Volume 71, Number 6, November-December 2019

Siriraj Medical Journal

SMJ

ISSN 2629-995XE-ISSN 2228-8082

ORIGINAL ARTICLE

432

Molecular Subtypes of Ductal Carcinoma In Situ (DCIS)

Identified by Expression of ER, PR, HER2, and Ki-67

Warapan Numprasit, et al.

438 Effect of Age on Recurrence in Hormone Receptor-Positive

Breast Cancer, and Factors Significantly Associated with

Cancer Recurrence

Warapan Numprasit, et al.

446 Outcomes of the Recombinant Human Epidermal Growth

Factor Addition to Chloramphenicol Ointment for Facial

Burn Wound Healing

Pornprom Muangman, et al.

450 Decision-making Factors in Non-operative Management of

Zygomatic Fractures

Somphon Roeksomtawin, et al.

457 Retrospective Analysis of Outcomes in Elderly Patients

with Adenocarcinoma of Stomach and Esophagogastric

Junction Following Three Different Treatments

Thammawat Parakonthun, et al.

466 The Malignant Potential in Adult Choledochal Cysts; an

Awareness Issue

Pholasith Sangserestid, et al

472 Survival and Factors Predictive of Survival in Patients with

Thymic Carcinoma

Suparauk Geanphun, et al.

480 Impact of Accuracy of Preoperative Transthoracic

Echocardigraphy on Complex Congenital Heart Surgery in

Pediatrics

Vutthipong Sanphasitvong, et al..

486 Presence of Residual Venous Thrombus at Warfarin

Withdrawal: Is It a Predictor for Recurrence After a First

Episode of Symptomatic Provoked Proximal Deep Venous

Thrombosis in the Thai Population?

Kanin Pruekprasert, et al.

491 Endovascular Thrombectomy versus Open Surgical

Thrombectomy for Thrombosed Arteriovenous

Hemodialysis Graft

Nattawut Puangpunngam, et al.

499 Outcomes of Autogenous Snuffbox Radiocephalic

Arteriovenous Fistula-First Strategy for Hemodialysis Access

Banjerd Praditsuktavorn, et al.

506 Formulaic Prediction of Z-Plasty Outcomes Relative to Z

Scar Lengthening, Z Flap Tension, and Area of Distortion,

and Determination of the Multiple Z-Plasty Configurations

that Optimally Increase Z Scar Length, Decrease Z Flap

Tension, and Decrease Area of Distortion

Nutthawut Akaranuchat, et al.

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Seigo Kitano (Oita University, Japan)

Ichizo Nishino (National Institute of Neuroscience NCNP, Japan)

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Volume 71, No.6: 2019 Siriraj Medical Journal

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432

Original Article

SMJ

Warapan Numprasit, M.D.*, Irin Chowchankit, M.D.*, Suebwong Chuthapisith, M.D.*, Malee Warnnissorn,

M.D.**, Waraporn Imruetaicharoenchoke, M.D.*

*Department of Surgery, **Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.

Molecular Subtypes of Ductal Carcinoma In Situ

(DCIS) Identied by Expression of ER, PR, HER2,

and Ki-67

ABSTRACT

Objective: e estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2

(HER2), and Ki-67 are used to classify invasive breast cancer into various subtypes. In the case of ductal carcinoma

in situ (DCIS), however, the information relating to subtypes using these markers is still limited.

Methods: e pathological specimens of 267 patients diagnosed with DCIS at Siriraj Hospital were analyzed. By

using the expressions of ER, PR, HER2, and Ki-67, breast cancer patients were classied into the ve molecular

subtypes: luminal A, luminal B/HER2 negative, luminal B/HER2 positive, HER2 overexpression, and triple-negative.

Based on the specic molecular subtypes, age, clinical presentation, tumor size, and tumor grade were analyzed

separately using univariate analysis.

Results: 135 (50.6%), 1 (0.4%), 58 (21.7%), 59 (22.1%), and 14 (5.2%) DCIS were luminal A, luminal B/HER2 negative,

luminal B/HER2 positive, HER2 overexpression, and triple-negative, respectively. Patients with luminal A DCIS

signicantly presented with mass, compared to the other subtypes that displayed with mass and microcalcication

in combination (p = 0.008). e luminal A subtype was also associated with tumors of a smaller size (less than 2

cm; p = 0.007) and a lower nuclear grade (p = 0.000) than the HER2 overexpression subtype.

Conclusion: Although luminal A DCIS was the most common DCIS subtype of ai women, HER2 overexpression

DCIS was signicantly correlated with poor clinicopathological features, including a large tumor size and a high

nuclear grade, which are recognized prognostic factors for tumor recurrence.

Keywords: Clinicopathological features; ductal carcinoma in situ; molecular subtypes; prevalence (Siriraj Med J

2019; 71: 432-437)

Corresponding author: Waraporn Imruetaicharoenchoke

E-mail: waraporn.imr@mahidol.ac.th

Received 31 May 2019 Revised 14 August 2019 Accepted 23 September 2019

ORCID ID: http://orcid.org/0000-0003-1566-5307

http://dx.doi.org/10.33192/Smj.2019.64

INTRODUCTION

DNA microarray proling of invasive breast cancer

is used to classify breast cancers into distinct subtypes that

are explicitly associated with oncological outcomes, and to

identify therapeutic options.

In addition, various studies

have conrmed that immunohistochemical staining of

paran sections are well-correlated with, and are used

as reliable surrogate markers for, molecular subtype

classications categorized by DNA microarrays.

e

staining of immunohistochemistry (IHC) applied to

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433

Numprasit et al.

pathological specimens includes antibodies for estrogen

receptor (ER), progesterone receptor (PR), human epidermal

growth factor receptor 2 (HER2), and Ki-67.

Based on the protein expressions of these IHC

markers, invasive breast cancer subtypes are categorized

into luminal A, luminal B/HER2 negative, luminal B/

HER2 positive, HER2 overexpression, and triple-negative.

Multiple previous studies have shown that luminal A has

the best prognosis and the lowest rate of locoregional

recurrence, whereas the HER2 overexpression and triple-

negative subtypes are strongly associated with a high

risk of regional recurrence and distant metastases.

3-5

Ductal carcinoma in situ (DCIS), which accounts

for 20%–25% of new breast cancer diagnoses, is the

proliferation of malignant mammary ductal epithelial cells

conned within the basement membrane.

Identication

of the predictive and prognostic markers associated with

the biology of DCIS would provide better therapeutic

options and oncological outcomes.

However, the study of subtype classications in DCIS

has been limited to date. is study primarily aimed to

establish the incidence of DCIS sorting by individual

molecular subtypes. e secondary aim was to identify

the relationship between each DCIS subtype and the

associated clinicopathological features and outcomes

in ai women.

MATERIALS AND METHODS

Data collection

A retrospective review was performed of pathological

specimens obtained from patients diagnosed with pure

DCIS at the Department of Surgery, Faculty of Medicine

Siriraj Hospital, between December 2006 and September

2012. A total of 267 pathological specimens were collected.

Protein expressions of ER, PR, HER2, and Ki-67 were

detected by IHC. Pathological specimens containing

microinvasions, extensive intraductal components

and nodal metastasis were excluded. Information on

the patient and tumor characteristics (comprising age,

clinical presentation, tumor size, and tumor grading)

was collected. is study was approved by the Ethics

Committee of the Siriraj Institutional Review Board,

Faculty of Medicine Siriraj Hospital (Si 435/2010).

