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MINISTRY OF EDUCATION AND
THE MINISTRY OF
TRAINING
DEFENSE
Military Medical University
---------

HOANG THANH TUAN

CLINICAL, PATHOANATOMICAL
CHARACTERISTICS, AND SURGICAL
TREATMENT FOR SKIN LESION CAUSED BY
RADIOTHERAPY
Major: Surgery
Code: 9720104

SUMMARY OF MEDICAL DOCTORAL THESIS

Hanoi - 2020


THIS RESEARCH WORKS IS ACCOMPLISHED AT:

Science instructor:
1. Assoc. Prof. Dr. Vu Quang Vinh
2. Assoc. Prof. Dr. Trinh Tuan Dung

Reviewer 1: Assco. Prof. Dr. Le Van Doan
Reviewer 2: Prof. Dr. Le Trung Hai
Reviewer 3: Assco. Prof. Dr. Ta Van To

The dissertation will be defended before School-level Thesis Council
at the Military Medical University.
At ... hour ..., day ... month ... year 2020.

The thesis can be found at:
1. The National Library of VietNam
2. Library of Military Medical University


1
INTRODUCTION
Radiotherapy is the method of using ionizing radiation to kill
cancer cells, which is one of the important modalities in the treatment
of malignant tumors. However, Apart from affecting the tumor,
radiotherapy also affects the surrounding healthy tissue, including the
skin and subcutaneous structures - at the irradiated location. Chronic
manifestations of radiotherapy-induced lesions include derma
atrophy form mild extent to the severe extent with skin ulcers and
local infection. Radiation ulcers often cannot heal on their own, due
to ischemia and poor granular tissue regeneration. Around the world,
surgical treatment for radiation-induced ulcers has achieved
remarkable results, however there are still many disagreements in the
treatment of this type of lesion. In Vietnam, there were a number of
reports on surgical treatment of chronic radiation-induced skin
lesions, but most of them were retrospective. There are unadequate
studies
on
clinical,
microorganism,
histopathological,

immunohistochemical characteristics, as well as the selection of
appropriate plastic surgery methods for this lesion. Therefore, we
conduct the thesis: " Clinical, pathoanatomiical characteristics and
surgical treatment for skin injury caused by radiotherapy ", with
two objectives:
1. Investigation
of
clinical,
histopathological
and
immunohistochemistry characteristics for chronic skin lesion
due to radiotherapy.
2. Evaluation of surgical results of flap transfer in treatment for
Radiotherapy-induced ulcers..

STRUCTURE OF THE THESIS
The thesis consists of 129 pages excluding references and
appendices, with 38 tables, 1 charts, 1 diagram, 12 images and 15
pictures. The introduction includes 2 pages; 30 pages for overview;
27 pages for subjects and research methods; 26 pages for research
results; 42 pages for discussion; 2 pages for conclusion and 1 page
for recommendation.There are 104 references, including 8
Vietnamese documents and 96 English ones.


2

Chapter 1. OVERVIEW
1.1. Overview of radiotherapy
1.1.1. Radiotherapy concept

Radiotherapy is a method using high-energy ionizing radiation to
deprive cancer cells.
1.1.2. Action mechanism of ionizing radiation
- Radiation affects the body through two mechanisms: (1) Directly
break DNA chains; (2) Indirectly form free radicals. Besides the
effect on the tumor, radiation also causes side effects on tissues and
organs at radiation site.
1.1.3. Indications for radiotherapy
- For cancer treatment: Radiotherapy alone for may be small size
tumors, inoperable cancers, symptomatic relief or in combination
with other treatments, such as surgery, chemotherapy.
- For treatment of hemangiomas: Applied from the early 20th
century. According to Lindberg S., in a study on 11.807 under-12
month children with hemangiomas recieving radiotherapy, author
found that there were 248 cases of cancer after treatment.
Radiotherapy is used only for patients with life - or function –
threatening hemangiomas
- For keloid scars
1.1.4. Systemic and local effects after radiotherapy
Side effects of radiotherapy mainly depend on the radiation dose,
the larger the dose and the more undesirable effects. Systemic effects
include fatigue, anemia, body aches, depression. The local effect can
be seen as edema skin, congestion; dry mouth, dry eyes; esophagitis..
1.2. Overview of skin lesion induced by radiotherapy
1.2.1. Normal skin histology
The skin composes 3 layers: epidermis, dermis and hypodermis.
The appendages of the skin include sebaceous gland, sweat gland,
and hair follicles.
1.2.2. Mechanism of radiotherapy-induced skin lesion
Radiation affect the young cells and rapidly divided cells, causing

damage to the germ cells of the skin and appendages, affecting
vascular endothelial cells resulting in post radiation skin lesion. In the
early stages, edema, hyperemia and congestion occur. In the late
stages, sclerosis, loss of appendages, skin ulcers is observed.
1.2.3. Diagnosis of radiotherapy-induced skin lesion


