had family
history of keloids (73%) (Table 2). Out of 45 patients, 8
had keloid tendency which amounts to 82% (Table 3). 23
patients underwent prior treatment for keloids of which
15 were given intralesional steroids and 10 underwent
surgery (Figure 3).
Table 1: Age distribution of patients.
Age (years)
Incidence
%
10-19
25
55.56
20-29
10
22.22
30-39
2
04.44
40-49
5
11.11
50-59
3
6.67
Total
45
100.0
Figure 1: Sex distribution.
Table 2: Family history of keloids.
Frequency
Percent
Valid percent
Cumulative percent
No
33
73.3
73.3
73.3
Yes
12
26.7
26.7
100.0
Total
45
100.0
100.0
Table 3: Keloid tendency.
Frequency
Percent
Valid Percent
Cumulative percent
No
37
82.2
82.2
82.2
Yes
8
17.8
17.8
100.0
Total
45
100.0
100.0
Table 4: Recurrence of keloids.
Frequency
Percent
Valid Percent
Cumulative percent
No
23
51.1
51.1
51.1
Yes
22
48.9
48.9
100.0
Total
45
100.0
100.0
Table 5: Comparison of gender with recurrence rates.
Gender
Total (n=45)
No recurrence (n=23)
Recurrence (n=22)
P overall
0.007
Male (%)
16 (35.6)
13 (56.5)
3 (13.6)
Female (%)
29 (64.4)
10 (43.5)
19 (86.4)
MALE
FEMALE
Joseph A et al. Int Surg J. 2019 Sep;6(9):3341-3346
International Surgery Journal | September 2019 | Vol 6 | Issue 9 Page 3344
Table 6: Comparison of recurrence with aetiology.
Total (n=45)
Ear piercing
(n=16)
Second stud
(n=6)
Surgery
(n=11)
Trauma
(n=12)
P overall
Recc:
0.059
No (%)
23 (51.1)
4 (25.0)
3 (50.0)
8 (72.7)
8 (66.7)
Yes (%)
22 (48.9)
12 (75.0)
3 (50.0)
3 (27.3)
4 (33.3)
Figure 2: Etiological correlation.
Figure 3: Previous treatment histories.
Figure 4: Recurrence of keloids after current therapy.
Out of 45 patients recurrence rate in males were 43.5%
while recurrence rates in females were 86.4%. (p overall
0.007). Out of 23 males, 52.2% had wound complications
while females had wound complication rate of 22.7%
(p=0.084). Average duration of keloids in males were
2.00 years (with IQR-1.00; 4.00) and in females it was
4.00 (IQR-1.25; 6.00). Males gave a family history rate
of 17.4% while females gave a family history of 36.4%.
Keloid tendency in males was 17.4% while in females it
was 18.2%. Out of 45 patient who underwent treatment,
22 patient developed recurrence which is 48.9% (Table 4,
Figure 4).
DISCUSSION
This study was conducted in Plastic Surgery Department
of Government Medical College Thiruvananthapuram to
determine the effect of epidermal growth factor on keloid
recurrence. Duration of study was for one and a half year.
45 patients underwent surgical excision of keloids
followed by application of epidermal growth factor over
surgical wound in the immediate post-operative period.
Recurrence of keloids was assessed at 3 months and 6
months periods and analysed.
In our study population more of females were present.
62% were females and 37% males. In literature,
prevalence of keloids is equal in both sexes.9 Increase in
female number in our study may be because of the
common practice of ear piercing in this region and
increased cosmetic concerns in females. More over ear
piercing is usually done by goldsmiths rather than
medical professionals in a hospital setup. The median age
of the study population was 18.0 (with an IQR 16.0;
26.0). Majority of patients in the study group falls in
younger age groups. 56% of the study population is
between 10-19 years of age and 24% between 20-19
years. Practice of ear piercing in and younger age group
may be attributed to increased incidence in younger
persons. Also younger people usually wish to remove
their scar marks and seek medical help often. Majority of
our patients developed keloids following ear piercing. Ear
lobule piercing as well as second stud piercing also led to
keloid formation. Majority of ear piercing was done by
gold workers in jewelleries using either needle or using
ear piercing gun. Very few patients sought medical help
for ear piercing. Following ear piercing, trauma was the
second cause of keloid formation in our study. Most of
them were untidy wounds with foreign bodies and caused
secondary infection Of the 45 cases studied, 17 patients
had some kind of wound complications after initial
injury. 14 patients had wound infection following
Surgery, ear piercing and trauma. 2 patients had foreign
body and 1 patient had stitch granuloma. Wound
infection, tension and foreign bodies in the surgical site
are well known triggering factors for fibrosis and
subsequent keloid formation.10-12 Keloids tends to occur
after months to ears after initial insult and tend to grow
during this face without any signs of regression unlike
other scars. The mean age after incidence of the keloid in
36%
13%
24%
27%
Ear lobule piercing Second Stud piercing
Surgery Trauma
0
5
10
15
20
25
NO TREATMENT TRIAMCINOLONE EXCISION SILICONE LASER
Recurrence
49%
No
recurrence
51%
Joseph A et al. Int Surg J. 2019 Sep;6(9):3341-3346
International Surgery Journal | September 2019 | Vol 6 | Issue 9 Page 3345
this study was 3.42. Maximum age was 10 years and a
minimum time period of 1 year was set to be included in
the study after the occurrence of the keloid. No definite
association between age of the keloids and chance off
recurrence were found, but early keloids tend to respond
well to certain treatment modality such as radiation and
cytotoxic drugs.13,14 There is a clear genetic background
for keloids but the exact alterations are yet to be
described.15- 17 Other studies have demonstrated reduced
expression of pro-apoptotic genes as well as differential
expression of these genes in same keloid itself. Pro-
apoptotic ADAM-12 gene up-regulation in the central
core of the Keloids are seen.18 These suggest an
important role for programmed cell death in the
progression of the disease and a genetic variability
depending on the location of the sample acquisition.