Molecular subtype classication

Based on expressions of ER, PR, HER2, and Ki-67,

the tumors were classied into the following subtypes:

 luminal A: ER positive, PR positive, HER2 negative,

and Ki-67 < 14%;

 luminal B/HER2 negative: ER positive, PR positive,

HER2 negative, and Ki-67 > 14%;

 luminal B/HER2 positive: ER positive, any PR,

HER2 positive, and any Ki-67;

 HER2 overexpression: ER negative, PR negative,

and HER2 positive; and

 triple-negative: all ER, PR, and HER2 negative.

Immunohistochemistry (IHC)

IHC was performed on 3-µm formalin-xed, paran-

embedded, pathological specimens. e expression of

each marker was detected by IHC using rabbit anti-ER

monoclonal antibody (ready-to-use; clone SP1, Ventana

Laboratories, Tucson, AZ); rabbit anti-PR monoclonal

antibody (ready-to-use; clone 1E2, Ventana Laboratories,

Tucson, AZ); rabbit anti-HER2 monoclonal antibody

(ready-to-use; clone 4B5, Ventana Laboratories, Tucson,

AZ); and rabbit anti-Ki-67 monoclonal antibody (1:300

dilution; clone MIB-1, DAKO Laboratories, Carpinteria,

CA).

Interpretation of staining

According to the American Society of Clinical

Oncology and the College of American Pathologists, ER

and PR assays are considered positive if there is at least

1% positive tumor nuclei staining in the samples.

HER2

assays are considered positive if there is IHC staining

of 3+ (uniform, with intense membrane staining of

> 30% of the tumor cells), but it is considered negative

if there is IHC staining of 0 (no immunostaining) or

1+ (weak immunostaining, with < 30% of the tumor

cells stained). However, IHC staining of 2+ (complete

membrane staining, with either uniform or weak staining

in at least 10% of the cells) is considered equivocal.

this study, we did not perform in situ hybridization in all

equivocal HER2 (2+); instead, we considered equivocal

HER2 as the HER2 negative subtype. In accordance with

the invasive breast cancer subtype classication from St.

Gallen in 2011, Ki-67 was used to classify patients into 2

subtypes: low Ki-67 < 14% as luminal A, and high Ki-67

≥ 14% as luminal B/HER2 negative.

Statistical analysis

A chi-squared test was used for the binary variables

and an analysis of the variance of the continuous variables

in order to compare the clinicopathological characteristics

of the four subtypes. Univariate logistic regression

was used to determine any associations between each

molecular subtype and age, clinical presentation, tumor

size, and tumor grade. A p-value < 0.05 was considered

to be statistically signicant. All statistical analyses were

performed by SPSS Statistics for Windows, version 15.0

(SPSS Inc., Chicago, Ill., USA).

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Original Article

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RESULTS

e population baseline characteristics are described

in Table 1. Of 267 patients with DCIS, the majority

(86.5%) were over 40 years of age. e DCIS patients

more commonly presented with a combination of mass

and microcalcication (36.7%), a tumor size of generally

less than 2 cm (60.7%), and a high nuclear-grade tumor

(52.4%). The results of the IHC staining are shown

in Table 2. e number of positive specimens for ER,

PR, and HER2 was 189 (70.8%), 181 (67.8 %), and 117

(43.8%), respectively (Table 2). Aer Ki-67 staining was

performed on the 136 patients with ER/PR positive and

HER2 negative, only 1 patient (0.7%) had high Ki-67

(≥ 14%). According to the ER, PR, HER2, and Ki-67

statuses, the DCIS was divided into 4 subtypes (Table 3),

with around half of the patients (50.6%) classied as

luminal A. Table 4 illustrates the correlations between each

tumor subtype and the clinicopathological characteristics

determined by a univariate analysis. In terms of age, there

were no dierences between each molecular subtype.

Moreover, the patients diagnosed with the luminal A

subtype signicantly exhibited mass, in contrast to the

other subtypes, which presented with mass combined

with microcalcication (p = 0.008). e tumor sizes of

the luminal A and B groups were signicantly smaller

than those of DCIS carrying HER2 overexpression (p =

0.007). In addition, approximately three quarters (72.6%)

of the luminal A DCIS had a signicantly low nuclear

grade, whereas the clear majority of the pathological

specimens with the other subtypes (91.5% of those with

the HER2 overexpression, 85.7% of the triple-negative,

100% of the luminal B/HER2 negative, and 63.8% of

the luminal B/HER2 positive) displayed a high nuclear

tumor grade (p < 0.000).

DISCUSSION

Ductal carcinoma in situ, a heterogenous disease,

has similar molecular proles to invasive breast cancer by

genetic proling.

IHC staining has replaced microarray

genetic testing to classify breast cancer into 4 subtypes,

based on the expressions of ER, PR, HER2, and Ki-67.

ese surrogate markers can be used to establish the

treatment and prognosis of breast cancer.

e present study demonstrated that luminal A DCIS

was the most common subtype (50.6%), followed by HER2

overexpression (22.1%), luminal B/HER2 positive (21.7%),

triple-negative (5.2%), and luminal B/HER2 negative

(0.4%). e DCIS incidences in our study were similar

to those found by two previous studies, with luminal A

DCIS being ranked rst.

11,12

However, the current study

found that the HER2 overexpression subgroup had a

TABLE 1. Population characteristics of the 256 patients

included in this study.

TABLE 2. Results of immunohistochemistry staining

of all 267 patients in this study.

Characteristics Number (%)

Age, n (%)

 ≤40years 36(13.5)

 >40years 231(86.5)

Clinicalpresentation

 Mass 76(28.5)

 Microcalcication 93(34.8)

 Combination 98(36.7)

Tumorsize

 ≤2cm 162(60.7)

 >2cmto≤5cm 83(31.1)

 >5cm 22(8.2)

Tumorgrading

 Lowgrade 38(14.2)

 Intermediategrade 88(33.0)

 Highgrade 141(52.8)

IHC study Number (%)

 Positive 189(70.8)

 Negative 78(29.2)

 Positive 181(67.8)

 Negative 86(32.2)

HER2

 Positive 117(43.8)

 Negative 150(56.2)

Ki-67(total136)

 Low(<14%) 135(99.3)

 High 1(0.7)

Abbreviations: ER, estrogen receptor; HER2, human epidermal

growth factor 2; PR, progesterone receptor

TABLE 3. Tumors classied according to molecular

subtype.

Subtype Number (%)

LuminalA 135(50.6)

LuminalB/HER2negative 1(0.4)

LuminalB/HER2positive 58(21.7)

HER2overexpression 59(22.1)

Triple-negative 14(5.2)

Total 267

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435

TABLE 4. Univariate analysis to determine the associations between the clinicopathological features and subtypes.