3
- Acute skin lesion: Occurs anytime, during and immediately after
radiation, which can last until 90 days post-radiotherapy. Symptoms
include: erythema, dry skin, edema, hyperpigmentation, dry or moist
desquamation, folliculitis.
- Chronic skin damage: Clinical manifestations include: skin atrophy,
vasodilation, sclerosis, pigmentation changes (increase or decrease),
hair loss, skin ulcers. Diagnostic subclinical measures such as:
Ultrasound, thermal imaging, microscopic capillary examination,
magnetic resonance imaging, bone radiography.
1.2.4. Histopathological and immunohistochemical characteristics of
chronic post-radiotherapy skin lesions
- Histopathology characteristics: Skin atrophy, capillary vasodilation,
fibrosis, pigmentation changes, reduction or loss of skin appendages,
vascular lesions, radiation fibroblasts.
- Immunohistochemistry: Assessment of vascular lesions through the
expression of CD31 and CD34. Quarmby S. (1999) and Gaugler
M.H. (2004) showed that CD31 plays an important role in adhering
platelet to vascular endothelial cells and involves the endothelial cell
proliferation. Allan (2009) showed that the increased CD34 led to
repeated inflammatory reactions causing tissular edema, forming
foam cells leading to the endoluminal protrusion of endothelial cells.
1.2.5. Staging and extent of lesion

- Dasgeb B. (2008) divided radiotherapy-induced damage into 3
stages: acute dermatitis, chronic dermatitis, necrosis and fibrosis.
- Matthews M. (2009) graded them into 3 stages: acute (first 6
months), subacute (second 6 months) and chronic (over 1 year).
- Saunder (2003) grouped them into 3 grades:
Grade 1: Skin atrophy, sclerosis, darkening, hair loss.
Grade 2: Small long-lasting ulcer (<7.5 cm in diameter), (chronic)
thickened skin atrophy, without bone lesion.
Grade 3: Longer-lasting ulcer (≥7.5 cm in diameter), deep-developed
ulcer to the bone and lower body.
1.2.6. Other radiotherapy-induced lesion
Apart from skin lesions after radiotherapy, there are also other lesions
such as mucosal lesions of head and neck cancer, lymphatic edema after
radiotherapy, fibrosis nerves plexus common in radiotherapy patients for
treatment of breast cancer, bone damage, secondary cancer after
radiotherapy.


4
1.3. Surgical treatment for chronic radiotherapy-induced ulcers
1.3.1. Effect of radiotherapy on wound healing
Repeated inflammatory reactions result from radiation exposure,
which in turn increase the body's inflammatory response, cell
reproductive and regenerative disorders causing tissular edema.
Radiation prevents platelet flow to the wound, delaying wound
healing. Radiotherapy also reduces fibroblasts, the elasticity of
wounds, causing vascular wall edema, stasis and vascular occlusion.
1.3.2. Overview of surgical treatment for radiotherapy-induced
chronic ulcer in the world and in Vietnam
Surgical treatment for radiotherapy-induced chronic ulcers has

achieved significant progress, but there are still many controversial
views. Currently, there are no officially approved and unified
guidelines about the surgical treatment for lesion.
- Harashina T. (1981), reported the treatment on 7 patients with chest
and armpit ulcers with a latissimus dorsi free flap, combined with a
partial thickness skin graft, showed a completely living flap, with
some broken grafted skin without regraft.
- Strawberry C.W. reported 6 of 52 patients with cervical radiationinduced ulcers were successfully treated with local skin flap or skin
graft. The remaining 46 patients required a musculocutaneous flap
transfer including pectoralis major and latissimus dorsi flaps, whit
good results.
- Wei K.C (2016), conducted a research on 13 cases of radiationinduced ulcers. The authors concluded that removal of all lesion area
was the most important in the surgical treatment for radiationinduced ulcers, while in his research, covering by varied methods had
no difference.
- Vu Ngoc Lam also reported treatment outcome for 36 patients with
post-radiotherapy chronic maxillofacial lesions.
* Consistent view of treatment
Fujioka M. in 2014 and Wei K.C. in 2016 agreed to eliminate
radiation-induced ulcers. It can be listed as follows:
- Completely remove the width and depth of the damaged tissue.
- Prevent infection, malignant diseases, control pain, close wounds.
- Ineffective treatment in case of local ulcer care alone.
* Inconsistent view of treatment
- Wei K.C. (2016), covering defects is not as important as removing
lesions completely.


5
- Zhou Y. (2019), 2-stage plastic surgery with great omental flap
combined with skin grafts is less complicated than 1-stage skin flap

transfer. According to Strawberry et al., a flap is required to treat
radiation-induced ulcers because of the inadequate amount of oxygen
and nutrient at previously irradiated wounds.
- Fujioka M. (2012): In the surgical treatment for radiation-induced
skin lesions, it is necessary to completely remove the entire lesion area
then cover immediately with a single constant vascular pedicle flap.
1.3.3. Management of chronic post-radiotherapy lesions
- Complete excision of lesion both in width and depth is important in
treating radiation-induced skin lesions.
- Wei K.C. (2016), ablation should be at least 2 cm in depth, but it
depends on the anatomy region. Fujioka M. (2012), it is necessary to
remove all infiltrated skin area, damaged bones and cartilage to
ensure the cleanest wounds before covering.
1.3.4. Plasty techniques of covering post-resection defects
- Skin grafts: Most authors in the world said that skin grafting was
not effective in covering defects in treatment of radiation-induced
ulcers. According Strawberry C.W., the failure rate was nearly 100%.
- Direct closure: This technique has low efficacy and high failure
rate. Di Meo L. (1984) showed that: Direct closure has been
employed with rare sucess and many complications because of poor
vascularization at the lesion area.
- Plasty technique with random flap:
+ Advantages: Softness and elasticity of the flap is compatible with
the damaged skin, the surgery is simple and easy.
+ Disadvantages: Limited area, direction and rotation of the flap.
- Plasty technique with expander flap
+ Advantages: Avoid large lesions area during surgery, without
affecting the function of the flap area. MacMillan R.W. revealed that
(1986), peri-lesion skin expansion shall provide tissue with well
supplied vessels for the ulceration.