These observations suggest a genetic predisposition that
may give us further insight into the pathophysiology of
keloids. Genomic studies don’t show any particular gene
responsible for keloid formation. 12 of the study group
persons have family history of keloids in the first degree
relatives. These patient tent to have increased incidence
of recurrence and keloid tentencies. 8 out of the 12
pateints had recurrence of the disease in our study that is
67% recurrence. Tendency of the patients to form keloids
were also enquired such as keloid formation in BCG
scars and previous traumas. History of multiple keloids in
same individual is also recorded. 20% of the patients in
the study showed tendency for keloid formation. Many of
these patients also have family history of keloids in near
relatives which also supports strong genetic back ground.
Out of 45 patients, 22 didn’t undergo any modality of
treatment. Few of the patients took multimodality
treatment. 15 patients took multiple triamcinolone
injections. 10 patients underwent excision and presented
back as recurrence. Six patients used silicone products on
their scars previously and one patient used laser
previously.
Keloids are fibro-proliferative disorders very notorious
for recurrence. By the definition of the study recurrence
means any extension of the scar beyond original surgical
wound and any elevation of scar from normal
surrounding skin. Surgical removal alone as a therapy has
an overall recurrence rates ranges from 40-100%.19
Adding adjuvant therapies will reduce recurrence after
excision. Most commonly used adjuvant is Intralesional
triamcinolone which combined with surgery have a
recurrence rate of 40-50%. Giving few fractionated
radiation to the post excision scar will further reduce
recurrence up to 20% in the expense of higher
complication rates. In our current study, recurrence rates
are documented as 48.9% which is better than surgical
excision alone and comparable to other adjuvants.
This is the first study published regarding the
effectiveness of epidermal growth factor in reducing
recurrence of keloids after excision. Advantage of using
epidermal growth factor is that, it doesn’t have any
potential adverse effects recorded in the study and can be
a potential replacement for current therapies. However
this study is limited by the low sample size as well as
limited follow up period. Moreover the study is uses
qualitative assessment so observer error can be there. We
are currently continuing the study extending the follow
up period as well as sample size, also including
quantitative variable for assessing scar quality
There is a dearth of randomized controlled trials and
quantitative analysis supporting the efficacy of epidermal
Growth factor in preventing keloid recurrence after
surgical excision. However, the subjective improvements
seen in some cases are encouraging. The authors hope
that this study will be a foundation for future studies and
will highlight the breadth of knowledge yet to be
explored by this therapy.
CONCLUSION
Keloids are an important cosmetic problem in our society
and recurrence is very common whatever may be the
treatment modality offered. Novel treatment involving
growth factors and immunomodulators are going to be
the key to the future.
This study enlighten into the possibility of using
epidermal growth factors in reducing recurrence rates of
keloids. Though the study is limited with small sample
size and short follow up period, this study can be used as
a step stone to large randomized controlled trials
regarding feasibility of using epidermal growth factor in
treating resistant keloids in the future.
ACKNOWLEDGEMENTS
I am grateful to Almighty for the help showered upon me
for this project. I express my sincere gratitude to my
beloved teacher Dr. Ajayakumar K Professor of
Department of Plastic and Reconstructive Surgery for his
kind guidance, inspiration and support throughout the
study. I am extremely thankful to Dr I. P Yadev sir
Associate professor Department of General Surgery for
analysing the study and guiding the formatting. I am
thankful to my beloved Head of the Department, Dr.
Aniraj R who inspired me to the core. I am thankful to all
the Faculties, Post Graduates, and other staff of
Department of Plastic and Reconstructive Surgery for the
great assistance and help given, without which this study
would not have materialized. Above all, I am indebted to
all Patients, and their caretakers and operation theatre
staff who participated in this study with their kind
cooperation. I am thankful to my parents and wife who
have been my pillars of strength throughout my life.
Funding: No funding sources
Conflict of interest: None declared
Ethical approval: The study was approved by the
Institutional Ethics Committee
Joseph A et al. Int Surg J. 2019 Sep;6(9):3341-3346
International Surgery Journal | September 2019 | Vol 6 | Issue 9 Page 3346
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Cite this article as: Joseph A, Kochunarayanan A,
Varghese F, Kalesh Sadasivan. Recurrence of keloids
after application of epidermal growth factor. Int Surg
J 2019;6:3341-6.