Age (n%)

 ≤40years 16(11.9) 0(0) 10(17.2) 9(15.3) 1(7.1) 0.669

 >40years 119(88.1) 1(100) 48(82.8) 50(84.7) 13(92.9)

Clinicalpresentation(n%)      0.008

 Mass 47(34.8) 0(0) 15(25.9) 11(18.6) 3(21.4)

 Microcalcication 54(40.0) 0(0) 18(31.0) 18(30.5) 3(21.4)

 Combination 34(25.2) 1(100) 25(43.1) 30(50.8) 8(57.1)

Tumorsize(n%)      0.007

 ≤2cm 93(68.9) 1(100) 36(62.1) 25(42.4) 7(50.0)

 >2cmto≤5cm 34(25.2) 0(0) 18(31.0) 24(40.7) 7(50.0)

 >5cm 8(5.9) 0(0) 4(6.9) 10(16.9) 0(0)

Tumorgrade(n%)

 Lowgrade 35(25.9) 0(0) 2(3.4) 1(1.7) 0(0) <0.001

 Intermediategrade 63(46.7) 0(0) 19(32.8) 4(6.8) 2(14.3)

 Highgrade 37(27.4) 1(100) 37(63.8) 54(91.5) 12(85.7)

* p<0.05 = signicant

Clinicopathological Luminal A Luminal Luminal HER2 Triple-

Variables (n = 135) B/HER2 B/HER2 overexpression negative P-value*

(%) negative positive (n = 59) (n = 14)

(n = 1) (n = 58) (%) (%)

(%) (%)

slightly higher proportion than the corresponding gures

reported by those other publications (13% and 16%).

e dierences in the DCIS subtypes might relate to

the inequity of their prognoses; likewise, the dierences

in the molecular subtypes might predict the prognoses of

invasive breast cancers. Although the present study could

not nd any relationships between the DCIS subtypes

and prognoses due to this not being included in our

objectives, many studies, such as that by Williams et al.,

have demonstrated that luminal A DCIS had a lower

recurrence either locoregionally or in regard to distance

than the other subgroups (7.6% vs 15.5%–36.1%).

Moreover, HER2 overexpression in DCIS has been found

to be an independent prognostic factor for invasive

recurrence compared to the luminal A subtype (HR

17.8; 95% CI 2.14–148; p = 0.008).

13,14

e correlations between the clinicopathological

features and DCIS dier for the various subtypes.

15,16

In our

study, despite mass associated with microcalcication being

a major complaint of DCIS patients, the luminal A DCIS

subgroup signicantly presented with a solitary, smaller

mass. is phenomenon implies that the aggressiveness

of the disease is related to microcalcication. However,

this study could not identify the characteristics of

microcalcication, such as comedonecrosis, which is

used to determine DCIS prognoses. In addition, tumor

size was an important factor, with approximately 65%

of the luminal DCIS patients having a smaller-sized

tumor than the patients in the other subgroups (< 2 cm).

is nding suggests that the less invasive properties

of luminal DCIS, with its smaller tumor size, present a

lower risk of recurrence.

In addition, we found that a high nuclear grade was

mostly associated with the luminal B, triple-negative, and

in particular, HER2 overexpression DCIS subgroups. To

our knowledge, nuclear grade is an important factor,

with a higher grade correlating with a higher risk of

recurrence and thus being associated with poor molecular

Numprasit et al.

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Original Article

SMJ

subtypes.

Recent publications have reported that a high

nuclear grade was signicantly found in non-luminal A

subtypes, and it was considered to be an independent

predictor for overall recurrence.

15,16

In this study, we could prove a relationship between the

molecular subtypes and the clinicopathological backgrounds.

All of these ndings could predict the prognosis of DCIS;

for instance, luminal A DCIS tended to have better

clinicopathological factors. We acknowledge that patient

age, tumor size, comedonecrosis, nuclear grade, surgical

margin, and adjuvant treatment are mandatory factors

for recurrence.

e goal of treatment should therefore

be to decrease the opportunities for disease relapse.

However, the most suitable DCIS treatment approach

has been long debated, particular in the case of breast

conserving surgery (BCS).

Heretofore, there has been

strong evidence of the benet of using radiation to decrease

local recurrence, regardless of the DCIS subgroup.

20,21

On the other hand, recent reports have challenged this

standard treatment by omitting radiation from the treatment

given to some patients in light of the growing knowledge

of the distinct dierences in the risk of recurrence of each

DCIS clinicopathological subgroup.

Unfortunately,

healthcare professional teams give little consideration

to the DCIS molecular subtypes when making treatment

decisions, even though breast cancer treatment is tending

to become more personalized.

Furthermore, in the near future, decision-making

about the treatment approach for DCIS patients will

not only depend on the clinicopathological parameters

or molecular subtypes, but will also include multigene

assays, which are more specic to individuals. As an

example, Oncotype Dx can estimate the 10-year risk

of locoregional recurrence based on an analysis of 12

genes.

is can be useful for escalating or de-escalating

the treatment for DCIS patients.

This study has several limitations. Firstly, its

retrospective design presented inherent limitations,

such as missing data. In addition, the positivity of HER2

depended only on IHC; HER2 2+ on IHC was not further

conrmed with in situ hybridization, and we used the

early denition of Ki-67 score which have altered from

present recommendation, however, it was slightly change

in DCIS incidence but not eect to other study results.

Lastly, as there were no available data on recurrence,

the eects of the DCIS molecular subtypes on the risks

of locoregional recurrence could not be evaluated.

CONCLUSION

In our study, luminal A DCIS was the main DCIS

molecular subtype and was related to less aggressive

clinicopathological features. Moreover, the HER2

overexpression subtype was mostly found concomitant

with a larger tumor size and a higher nuclear grade. e

use of the ER, PR, HER2, and Ki-67 statuses on IHC

may suggest the need for further aggressive therapy for

some particular subtypes of DCIS.

ACKNOWLEDGMENTS

is study was nancially supported by the Siriraj

Hospital Research Fund of the Faculty of Medicine.

e authors thank to Mr. Suthipol Udompunthurak for

his excellent assistance with the statistical analyses. All

authors declare that there are no conicts of interest.

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Numprasit et al.

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Original Article

SMJ

Warapan Numprasit, M.D.*, Chaninporn Saengsri, M.D.*, Ng char Hong, MBChB, MS.**, Pongthep Pisarnturakit,

M.D.*

*Department of Surgery, Faculty of Medicine Siriraj Hospital Mahidol University, Bangkok 10700, ailand, **Sunway Medical Centre, Malaysia.

Effect of Age on Recurrence in Hormone Receptor-

Positive Breast Cancer, and Factors Signicantly

Associated with Cancer Recurrence

ABSTRACT

Objective: Age is an important factor for predicting survival, with worse prognosis among young women compared

to middle-aged women. Hormone receptor-positive breast cancer is the most commonly reported diagnoses among

younger women. is study aimed to investigate the eect of age on recurrence in hormone receptor-positive breast

cancer patients, and to identify its signicant related factors.

Methods: Operable hormone receptor-positive breast cancer patients who underwent surgery at the Division

of Head, Neck, and Breast Surgery, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol

University, Bangkok, ailand during 2008-2013 were retrospectively recruited. Age at diagnosis, follow-up

time, staging, tumor characteristics, treatment, and date of recurrence were collected, recorded, and analyzed.

Results: Of the 431 patients that were included, 145 patients were aged 40 years or younger, and 286 patients

were aged older than 40 years. e median follow-up time was 4.1 years. In multivariate analysis, the unadjusted

recurrence rate was higher in T3-4, node positive, high pathological grade, and lymphovascular invasion. Aer

adjusting for age, only N stage N1 remained statistically signicant (hazard ratio [HR]: 2.75, 95% condence interval

[CI]: 1.18-6.40; p=0.19). e recurrence rate was found to be non-signicantly higher in younger patients than in

older patients (11% vs. 5.6%, p=0.21).