+ Disadvantages: Non-applicable to lesioned areas without hard
base. It needs 2 times surgery, with the risk of bleeding, exposed
cutaneous dilatation and infection.
- Plastic surgery with seamless pedicle flaps:


6
+ Advantages: Properties of the flap remains unchanged, thus
ensuring the aesthetics and functionality, without secondary
retraction. A great volume of flap can be obtained.
+ Disadvantages: Limited coverage; badly scarred donor site;
difficult direct closure.
- Plasty with perforator skin flaps:
+ Advantages: Widely used, diverse choices, without sacrificing any
blood vessels.
+ Disadvantages: Perilesional sclerosis, vascular lesions. Therefore,
perforator flap is recommended in case perforator branches far away
from the lesion area are detected.
- Free flap transfer with vascular microsurgery: The application of
the microsurgical flap transfer allows the surgeon to select the best
suitable tissue for the area and reconstruct of the lesion. The most
difficulty of this technique is to find a vascular supply on a sclerotic
base. Micro-surgical flap is often applied to the treatment of head and
neck ulcers.

Chapter 2. SUBJECT AND METHODS OF THE
RESEARCH
2.1. Research subjects
30 patients with chronic skin lesions due to cancer and
hemangioma radiotherapy, of them 24 patients were ulcers and 6

patients with non-ulcerative skin atrophy. Patients were treated at
Plastic - Aesthetic and Reconstruction surgery center, National Burn
Hospital from February 2014 to September 2017. All the patients
were evaluated lesion characteristics. The result of flap transfer
surgery and the treatment on 24 patients with chronic ulcers due to
cancer radiotherapy was also assessed.
2.1.1. Selective criteria
Patients with skin lesions due to cancer and hemangioma
radiotherapy, undergoing surgery were enrolled in the study
2.1.2. Exclusion criteria
- Patient with skin lesions but in the process of cancer treatment
- Patients with metastatic cancer.
- Patient were not healthy enough to perform surgery.
- Patients not agree to participate in the study.
2.2. research methods


7
Prospective research, clinical intervention, non-control group.
2.2.1. Clinical characteristics study
Describing the characteristics of clinical lesions on 30 patients
with radiation-induced skin lesions, including: Age, gender,
pathology indicated for radiotherapy, type of radiotherapy machine,
characteristics of lesion location, grading lesion levels related factors,
time of lesion appearance, time of ulcer formation (24 patients),
lesion area, ulcer area, previous ulcer treatment methods and its
therapeutic effect.
2.2.2. Determining microbiological, histopathological and
immunohistochemical characteristics
- Microbiological: Identifying bacteria and make bacterial culture.

- Histopathology: Evaluating characteristics of chronic radiationinduced skin lesions on 30 patients, the cancer situation at the
preoperative ulcers, characteristics of ulcerative structure (24
patients), and basic evidences to redefine lesion removal limit in the
clinic.
- Immunohistochemistry: Assessing vascular lesions through the
hyper expression of CD31 and CD34 antigen markers in vascular
endothelial cells.
2.2.3. Evaluation of flap transfer surgical results in treatment of
chronic radiation-induced ulcer
- Lesion management: Complete excision of the entire lesion area
both vertically and deeply. Its goal is to prevent cancer from
recurrence, help the healing faster.
- Surgical method selection:
+ Local flap transfer: lesions of grade I, II, narrow infiltrated
area, good elastic peripheral skin.
+ Flap transfer with seamless vascular pedicle: Applied for
defects in average and large area, at locations where a seamless
periocular skin flaps can be designed around the usable lesions.
+ Skin flap of perforator branches: For defects in average width,
with perilesional softness, identifiable appropriate perforator skin
flap, capable of covering the defect.
+ Microsurgical vascular flap transfer: Cases of deep lesions
with exposed bone or important organs, extensive lesions or aesthetic
requirements, but skin flap with unfeasible vascular pedicle.


8
+ Tissue expander: Applied for long, narrow lesions, less sclerotic
areas around but local flap transfer method cannot be used. Usually
applied to polyvascular areas, surrounding elastic skin areas like the

regions of head, face, neck and minor lesions like hemangioma
radiotherapy.
- Surgical treatment for radiation-induced ulcers with flap transfer:
Assess the defected area, then select the flap according to the position
of the lesion, handle flap area: closed suture or combined with skin
grafts.
- Postoperative care: Using antibiotics according to bacterial culture,
high doses, broad spectrum. Systemic and local follow-up. Assessing
the flap status, in-site complication, flap removal area.
- Assessment of the flap transfer surgery result: According to criteria
as reported by Nguyen Gia Tien and Tran Van Anh.
+ Flap condition: complete survival, partial or total necrosis.
+Healing wound: primary intention, secondary intention or
unhealing.
+ Evaluation of accidents during surgery; local complications.
+ Assessment of failure; drainage time, length of hospital stay,
total number of surgeries.
+ Monitoring results after 3 months, 6 months and 24 months:
Recurrent ulcers, scar properties, flap mobility.
2.2.4. Data processing
Data were entered using Epi Data 3.1, managed and analyzed on
SPSS 20.0
2.3. Research ethics
Research ensures compliance with ethical principles in
biomedical research. Patient's personal information is encrypted,
confidential and served for research purposes only. Patients are
clearly explained about the purpose of the study and voluntarily
participated in the study. The patient has the right to stop
participating in the study at any time, without discrimination in care
and treatment.