Conclusion: e results of this study revealed no signicant dierence between age groups for recurrence-free

survival in women with hormone receptor-positive breast cancer; however, younger women did demonstrate a

higher rate of recurrence. N stage N1 is an independent predictor of cancer recurrence.

Keywords: Age; hormone receptor-positive breast cancer; recurrence (Siriraj Med J 2019; 71: 438-445)

Corresponding author: Pongthep Pisarnturakit

E-mail: pongthep.pis@mahidol.ac.th

Received 31 May 2019 Revised 19 November 2019 Accepted 20 November 2019

ORCID ID: http://orcid.org/0000-0002-2047-0849

http://dx.doi.org/10.33192/Smj.2019.65

INTRODUCTION

Breast cancer is the most common cancer among

women in ailand. Even though breast cancer more

oen occurs in women over age 50, it also aects younger

aged women. In 2018, there were 12,770 cases of breast

cancer diagnosed in women under the age of 40 in the

US.

Age is an important factor for predicting survival,

with worse prognosis among young women compared to

middle-aged women.

Some studies reported that breast

cancer among younger-aged women is usually found at a

later stage and that it has more aggressive subtypes, such

as triple negative and HER2 overexpression.

3,4

However

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439

luminal subtype or hormone receptor positive breast

cancer has been and continues to be the most common

diagnosis in this younger age group.

Hormone receptor-positive breast cancer has better

prognosis relative to survival and recurrence when

compared to other types of breast cancer.

5,6

us, the

hypothesis that the observed poor survival among young

women depends solely on cancer subtype is questionable.

Previous studies reported that hormone receptor status

aects survival outcome in early-onset breast cancer,

but their results are controversial. One large cohort

study found that younger aged patients (≤40 years) with

luminal A subtype had poorer disease-free survival and

poorer distant metastasis-free survival than patients

in the middle-aged group (41-60 years).

In contrast,

Fallahpour, et al. found mortality rate increase with

increasing age regardless of molecular subtype.

e aim of this study was to investigate the eect of

age on recurrence in hormone receptor-positive breast

cancer patients, and to identify factors signicantly

associated with cancer recurrence.

MATERIALS AND METHODS

Study design and population

is retrospective study included operable hormone

receptor-positive breast cancer patients who underwent

surgery at the Division of Head, Neck, and Breast Surgery,

Department of Surgery, Faculty of Medicine Siriraj

Hospital, Mahidol University, Bangkok, ailand during

the 2008-2013 study period. All included patients had

histologically-proven hormone receptor-positive breast

cancer. Patients with metastatic disease, with history of

neoadjuvant treatment, and/or with less than 2 years

of follow-up were excluded. e protocol for this study

was approved by the Siriraj Institutional Review Board

(Si 658/2016), and the requirement to obtain written

informed consent was waived due to the retrospective

design of this study.

Data collection

Age at diagnosis, date of last follow-up, pathological

staging, tumor characteristics, surgical treatment, adjuvant

treatment, and date of recurrence diagnosis were collected,

recorded, and analyzed.

Statistical analysis

Bivariate analysis of age, stage, tumor characteristics,

surgical treatment, adjuvant treatment, and recurrence

was performed. Statistical analyses were performed using

SPSS for Windows version 22.0 (SPSS, Inc.; IBM Corp.,

Armonk, New York, USA). Categorical variables were

compared using chi-square test or Fisher’s exact test.

Hazard ratios were used to compare recurrence between

groups. Multivariate analysis by Cox proportional hazards

model was performed to identify independent predictors

of disease recurrence. Survival analysis was performed

using the Kaplan-Meier method, with comparisons

between groups performed using log-rank analysis.

A result was considered statistically signicant it its

pvalue was less than 0.05.

RESULTS

Demographics

Of the 431 patients that were included, 145 patients

were aged 40 years or younger, and 286 patients were aged

older than 40 years. e median follow-up time was 4.1

years. ere was no signicant dierence between age

groups for T stage, N stage, lymphovascular invasion, or

hormone receptor status. e recurrence rate was found

to be non-signicantly higher in younger patients than

in older patients. Pathological grade was signicantly

higher in the younger age group than in the older age

group (p<0.001) (Table 1).

Recurrence-free survival

Recurrence-free survival at 5 years in patients aged

≤40 years was 87.3% compared with 93.1% among patients

aged >40 years (p=0.21) (Fig 1). Recurrence-free survival

was signicantly higher in both lower T stage (p=0.07)

and lower N stage (p=0.003) (Fig 2 and 3).

Univariate analysis

Univariate analysis revealed T3-4, node positive,

high pathological grade, and lymphovascular invasion

to be statistically signicantly associated with breast

cancer recurrence. e recurrence rate was found to be

higher among younger patients (11.0%) than among

older (5.6%) patients; however, the dierence between

groups failed to achieve statistical signicance (hazard

ratio [HR]: 1.59, 95% condence interval [CI]: 0.76-3.30;

p=0.21) (Table 2).

Multivariate analysis

Aer adjusting for age, N stage N1 was identied

as the only independent predictor of cancer recurrence

(HR: 2.75, 95% CI: 1.18-6.40; p=0.19) (Table 3).

DISCUSSION

Age at diagnosis has long been established as an

important prognostic factor in terms of predicting survival

and recurrence. Many studies reported the survival of

young breast cancer (YBC) patients to be signicantly

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TABLE 1. Staging, tumor characteristics, and treatments compared between age groups.

Variables Age ≤40 (n=145) Age >40 (n=286) p-value

Number Percentage Number Percentage

Follow-up time (yrs), 4.53±1.27  4.03±0.46 <0.001

mean±SD

T stage

 T1 67 46.2% 152 53.1% 0.54

 T2 72 49.7% 126 44.1%

 T3 5 3.4% 7 2.4%

 T4 1 7.0% 1 3.0%

N stage

 N0 85 58.6% 192 67.1%

 N1 34 23.4% 59 20.6% 0.05

 N2 19 13.1% 17 5.9%

 N3 7 4.8% 18 6.3%

Pathological grade

 Low 21 14.5% 56 19.6%

 Intermediate 80 55.2% 190 66.4% <0.001

 High 44 30.3% 40 14.0%

Lymphovascular invasion

 Negative 84 69.4% 174 74.7% 0.31

 Positive 37 30.6% 59 25.3%

HER-2

 Negative 91 77.1% 203 86.4% 0.03

 Positive 27 22.9% 32 13.6%

%ER, mean±SD 69.7±19.7  71.3±17.4  0.41

%PR, mean±SD 54.0±30.8  53.8±28.9  0.95

Breast surgery

 Wideexcision 62 42.8% 92 32.2% 0.03

 Mastectomy 83 57.2% 194 67.8%

Axillary surgery

 SLNB 78 53.8% 188 65.7% 0.02

 ALND 67 46.2% 98 34.3%

Radiation

 No 129 89.0% 270 94.4% 0.017

 Yes 16 11.0% 16 5.6%

Chemotherapy

 No 20 13.8% 121() 42.3% <0.001

 Yes 125 86.2% 165() 57.7%

Recurrence

 No 129 89.0% 270 94.4% 0.05

 Yes 16 11.0% 16 5.6%

A p-value<0.05 indicates statistical signicance

Abbreviations: SD, standard deviation; T stage, tumor stage; N stage, lymph node stage; HER-2, human epidermal growth factor receptor

2; ER, estrogen receptor; PR, progesterone receptor; SLNB, sentinel lymph node biopsy; ALND, axillary lymph node dissection

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Fig 1. Recurrence-free survival stratied by age.

Fig 2. Recurrence-free survival stratied by T-stage.

Fig 3. Recurrence-free survival stratied by N-stage.

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Original Article

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TABLE 2. Univariate analysis for factors signicantly associated with cancer recurrence.

Factors No recurrence Recurrence Crude HR 95% CI p-value

Number Percentage Number Percentage

Age

 ≤40 129 89.0% 16 11.0% 1.59 0.76-3.30 0.22

 >40 270 94.4% 16 5.6% 1 

T stage

 T1 208 95.0% 11 5.0% 1

 T2 180 90.9% 18 9.1% 1.76 0.83-3.73 0.14

 T3-4 11 78.6% 3 21.4% 3.79 1.05-13.68 0.04

N stage

 N0 266 96.0% 11 4.0% 1

 N1 81 87.1% 12 12.9% 3.20 1.41-7.27 0.005

 N2 32 88.9% 4 11.1% 2.68 0.85-8.43 0.09

 N3 20 80.0% 5 20.0% 4.98 1.72-14.41 0.003

Pathological grade

 Low 74 96.1% 3 3.9% 1

 Intermediate 254 94.1% 16 5.9% 1.46 0.42-5.03 0.54

 High 71 84.5% 13 15.5% 4.00 1.14-14.06 0.03

Lymphovascular invasion

 Negative 246 95.3% 12 4.7% 1

 Positive 83 86.5% 13 13.5% 3.03 1.38-6.65 0.006

HER-2

 Negative 272 92.5% 22 7.5% 1

 Positive 53 89.8% 6 10.2% 1.26 0.51-3.12 0.61

Breast surgery

 Wideexcision 146 94.8% 8 5.2% 1

 Mastectomy 253 91.3% 24 8.7% 1.77 0.79-3.96 0.16

Axillary surgery

 SLNB 256 96.2% 10 3.8% 1

 ALND 143 86.7% 22 13.3% 3.42 1.62-7.24 0.001

Radiation

 No 180 95.2% 9 4.8% 1

 Yes 219 90.5% 23 9.5% 1.94 0.89-4.20 0.092

Chemotherapy

 No 139 98.6% 2 1.4% 1

 Yes 260 89.7% 30 10.3% 6.48 1.54-27.2 0.011

A p-value<0.05 indicates statistical signicance

Abbreviations: HR, hazard ratio; CI, condence interval; T stage, tumor stage; N stage, lymph node stage; HER-2, human epidermal growth

factor receptor 2; SLNB, sentinel lymph node biopsy; ALND, axillary lymph node dissection

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lower than that of older breast cancer patients.

8-10

Even

though the denition of YBC varies, 40 years of age is

a generally accepted cuto value that is used in most

studies.

10,11

Brandt, et al. compared breast cancer-specic

mortality between women aged <40 and women aged 40-49,

and they found that younger women had a signicantly

worse 10-year-mortality rate (risk ratio [RR]: 1.40, 95%

CI: 1.04-1.88).

A recent meta-analysis reported 5- and 10-year

local recurrence risk, and both were higher in YBC

than in older-onset patients (5-year – RR: 2.64, 95%

CI: 1.94-3.60; and, 10-year – RR: 2.37, 95% CI: 1.57-

3.58).

In contrast, the present study, which focused on

disease recurrence, found no signicant dierence in

RFS between the younger-onset and older-onset groups

(11.0% vs. 5.6%, respectively; p=0.22). is nding may be

explained by the fact that a signicantly greater number

of young women received chemotherapy (CMT) than

the number older women who received CMT (86.2% vs.

57.7%, respectively; p<0.001). Receiving CMT could imply

more aggressive phenotypes and higher recurrence risk

among younger aged patients. On the other hand, CMT

may lower the risk of recurrence in this group. One study

found signicant improvement in the local recurrence

rate among YBC who underwent breast conserving

surgery and that were treated systemically (HR: 0.42,

95% CI: 0.28-0.60; p<0.0001).

e largest retrospective

study analyzed the risk of local and distant recurrence

compared between YBC and older-onset patients, and

they found no signicant dierence between groups for

either parameter (5-year LR: 3.9% vs. 4.5%; and, 5year

DFS: 75.3% vs. 77.7%).

e unfavorable prognosis of YBC patients may

be explained by the fact that they had more aggressive

biological subtypes and/or clinicopathological baselines.

Typically, YBC is associated with poor prognostic factors,

such as large tumor size, nodal involvement, high-

grade tumor, absence of hormone receptor, and HER2

TABLE 3. Multivariate analysis for factors that independently predict cancer recurrence.

No recurrence Recurrence Crude 95% CI p-value Adjusted 95% CI p-value

Number Percentage Number Percentage HR HR

Age

 ≤40 129 89.0% 16 11.0% 1.59 0.76-3.30 0.22 0.81 0.37-1.73 0.59

 >40 270 94.4% 16 5.6% 1   1

T stage

 T1 208 95.0% 11 5.0% 1   1

 T2 180 90.9% 18 9.1% 1.76 0.83-3.73 0.14 1.23 0.55-2.74 0.61

 T3-4 11 78.6% 3 21.4% 3.79 1.05-13.68 0.04 1.77 0.40-7.89 0.45

N stage

 N0 266 96.0% 11 4.0% 1   1

 N1 81 87.1% 12 12.9% 3.20 1.41-7.27 0.005 2.75 1.18-6.40 0.02

 N2 32 88.9% 4 11.1% 2.68 0.85-8.43 0.09 2.16 0.65-7.16 0.21

 N3 20 80.0% 5 20.0% 4.98 1.72-14.41 0.003 2.87 0.82-9.94 0.09

Pathological grade

 Low 74 96.1% 3 3.9% 1   1

 Intermediate 254 94.1% 16 5.9% 1.46 0.42-5.03 0.54 1.05 0.30-3.73 0.93

 High 71 84.5% 13 15.5% 4.00 1.14-14.06 0.03 2.16 0.56-8.28 0.26

A p-value<0.05 indicates statistical signicance

Abbreviations: HR, hazard ratio; CI, condence interval; T stage, tumor stage; N stage, lymph node stage

Numprasit et al.

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overexpression.

8,15,16

In our experience, the hormone

receptor-positive subtype has better prognosis compared

to the others; especially luminal A, which has the best

survival. A large population-based study in Surveillance,

Epidemiology, and End Results (SEER) data assessed the

survival of operable breast cancer according to molecular

subtypes, and they found the greatest 5-year breast cancer-

specic survival in the hormone receptor positive and

HER2 negative group (HR+/HER2-) (95.5%) compared

to the triple-negative group (83.1%).

e present study

also found superior overall survival in the HR+/HER2-

subtype. Although hormone receptor positive breast

cancer has a more favorable prognosis, many clinicians

remain concerned that the age of diagnosis may adversely

aect survival. Several publications reported disparate

survival and recurrence results when age was used to

assess the outcomes. Liu, et al. reported poor 5-year

disease-free survival (DFS) and poor distant metastasis-

free survival (DMFS) in luminal A young women (age

≤40 years) compared to age 41-60 (5-year DFS: 80% vs.