9

Chapter 3. RESULTS
3.1. Clinical features, pathological surgery of chronic radiationinduced skin lesions
3.1.2. Causes of radiotherapy and lesion site
Table 3.3. Location of the lesion
Location
Number of patients
Percentage (%)
Chest wall
14
46.7
Head-face-neck
10
33.3
Limbs
3
10
Sacro-coccyx
3
10
Total
30
100
Lesions in the chest area were the most common (46.7%), mainly found in
patients undergoing radiotherapy for breast cancer (13 patients).
3.1.3. Extent of the lesion and related factors
Table 3.4. Extent of the lesion classified by Saunder 2003

Extent of the lesion
Number of patients
Rate (%)
Grade I
6
20
Grade II
9
30
80
Grade III
15
50
Total
30
100
Patients with grade II and III lesions accounted for 80% of the
participants.
3.1.4. Characteristics of radiotherapy-induced ulcer
Table 3.12. Depth of the ulcer (n = 24)
Depth of the ulcer
Number of patients (%)
Skin, muscle
10 (41,67%)
Skin, muscles, bone
12 (50%)
Skin, muscle, bone, deeper
2 (8,33%)
Total
24 (100%)

Up to 50% of radiation-induced ulcers invaded deeply into
muscle tissue and bone. In particular, there were 2 patients with per
costal deep ulcers to the pericardium and parietal pleura.
- Bacterial culture: Out of 24 ulcers with bacterial culture on site, 23
samples grew bacteria (95.8%). Of which, 10 samples were S. aureus,
11 samples of P. aeruginosa, and 2 samples on both types of bacteria.
3.1.5. Histopathology


10
3.1.5.1. Results of preoperative ulcer biopsy
Table 3.17. Results of pre-operative ulcer biopsy (n=24)
Persistence of radiation-induced
n
ulcerative cancer
Poorly differentiated squamous cell
1
carcinoma
Type of cancer
Lowly differentiated adenocarcinoma 1
Poorly differentiated carcinoma
1
Secondary cancer
0
No cancer
21
Total
24
Among 24 patients with radiotherapy related-ulcers, 3 cases (12.5%)
were still cancerous, no case with secondary cancer was detected .

3.1.5.2. Biopsy results at ulcerative center
Table 3.18. Histopathological image of ulcerative center (n = 24)
Lesion
Image of
Epithelial
Chronic
Necrosis granular
discontinuity cellulitis
Expression
tissue
Yes
24
24
24
0
No
0
0
0
24
Total
24
24
24
24
The ulcerative center was characterized by epithelial discontinuity,
infiltrated chronic cellulitis, central necrosis and especially without
granular tissue.
3.1.5.3. Biopsy results at infiltrated and marginal areas

Table 3.20: Vascular lesions of infiltrated and marginal regions
Lesional areas
Vascular lesions
Wall
Embolism
Obstruction
thickening
N
%
N
%
N
%
Infiltrated region
22
73,33
21
70
7
23,33
Marginal region
1
3,33
6
20
29
96,67
In the infiltrated region, the main lesions were embolism (73.33%)
and vascular obstruction (70%). At the margins, the main lesion was
vascular wall thickening (96.67%).

11
3.1.6. Immunohistochemical examination to evaluate radiationinduced vascular lesion
Table 3.21. Proportion of blood vessel area positive with CD31
per unit volume (SVCD31)
Central
Infiltrated
Marginal
Antigen
region (1)
region (2)
region (3)
Sv (mm-1)
5.3
2.9
1.7
Relative error
1.97%
2.66%
3.43%
with p=0.05
p (T test)
p1-3 < 0.0001; p2-3 < 0.0001; p1-2 < 0.0001
The expression level of CD31 antigen marker increased gradually
from the marginal to the infiltrated and central region.
- The expression level of CD34 antigen marker also increased
gradually from the marginal to the infiltrated and central region.
3.2. Results of flap transfer surgery in treatment of radiationinduced chronic ulcer
3.2.2. Flap selection according to the location of lesion and

management of the flap donor site
Table 3.28. Flap selection according to the location of lesion
Location Head
Saccro- Lower
Percentage
and Chest
Total
coccyx limbs
(%)
Flap type
neck
Perforator flap
3
2
3
3
11
42.30
Pedicled flap
8
8
30.80
Local flap
1
3
1
5
19.20
Expander flap
1

1
3.85
Microsurgical
1
1
3.85
flap
Total
6
13
3
4
26
100
The pedicled and perforator flaps were the main choice (73.1%),
followed by the local and microsurgical flaps.
Table 3.29. Methods for managing flap donor sites (free flap,
pedicled flap, perforator flap)
Method of management
Number
Percentage (%)
Closed suture
8
40
Narrowing suture + skin grafting
12
60


12

Total
20
100
Closed suture for the flap donor was performed in 60% of the cases,
the remaining 40% required partial thickness skin autografting.
3.2.3. Skin flap and wound healing conditions
Table 3.31. Flap condition
Flap condition Complete
Partial necrosis Total necrosis
survival
Total
N
%
N
(%)
N
(%)
Type of flap
Perforator flap
10 90.9
1
9.09
11
Pedicled flap
7
87.5
1
12.5
8
Local flap

5
100
5
Expander flap
1
1
Microsurgical flap
1
1
Total
24 (92.4)
1 (3.8)
1 (3.8)
26
24/26 complete survival flap. 2 cases of partial or total flap necrosis
needed to be operated for a second time by new flap transfer.
Table 3.32. Condition of post-grafted wound healing
Process of wound healing
Number
Percentage (%)
Wound
Primary
14
58.33
91.67
Secondly
8
33.34
healing
Non-healing