91.6%; p<0.001; and, 5-year DMFS: 83.8% vs. 93.8%;

p<0.001). ese dierences between groups may be due

to more aggressive clinicopathological characteristics

in younger-onset patients. In our study, young women

had signicantly higher in tumor size (T3-4), more

nodal metastasis, more lymphovascular invasion, and

high nuclear grade; however, the dierence in survival

between groups was not signicant. Worse outcome

among younger women may also be explained by the

fact that younger women continue to menstruate aer

chemotherapy. SOFT and TEXT trial could clarify in this

case with their results showed that breast cancer patients

whom still premenopausal status take the benet of

adding ovarian suppression to tamoxifen or exemestane,

in order to increase disease free survival and freedom

from distant recurrence, in patients who previously

received chemotherapy.

Limitations

is study has several limitations. First, the retrospective

design of our study confers inherent weaknesses that

include missing or incomplete data. Second, our relatively

small sample size and short follow-up time (median: 4.1

years) may have limited the power of our survival analysis,

and our ability to identify all signicant associations

and dierences. ird, trastuzumab was not a standard

treatment for breast cancer patients who had HER2

overexpression during the study period, so the observed

high recurrence rate may have been due to inadequate

treatment. Fourth, our data was from a single center that

is ailand’s largest national tertiary referral center. As

such, we are oen referred cases that are judged to be

dicult to manage in other care settings. is may limit

the generalizability of our data to other care settings.

Fih and last, we did not have genetic prole data that

can be used to predict the benet of chemotherapy in

high-risk groups.

CONCLUSION

e results of this study revealed no signicant

dierence between age groups for recurrence-free survival

in women with hormone receptor-positive breast cancer;

however, younger women did demonstrate a higher rate

of recurrence. N stage N1 is an independent predictor

of cancer recurrence.

ACKNOWLEDGMENTS

e authors gratefully acknowledge Miss Julaporn

Pooliam of the Division of Clinical Epidemiology,

Department of Research, Faculty of Medicine Siriraj

Hospital, Mahidol University, Bangkok, ailand for

assistance with statistical analysis.

Conict of interest declaration: All authors declare no

personal or professional conicts of interest relating to

any aspect of this study.

Funding disclosure: is was an unfunded study.

REFERENCES

1. Society AC. Breast Cancer Facts & Figures 2017-2018. Atlanta:

American Cancer Society, Inc. 2017.

2. Adami HO, Malker B, Holmberg L, Persson I, Stone B. e

relation between survival and age at diagnosis in breast cancer.

N Engl J Med 1986;315:559-63.

3. Carvalho FM, Bacchi LM, Santos PP, Bacchi CE. Triple-negative

breast carcinomas are a heterogeneous entity that differs

between young and old patients. Clinics (Sao Paulo) 2010;65:

1033-6.

4. Collins LC, Marotti JD, Gelber S, Cole K, Ruddy K, Kereakoglow

S, et al. Pathologic features and molecular phenotype by patient

age in a large cohort of young women with breast cancer.

Breast Cancer Res Treat 2012;131:1061-6.

5. Pan XB, Chen RJ, Huang ST, Jiang YM, Zhu XD. Systematic

review and metaanalysis of the ecacy of breast conservation

therapy followed by radiotherapy in four breast cancer subtypes.

Oncotarget 2017;8:57414-20.

6. Fallahpour S, Navaneelan T, De P, Borgo A. Breast cancer

survival by molecular subtype: a population-based analysis of

cancer registry data. CMAJ Open 2017;5:E734-e9.

7. Liu Z, Sahli Z, Wang Y, Wol AC, Cope LM, Umbricht CB.

Young age at diagnosis is associated with worse prognosis in

the Luminal A breast cancer subtype: a retrospective institutional

cohort study. Breast Cancer Res Treat 2018;172:689-702.

8. Han W, Kang SY. Relationship between age at diagnosis and

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445

outcome of premenopausal breast cancer: age less than 35 years

is a reasonable cut-o for dening young age-onset breast

cancer. Breast Cancer Res Treat 2010;119:193-200.

9. Johansson ALV, Trewin CB, Hjerkind KV, Ellingjord-Dale M,

Johannesen TB, Ursin G. Breast cancer-specic survival by

clinical subtype aer 7 years follow-up of young and elderly

women in a nationwide cohort. Int J Cancer 2019;144:1251-61.

10. Brandt J, Garne JP, Tengrup I, Manjer J. Age at diagnosis in

relation to survival following breast cancer: a cohort study.

World J Surg Oncol 2015;13:33.

11. Anders CK, Johnson R, Litton J, Phillips M, Bleyer A. Breast

cancer before age 40 years. Semin Oncol 2009;36:237-49.

12. He XM, Zou DH. e association of young age with local

recurrence in women with early-stage breast cancer aer

breast-conserving therapy: a meta-analysis. Sci Rep 2017;7:11058.

13. van Laar C, van der Sangen MJ, Poortmans PM, Nieuwenhuijzen

GA, Roukema JA, Roumen RM, et al. Local recurrence following

breast-conserving treatment in women aged 40 years or younger:

trends in risk and the impact on prognosis in a populationbased

cohort of 1143 patients. Eur J Cancer 2013;49:3093-101.

14. Radosa JC, Eaton A, Stempel M, Khander A, Liedtke C, Solomayer

EF, et al. Evaluation of Local and Distant Recurrence Patterns

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Age. Ann Surg Oncol 2017;24:698-704.

15. Kataoka A, Iwamoto T, Tokunaga E, Tomotaki A, Kumamaru

H, Miyata H, et al. Young adult breast cancer patients have

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Sweeney KJ, et al. Younger age as a prognostic indicator in

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17. Hwang K-T, Kim J, Jung J, Chang JH, Chai YJ, Oh SW, et al.

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Numprasit et al.

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Original Article

SMJ

Pornprom Muangman, M.D.*, Nattakarn Changchit, M.D.*, Kusuma Chinaroonchai, M.D.*, Nantaporn

Namviriyachote, M.D.*, Natthida Owattanapanich, M.D.*, Harikrishna K.R. Nair, M.D.**

*Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand, ** Wound Care Unit, Department of

Internal Medicine, Kuala Lumpur Hospital, Malaysia.

Outcomes of the Recombinant Human Epidermal

Growth Factor Addition to Chloramphenicol

Ointment for Facial Burn Wound Healing

ABSTRACT

Objective: Delayed healing of facial burns can result in scarring and psychological morbidity. Epidermal growth

factor may promote wound granulation and angiogenesis to enhance wound healing. We compared the eect of

Chloramphenicol ointment alone with Recombinant Human Epidermal Growth Factor (rhEGF) plus chloramphenicol

on facial burn wound healing.

Methods: A randomized controlled trial was conducted in patients admitted to the Burn Unit. Subjects aged 18 to

65 years with acute second-degree facial burn wounds that did not require surgical treatment were enrolled. Subjects

were divided equally and randomized to receive either topical chloramphenicol ointment twice daily (control) or

rhEGF ointment once daily and chloramphenicol ointment twice daily. Wounds were assessed at frequent intervals.