2
8.33
Total
24
100
The rate of post-grafted wound healing reached 91.67%, non-healing
surgical wound was found in only 2 patients (8.33%) due to necrosis.
3.2.4. Accidents and complications
Post-operative
Number of
Percentage (%)
complications
patient
Infection
5
19.2
Fistula incision
2
7.7
Burst incision
2
7.7
Fluid accumulation, edema
2
7.7
Hematoma at donor site
0
0
Hematoma at recipient site
0

0


13
Partial necrosis
1
3.85
Total necrosis
1
3.85
Total
13
50
Out of 26 grafted flaps, the complication encountered was mostly
infection (19.2%), 7.7% had fistula incision, ulcerative incision, fluid
collection and edema. Both partial and total necrosis occurred in 1
case.
3.2.6. Results after 3 months, 6 months and 24 months’ surgery
Ulcerative recurrence: No cases of recurrent ulcer occurred after 3
months and 6 months discharged; 10 patients with a 24-month
follow-up did not develop ulcerative recurrence

Chapter 4. DISCUSSION
4.1. Clinical features, pathological surgery of chronic radiationinduced skin lesions.
4.1.1. The distribution by age and gender of the study patient group
The average age of patients in the study was 49.96 ± 18.52, of
which that of the hemangioma radiotherapy group was 22.2 ± 8.4;
and 55.5 ± 14.5 in the cancer radiotherapy group. This showed that
the average age of the research group was middle-aged, which has a
high risk of cancer.

4.1.2. Causes of radiotherapy and lesion position
There were 25 patients with skin lesion due to cancer
radiotherapy, only 5 patients with skin lesions due to hemangioma.
The lesions were mainly in the chest area (14 patients,  46.7%),
followed by the head-face- neck area (10 patient, accounted for
33.3%), the rest were limbs and other regions. The reason was that
these patients developed diseases after breast and head cancer
treatment, similar to Gorgun B.’s findings (1989).
4.1.3. The factors affecting the lesion level
- Radiotherapy indication: Cancer radiotherapy causes more serious
damage than hemangioma radiotherapy, because the total radiation
dose of the former is much higher than the dosage of the latter.
Therefore, the higher the total radiation dose, the more severe the
lesional extent to healthy tissue.


14
- Radiation position: The lesion was mainly in the chest and
sacrococcyx areas, which are the compressed area on the bone base.
This result was similar to Roberts W.S. (1991). The authors believed
that ulcers often appear in compressed areas, subject to much friction,
wet areas or on bone base.
- Radiotherapy machine: Cobalt 60 machine causes more serious skin
damage than accelerators. Therefore, Cobalt 60 was replaced
gradually by linear accelerators, more modern, with fewer side
effects.
4.1.4. Lesion area
The local lesion due to radiotherapy is not only the ulcer, but also
the entire infiltrated area, the sclerosis surrounding the ulcer.
Therefore, the post-radiotherapy local lesion area covers both the

ulcer area and the infiltrated area. In our study, the average ulcerative
area is 35.4 ± 36.8 cm 2, of which the largest 150 cm2. The average
lesional area is 103.6 ± 76.4 cm 2, with the largest 300 cm 2. It can be
seen that although the ulcer is not large, the surrounding infiltration
area can spread many times the size of main ulcer.
4.1.5. Histopathological characteristics at the ulcer site
Typical images of common chronic skin ulcer: continuous
epithelial loss, infiltration of chronic inflammatory cells such as
monocytes, lymphocytes, at the ulcer center with necrotic tissue. In
addition, No granule tissue image in all 24/24 samples at the ulcer
center. Therefore, radiation-induced ulcer, even small one can not
heal itself; in addition, removing necrotic tissue and then wait for
granule organization for skin grafting is not as effective as for other
common chronic ulcers.
4.1.6. Histopathological characteristics of infiltrated areas
- Skin atrophy: This is a post radiotherapy common complication, the
most common image is wrinkled skin, then desquamation dry skin.
This condition was observed in all 30 patients, similar to the Frazier
T.H.'s finding (2007). Skin atrophy impacts on the process of healing,
leads to delayed healing time of wounds or ulcers.The fibrous dermis
will lead to anemia and skin atrophy, causing the later ulcerative
formation.


15
- Sclerosis: On histopathology, found on 22/30 patients, there was a
phenomenon of elastic fibers lesions of the skin, change of epidermis
such as local atypical hyperkeratosis and local dermatitis and
keratosis disorders
- Pigmentation cell changes: There are 26 biopsy samples of