Wound size, complete healing day, pain score, infection, side eects, Vancouver Scar Scale and the cost of treatment

were recorded.

Results: Twenty-six wounds were enrolled. The mean wound size was similar in both groups (rhEGF plus

chloramphenicol treated group 38.5±18.2 cm

vs control group 42.1±19.4 cm

). Burn wounds in the rhEGF group

healed more rapidly, though the dierence was not statistically signicant (8.5 ± 3.4 days vs 9.3 ± 4.4 days, p=0.3).

No dierence was observed in the Vancouver scar scale. Mean post-treatment pain scores were the same in both

groups. ere were no infections or side eects in either group. e rhEGF-treated group was more expensive

(1463.1 ± 142.6 vs 19.2 ± 1.9 baht).

Conclusion: ere are no dierence in outcomes of acute facial burn wound healing treated with rhEGF and

chloramphenical ointment compared to chloramphenicol treatment alone. e further study to evaluate the eect

of rhEGF in patients who have some factors that delay wound healing should be done.

Keywords: Burn; wound healing; epidermal growth factor (Siriraj Med J 2019; 71: 446-449)

Corresponding author: Nantaporn Namviriyachote

E-mail: pmuangman@yahoo.com

Received 21 August 2019 Revised 15 October 2019 Accepted 18 October 2019

ORCID ID: http://orcid.org/0000-0001-9828-0060

http://dx.doi.org/10.33192/Smj.2019.66

INTRODUCTION

Facial burns represent 27-60% of all burn patients

1-3

and may result in physical and psychological morbidities.

Burn scar contracture can cause diculty with mastication,

breathing, facial expression, and pronunciation. Furthermore,

patients may develop keratopathy from ectropion,

making it dicult to breathe due to depression of the

nasal bridge and chondritis.

Facial appearance aects

many social outcomes such as personal identication,

interpersonal communication. Facial deformities may lower

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447

self-condence and self-esteem that can lead to social

anxiety and mental illness.

Burn wound healing is a complex process. Previous

studies have described new drugs that can promote wound

healing without infection and decrease scar formation.

5-8

Epidermal growth factor (EGF) is secreted by platelets,

monocytes and broblasts, and stimulates epidermal

cells, broblasts, smooth muscle cells and endothelial

cells to promote wound granulation and angiogenesis.

Recombinant human epidermal growth factor (rhEGF) has

been reported to improve wound healing in diabetic foot

ulcer and radiation-related oral mucositis without major

side eects.

9-13

rhEGF can also decrease inammation

and scarring in the murine mode.

e chloramphenicol ointment is one of the topical

ointments that has been used as standard treatment of

facial burn wounds in some clinics because it provides

an optimal environment for eective wound healing and

reduces the risk of infection. Previous literatures reported

its ecacy for infection prophylaxis and infection treatment

purposes.

e chloramphenicol shows broad spectrum

which covers both gram positive and gram negative

bacteria.

Moreover, an ointment preparation mainly

contains oil base so it can adhere to the wound bed more

eective than cream and solution. It provides occlusive

property so it is a good option in topical antibiotics. e

combination of rhEGF with chloramphenicol might

improve healing ecacy. We aimed to compare the

eect of chloramphenicol ointment and recombinant

human epidermal growth factor (rhEGF) therapy with

chloramphenicol ointment alone for facial burn wound

healing. We hypothesized that the addition of rhEGF

would enhance the rate of wound healing, and decrease

scar formation without side eects or infection.

MATERIALS AND METHODS

A prospective randomized controlled trial was

conducted at the Department of Surgery, Faculty of

Medicine Siriraj Hospital, Bangkok, ailand. From

July of 2017 to September of 2018, patients aged 18 to 65

years with facial burn wounds were enrolled. According

to Guo et al (2010), the sample size was calculated based

on healing time between EGF-treated group and control

group.

Patients with an acute (< 48 hours) second-degree

facial burn wound that was expected to heal without

surgical treatment were eligible. Subjects with burns

involving the eyelids, those with compromised immunity,

renal disease, diabetes and pregnant or lactating women

were excluded. Informed consent was obtained. Data

were collected on sex, age, underlying diseases, cause

of burn, and burn wound characteristics.

e wound was cleaned and debrided to evaluate

the size and degree of burn by surgeons and experienced

burn unit nurses. Subjects were evaluated with the eKare

inSight™ 3D Wound Assessment (Daewoong Pharmaceutical

Co. Ltd, Seoul, South Korea) tool which measures the

area (cm

) of the wound.

Wounds were equally allocated by simple random

sampling method into a rhEGF-treated group (study

group) and chloramphenicol group (control group).

e control group dened as the wound was applied

with topical chloramphenicol ointment twice each day.

e study group or rhEGF-treated group was received

topical recombinant human epidermal growth factor

ointment (Easyef® Ointment Daewoong Pharmaceutical

Co. Ltd, Seoul, South Korea, 1g contains rhEGF 1 μg)

once daily in the morning combine with chloramphenicol

ointment twice each day. In case the area of wound could

not be divided to two groups, it would be assigned to

receive either rhEGF plus chloramphenicol ointment

or chloramphenicol ointment alone. Burn unit nurses

and patients dressed the wound and were blinded to the

intervention.

e wound was assessed at every other day by a

single, experienced burn unit nurse who has responsibility

to evaluate all wounds in this study. Size of the wound,

infection, pain score and side eects were recorded until

complete wound healing was achieved. Complete healing

was dened as full epithelialization of the wound with

absence of discharge. e pain score was evaluated using

a numericalscale. e Vancouver Scar Scale (VSS) was

used to evaluate the post-burn scar aer two months.

e costs of treatment including medicines and other

dressing materials were evaluated aer complete wound

healing.

Statistical analysis

Statistical analysis was performed using SPSS

version 21 statistical soware and Microso excel. Each

measurement is shown as mean ± standard deviation.

e dierences between group measurements such as

wound area, healing time and cost of treatments were

examined by T-test. A p-value of less than 0.05 was

considered statistically signicant.

RESULTS

Twenty-six wounds from fourteen patients (ve

men and nine women) who aged between 18 to 57 (mean

36.8±13.6 years) were enrolled in this study. No subject

had underlying medical illness. Nine cases were thermal

burns, three were scalds, and two were electrical burns.

e size of wounds in each group was similar. e average

Muangman et al.

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Original Article

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wound size in the rhEGF-treated group was 38.5±18.2

compared to 42.1±19.4 cm

in the control group

(p = 0.31).

e results comparing between study and control

group were shown in Table 1. Wounds in rhEGF-treated

group healed faster, but the dierence was not statistically

signicant. e complete healing day in the rhEGF-

treated group was 8.5±3.4 days compared to 9.3±4.4

days in the control group (p Value = 0.3). Scar formation

aer two months was similar. e Vancouver scar scale

(VSS)

ranged from 0 to 3 with a mean in both groups was

1.6 ± 0.8.

e mean pre-treatment and 30-minutes post-

treatment pain scores were the same in both groups, and

decreasing post-treatment pain scores were observed

overall (pre-treatment 3.7±2.9; post-treatment 2.8±2.1).

Fig 1 showed the ecacy of rhEGF plus chloramphenicol

compare to chloramphenicol alone at 0, 2 weeks and

2 months aer injury.