hyperpigmentation (80%), 4 samples of hypopigmentation. The post
radiotherapy hyper or hypopigmentation is not a typical
manifestation, so it is a factor to assess the extent of radiotherapyinduced lesion.
- Skin appendage lesion: All 30 patients were not subjected to hair
follicles, sebaceous glands as well as sweat glands in the infiltrated area.
- Radiation fibroblasts: This is a feature of radiotherapy-induced
chronic dermatitis, deformed fibroblasts with atypical large nuclei
and alkaline cytoplasm. 13/30 specimens had this image in the
infiltrated area.
4.1.7. Histopathological characteristics of margin areas
The basal lesion margin was significantly reduced compared to
the infiltrated area. The remaining lesions were mainly
hyperpigmentation (66.67%), adnexal damage (50%), atrophy of the
skin (33.33%). In particular, we did not see radiation fibroblast
lesions - a feature of ulcerative radiation
4.1.8. Condition of subcutaneous blood vesels lesion due to
radiotherapy
- Histopathology: Blood vessels lesion is a characteristic of radiationinduced skin lesion that reduces circulation flow, parenchyma
atrophy, fibrosis and tissue necrosis at the irradiated site, leading to
complications such as ulcers and secondary cancer. The blood vessels
lesions of the infiltrated region were mainly occlusive images
(73.3%), embolization images (70%). At the marginal area, the lesion
was mostly wall thickening. There was only one case of embolism
among 30 samples. From the above results, it showed that: infiltrated
area included severe blood vessels lesions with few healthy blood
vessels, unable to ensure blood supply to the the edge of incision.
- Immunohistochemistry: The ratio of blood vessels area and length
positive to CD31 and CD34 on vascular endothelial cell membrane

16
that gradually decreased from the central lesion to the fringe area,
this difference was statistically significant. Vascular lesions in the
central, the infiltrated and marginal areas were at different extents, of
which the marginal region having the least vascular lesions. CD31 is
an important factor in increasing platelet adhesion, contributing to
increased thrombosis and tissue damage. Increased CD34 is
associated with chronic inflammatory response, Resulting in foam
cell proliferation, leading to the emergence of endothelial cells into
the vessel lumen causing embolization.
4.1.9. Features of chronic radiation-induced ulcer
- Ulcer appearance time: The average was 9 years and 8 months after
radiotherapy, 12 patients (50%) developed ulcers after 5 years
radiotherapy. This showed the dull and prolonged pathological
progression of the disease, might develop acute and subacute postirradiated lesions, which repaired themselves, but the chronic lesions
may last many years later.
- The progress of radiotherapy-induced ulcers: Up to 16/24 patients
were hospitalized after more than 1 year of ulcer appearance. Most
patients were treated previously with bandages and antibiotics, but
there was no improvement, and ulcer to be worse. Zhou Y. (2019)
said that radiation-induced ulcer care only made the ulcer wider,
which was explained by local ischemia, leading to a reduction in the
anti-inflammatory cells. Therefore, we totally agreed with
international authors that conservative treatment for chronic
radiotherapy-induced ulcers is not effective.
- Depth of the ulcer: The majority of ulcers in the study group were
deeply damaged to the bone (14/24 patients, accounting for 58.33%).
of whom, 2 patients with deep bone-pierced lesions to the internal
organs, 1 patient with deep ulcer to the pericardium, 1 patient with
ulcer to the pleura. This result is similar to Ma X.’s report (2017).

Thus, radiotherapy not only affects the skin, subcutaneous structure
but also has a deeper impact, causing damage to muscles, bones as
well as the organs below irradiated area.


17
- Ulcer infection: Infection is a typical feature of an ulcer. Among 24
ulcers with bacterial culture, the bacterial growth rate was 95.8%,
mainly S. aureus and P. aeruginosa, which was similar to Narushima
M. and Motegi S.I.’s report. Local infections of chronic radiationinduced ulcers were severe and in poor response to antibiotics
because the radiation caused damage to the vessel lesions, limited the
cell division, leading to the decrease of protector cells, replaced with
chronic cellulitis and fibrosis. Therefore, during the surgery, it is
necessary to remove all these lesions, use good supply flaps,
antibiotics according to antibiogram and post-operative hyper basic
oxygen therapy, which are good measures to improve this infection
status.
- Cancer status at the ulcer: The biopsy of the radiation-induced
ulcer to assess the pre-operative ulcerative cancer status is a
mandatory indication, to investigate the situation of on-site cancer,
then, to plan the most suitable and best treatment for each patient.
Among 24 patients with radiotherapy ulcers, there remains ulcerative
cancer in 3 cases (12.5%) including: 1 patient with poorly
differentiated squamous cell cancer, 1 patient with low differentiated
adenocarcinoma, 1 patient with poorly differentiated carcinoma.
In summary, study results of the clinical features, microorganisms,
histopathology, immunohistochemistry of radiation-induced skin
lesions, indicated that the progression of radiation-induced skin
lesions is dull, chronic, lasting many years. Throughout this process,
ischemia, bacterial infection and necrosis, ulcers are commons and

may occur on their own or after a trauma.
4.2. Evaluation of flap surgical results for flap transfer ulcer due to
radiotherapy
4.2.1. How to do surgery for treating radiotherapy-induced lesions?
Treatment of radiation-induced skin lesions requires removal of
all ulcers and infiltrated area in both width and depth. According to
Wei K.C, the most severely affected area is within 2 cm of the skin
surface, so the depth should be removed is at least 2 cm. However, on
the clinical fact, removal of the lesion in depth must be based on each


18
specific case, each position and level of specific lesion. 3 patients
with ulcerative cancer were consulted by oncologists and evaluated
the stage of cancer, the degree of invasion, metastasis of cancer cell,
then underwent the surgery for removing tumor and lesional area in
both width and depth, no patient had lymph node metastases. .
4.2.2. What type of flap should be used in treatment of radiotherapyinduced ulcer?
The majority of authors in the world agreed that using wellsupplied flap is necessary to immediately cover the defect after
removal of the lesion. Of 24 patients, we used 26 skin flaps (because
2 necrotic flaps needed to be replaced by others). Including 11
perforator skin flaps (42.3%), 8 pedicled flaps (30.8%), 5 local flap
(19.02%), 1 expander flap (3.85%), 1 microsurgical flap (3.85%).
4.2.2.1. Flap selection in plasty covering the chest area
With 12 thoracic defects, we needed to use 13 skin flap (2
perforator flaps, 8 pedicled flaps, 3 local flaps), including 8
latissimus dorsi flaps (61.53%). Among these flaps 7 well-survived
flaps, 1 total necrosis, success rate reached 87.5%. In the world, for
chest defects, the majority of authors choose latissimus dorsi flaps,
often used for all lesions in the chest wall because of less damage to

the flap area, rich and constant vascular system.
4.2.2.2. Head, face and neck surgery
With chronic radiation-induced ulcers in the head or mid-face
area, micro-surgical flap transfer is recommended for plastic surgery.
Among 6 patients with head and neck ulcerative lesions, 1 patient
with submaxillary ulcer was applied antero-internal femoral flap, and
1 patient with neck ulcer was covered with perforator flap of the
superficial cervical artery, which had good results. Vu Ngoc Lam did
a research on 15 patients using 13 microsurgical flaps and 3 pedicled
flap for treating radiation-induced cervico-facial ulcers, including 8
fibular flaps, 5 antero-external thin flaps, 2 great pectoral muscle
flaps. Bourget A. (2011), more than 137 patients required post
radiotherapy maxilla-facial surgery were indicated to use microsurgical flap. In summary, for head and neck radiation-induced


19
ulcerative plasty whereas microsurgical skin flap for the facial area is
the best choice, with the neck area, the top priority is given to the
constant pedicle-supplied flap.
4.2.2.3. For ulcerative lesions of coccyx area after radiotherapy
In plasty for radiation-induced ulcer sacro-coccyx area, the plasty
material not only acts as a good healing but also to well withstand
leaning and bearing pressure. According to many authors in the world,
the musculo-cutanous flap of the gluteus maximus are the most
important ones for covering sacro- coccygeal ulcers. Today, the gluteal
artery perforator (GAP), which is able to preserve the gluteus almost
intact, with the minimum degree of lesion at the flap removal site, has
been widely used in ulcerative plasty at the sacro- coccygeal area.
4.2.2.4. Reconstruction of lower extremities ulcers
Among 3 patients with lower limb ulcers, 2 patients were used

the perforator flap, 1 patient used the local flap, the result showed
that there is 1 flap with distal necrosis needing another flap transfer
surgery for distal plasty, 2 others had well healed incisions. Hence,
thanks to the abundance of perforator branches, using perforator flap
brings many advantages for the lower limb ulcer plasty. In the thigh
area, we can use the perforator flap of antero-external, posterior
femoral and descending genicular arteries. In the lower leg area, the
perforator skin flap of the anterior and posterior tibial or fibular
arteries can be used.
4.2.3. Status of flap donor site
The selection of skin flap not only meets the requirements of the
covering position but also ensures the restoration of the flap donating
area as well. There are 2 methods of management: closed and partial
suture combined with skin grafts. The study used 26 flaps, including
11 perforator flaps, 9 pedicaled flaps and 1 microsurgical flaps.
Among these 20 flaps, 8 flap donor sites can be closed by suture, 12
sites need partial suture and skin grafts. Flap donor site must be large
enough to cover the defects, however recipient flap has no or less
effect on the function of the donation site. In order to minimize the
damage to the flap donation, it is necessary to select the appropriate


20
skin flap, the flap design must be suitable for the rotator arch, the
direction and accessory wing of the flap. After the dissection, the flap
should be removed widely, with good mobility of 2 skin margins of
the donation area before partial or closed suture.
4.2.4. Condition of the flap
Among 24 ulcers, we used 26 flaps (because there was 1 flap of
total necrosis and 1 flap of partial necrosis, another two flaps were

needed). Complete survival flap reached a high percentage (92.4%).
- Pedicled flap: This is a well-supplied flap, 7 out of 8 flaps survive
well.
- Micro-surgical skin flap: Because the blood vessels in irradiated
area is damaged, using this flap will be difficult. In the study, 1
patient receiving microsurgical flap brought good results.
- Perofator flap: Due to local vascular lesions, it was not easy to
select the near-ulcer perforator branches, but thanks to the diverse
distribution of the perforator skin flaps, we used 11 perforator skin
flaps, of which 10 flaps were completely alive, only 1 flap was
partially necrotic.
- Local flap: Most authors think that the local skin flaps are less
effective. However, our study used 5 local flaps and gave all good
results. This can be explained by the fact that our patients in this
group all have narrow lesions, the perilesional skin was well elastic,
with shorter time of post-radiation.
- Expander flap: used an for 1 patient with scalp-haired ulcer.
In summary, the selection of a suitable skin flap for each patient plays
an important role in the flap transfer surgery. Good blood supplied skin
flaps such as pedicle flaps, perforator skin flap, microsurgical flaps
were the first priority. However, in certain cases, the appropriate
application of the local skin flap, expander flap still brings good
treatment results.
4.2.5. Process of healing wounds
Radiotherapy has impact on the healing process. In order to
ensure a good healing, the lesion must be managed both width and
depth, with use of well-supple flaps. 91.67% of patients had postoperative wound healing, of which 14 patients in the primary, 8


21

patients in the secondary, non-healing was found in 2 cases due to
necrotic flap to be reoperated and replaced with a different skin flap.
The wound healing invasion site was rather good incision. The
process of wound healing after flap transfer for treatment of
radiotherapy ulcer depends on many factors. To make the best wound
healing process, we needed to assess the effects of radiation on local
lesions, ablate those lesions, then use good supply flaps
4.2.6. Accidents during surgery, local complications after surgery
4.2.6.1. Intra-operative accidents.
One patient was threatened with cardiac arrest, however, was
promptly rescued. After management, the patient was stable and
continued to undergo the surgery. Besides anesthetic accidents, there
vascular lesion related accidents at the lesional site were detected.
Urayama H. (1998) reported 1 case of post radiotherapy axillary
artery lesion for breast cancer, Koh A.J. (2007) also reported 1 case
of radiation-induced vertebrobasilar artery lesion for throat cancer. In
2010, Vu Quang Vinh also reported 2 cases of axillary and carotid
arteries during surgery. Therefore, it is necessary to monitor, take
care and control accidents and complications, especially at the lesions
with inferior blood vessels (armpit, neck, groin), important organs
(chest wall) immediately after radiotherapy. When there is a sign or
risk of ulceration, it requires an early surgical treatment.
Conservative treatment is not recommended due to prolonged
duration of ulceration, infection and deep necrosis ...
4.2.6.2. Local postoperative complications
Due to the complicatedness of the lesions as well as the
characteristics of patients after cancer treatment, most authors in the
world have recorded a high rate of complications after surgical
treatment for radiation-induced ulcers. Common local complications
include infection, hematoma, edema, incision fistula, incision ulcer.

Complications of the flap consists of flap necrosis,flap hyponutrition.
The complication rate in the study was 50%, similar to Saito A.'s
report being 61%. In the study, one skin flap sufferd from distal
necrosis, although the flap necrotic area was only less than 10% of


22
the flap area, but the incision was subsequently infected and could
not be healed, requiring to be replaced with another skin flap.
4.2.7. Total number of times of surgery and drainage time
- Total Number of surgeries: In the study, 24 patients underwent 28
surgeries, average being 1.17 times. Rudolph R. treated 28 patients
undergoing 42 surgeries, average being 1.5 times. Radiation ulcer is a
complicated lesion, with a serious infection and anemia, and patients
following therapy for cancer may be in badly physical condition. All
of these factors contribute to higher failure rate, more complications
and more challenging surgical treatment.
- Drainage time: The authors approved that placing postoperative
drainage with continuous suction optimizes drain efficiency helping
the skin flap attatch to the wound base, negative pressure suction also
better stimulates angiogenesis. Drainage is retained until < 5 ml/24h.
The average time in the study was 11 ± 6.2 days.
4.2.8. Results of 3 months and 6 months after surgery
- Recurrent ulcers: Although the lesions have been removed to a
maximum, covered with good supply flaps, the ulcer may still
reappear after skin flap plastic surgery, especially in the pressure
area. Lin C.H (2012) indicated that the incidence of ulcer recurrence
was 6-56% in the sacro-coccyceal region. In our study, there were no
cases of ulcer replase.
- Scar natures: after 3 and 6 months we have not recorded any cases

of hypertrophic scars or keloid scars. 22/24 postoperative patients
had flat scars and 2 patients had concave scars on the skin surface.
This showed that the ability of regeneration and proliferation
structures around the radiotherapy lesion, of the organization was not
yet to recovered completely, because of the poor ability to
proliferation of new vessels, there is no hypertrophic scar following
the surgery.
- Mobility of the flap: The results showed poor mobility of postoperative skin flap in all 24 study subjects. There was even a case of
flap adherent firmly to the lesional base. According to a study by
Christensen on 78 breast-plasty patients, 89% of flaps were soft,


23
because these patients were used flaps of rectus abdominis where
fatty layer is thicker, so the skin flap is softer.
CONCLUSION
1. Clinical, histopathological and immunohistochemistry
characteristics of chronic radiation-induced skin lesion.
• Clinical characteristics:
- The most common lesions were in the bone base or pressure site
(56.7%), including: chest (46.7%), sacro-coccyx (10%) and lesions at
these two sites were often severe (15/17 patients with degree II - III,
accounting for 88.2%). Out of 16/30 patients treated with Cobalt 60,
there were up to 10 cases of grade III and 4 cases with grade II. In
particular, up to 24/25 cases of cancer radiotherapy had lesions of
grade II - III (96%), while hemagioma radiotherapy had only grade I
lesions (no ulcers).
- Most ulcers had severe infections, the bacteria growth rate was
95.8%, mainly S. aureus and P. aeruginosa.
• Histopathology and immunohistochemistry

- Characteristics of radiotherapy-induced ulcer: the most typical was
the absence of granular tissue. Up to 58.3% had deep ulcer in
submuscular layer, in which 2 patients with ulcer to the pericardium
and pleural walls. There were 3 cases of cancer at the ulcer.
- Level of blood vessels lesions: lesions in the infiltrated areas were
more severe, mainly occlusion (73.3%) and subocclusion (70%); less
severe lesions in the marginal region, mainly vascular wall
thickening (96.7%).
- In immunohistochemistry staining, quantitative expression of CD31
and CD34 antigens showed a remarkable difference between the two
above regions (p < 0.05).
2. Results of flap transfer to treat radiotherapy-induced chronic
ulcers
- Cover flap selection: Depending on the location of the lesion and
ulcer property the ulcer nature. However, the majority of good supply
skin flaps selected: 8 pedicled flaps, 11 perforator flaps, 1
microsurgical flap; 1 patient with opened trachea needed a plasty
with Medpor before flap transfer. Flap donor site was mainly had