All wounds in both groups healed without infection

or complications such as rash, swelling or urticaria.

e total cost of study group was higher than the control

group. e mean cost of EGF-treated group was 1463.1±142.6

baht and chloramphenicol group was 19.2±1.9 baht

(p ≤ 0.05). (Table 1)

DISCUSSION

Burn wound healing is a complex process. Due

to the ability of rhEGF that can stimulate epidermal cells,

broblast, smooth muscle cells and endothelial cells to

promote wound granulation and angiogenesis. is

growth factor was eective using in chronic wounds

such as diabetic foot ulcer, and radiation ulcer.

11-13

Complete healing occurred more rapidly in the rhEGF-

treated group; however, the rhEGF plus chloramphenicol

cannot accelerate facial burn wound healing eectively

compared with chloramphenicol alone. Without surgical

treatment, an acute second-degree facial burn wounds

usually heal spontaneously within two weeks.

Treatment with rhEGF plus chloramphenicol did

not increase post-burn hypertrophic scar formation or

TABLE 1. Comparison results between study group (rhEGF+Chloramphenicol group) and control group

(Chloramphenicol group).

Study group Control group P-value

Completehealingday(Days) 8.5±3.4 9.3±4.4 0.30

Vancouverscarscaleat2months 1.6±0.8 1.6±0.8 >0.05

Pre-treatmentpainscore 3.7±2.9 3.7±2.9 0.17

Post-treatmentpainscore 2.8±2.1 2.8±2.1 0.17

Sideeffects No No -

Totalcost(Baht) 1,463.1±142.6 19.2±1.9 <0.05

Fig 1. Facial burn wound treated with chloramphenicol (A) and rhEGF+ chloramphenicol (B).

Day 0 Day 14 Day 60

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facial scar contracture compared with chloramphenicol

alone. e Vancouver Scar Scale at two months was the

same in both groups. Although there was no signicant

in scar reduction, previous animal study has already

proved the ecacy of rhEGF in visible external scars

formation over control group.

Moreover, the second

degree dermal layer burn wound usually create the scar

less than deep layer wound because it most likely to heal

by spontaneous epithelial wound healing.

Treatment with rhEGF and chloramphenicol did

not increase pain, infection or result in any side eects,

suggesting that this therapy is safe to use in facial burn

wounds. Our study showed, there was similar outcome

about decreasing pain score aer treatment of both rhEGF-

treated and chloramphenicol group but no statistical

signicance. It is possibly that the facial wound is a small

area which presents many sensory nerves, it is dicult

to dierentiate the pain feeling between these two areas.

Finally, the cost of rhEGF treatment is greater than

chloramphenicol. Due to insignicant eect to accelerate

burn wound healing, we might consider rhEGF just as

an alternative drug in facial burn wound or challenge in

patients who have some factors that might delay wound

healing.

Further studies are needed to evaluate the ecacy

of rhEGF in deeper facial burn wounds which might not

spontaneously heal, and in patients who have risk factors

that could delay wound healing. Deep layer facial burn

wounds cause more cellular dysfunction and post-burn

scar formation. rhEGF might demonstrate the benet

of treatment in those patients.

CONCLUSION

ere are no dierence in outcomes of acute facial burn

wound healing treated with rhEGF and chloramphenical

ointment compared to chloramphenicol treatment alone.

e further study to evaluate the eect of rhEGF in patients

who have some factors that delay wound healing or in

deeper burn wounds with less chance of spontaneous

epithelialization healing should be done. ere were no

increases in hypertrophic scar, scar contracture, infection

or other side eects aer using rhEGF. erefore, rhEGF

is safe to use just as an adjunct therapy in dermal facial

burn wounds.

ACKNOWLEDGMENTS

We thank Daewoong Pharmaceutical Company for

Support Easyef® Ointment and eKare inSight™ 3D Wound

Assessment in this study. e nancial relationships did

not pose a conict of interest to authors.

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scar formation in murine full-thickness wound healing. J

Korean Med Sci 2010;25:589-96.

15. Erel E, Goodyear S, Misra A. A survey of chloramphenicol

use in plastic surgery: a follow-up. J Plast Reconstr Aesthet

Surg 2010;63:e102-e3.

16. Dasgupta A. Chapter 3 - Advances in antibiotic measurement.

In: Makowski GS, editor. Advances in Clinical Chemistry.

Elsevier; 2012.p.75-104.

17. Guo X, Tan M, Guo L, Xiong A, Li Y, He X. Clinical study

on repair of burn wounds of degree II with recombinant

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Xiu Fu Chong Jian Wai Ke Za Xhi 2010;24:462-4.

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Facial burns - our experience. Mater Sociomed 2013;25:26-27.

Muangman et al.

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Somphon Roeksomtawin, M.D.*, Palakorn Sontepa, M.D.*, Kanchana R. Kildegaard, Ph.D.**, Jatuporn Sirikun, M.D.*

*Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand, **e Novo Nordisk Foundation Center

for Bio sustainability, Technical University of Denmark, Lyngby, Denmark.

Decision-making Factors in Non-operative

Management of Zygomatic Fractures

ABSTRACT

Objective: A zygomatic fracture is one of the most common fractures of the maxillofacial bone. e treatment of

zygomatic fractures can be performed either by surgical or non-surgical management. However, few studies have

evaluated the reasons for choosing non-surgical treatment.

Methods: A retrospective observational study was performed of patients with zygomatic fractures that presented in

Siriraj Hospital, ailand, from January 1, 2010, to December 31, 2014. e factors associated with the non-operative

treatment of zygomatic fractures were evaluated. Moreover, we analyzed the patient data, such as their age, etiology,

type of fracture, complications, associated facial fractures, and associated other organ injuries.

Results: ere were 337 patients with a zygomatic fracture during this period. Most of the cases involved males. Trac

accidents represented a common cause of the fracture. e mean patient age was 36 years old. Trimalar fracture of

the zygoma was the most common type of fracture. e most common complication with zygoma fractures was

infraorbital nerve injury. Of the study population, 161 patients (47.8%) received non-operative treatment and 176

patients (52.2%) received operative treatment. Older age (adjusted odds ratio (95% CI); 1.02 (1.00-1.03), p-value =

0.049), no diplopia (adjusted odds ratio (95% CI); 12.30 (3.28-46.14), p-value < 0.001), no infraorbital nerve injury

(adjusted odds ratio (95% CI); 6.76 (3.81-11.99), p-value < 0.001), and no cosmetic concern (95% CI); 92.82 (11.97-

719.44), p-value < 0.001) were the only four factors related to non-operative management decisions.

Conclusion: Older age, no diplopia, no infraorbital nerve injury, and no cosmetic concern of the patient were the

factors associated with the non-operative treatment of zygomatic fractures.

Keywords: Zygomatic fracture; factors; non-operative treatment (Siriraj Med J 2019; 71: 450-456)

Corresponding author: Somphon Roeksomtawin

E-mail: somphon_r@yahoo.com

Received 20 August 2019 Revised 30 September 2019 Accepted 4 October 2019

ORCID ID: http://orcid.org/0000-0002-7214-1342

http://dx.doi.org/10.33192/Smj.2019.67

INTRODUCTION

A zygomatic fracture is a common fracture of the

facial skeleton. e incidence and etiology of zygomatic

fractures vary and dier among the reported studies.

For example, one study reported that the main causes of

zygomatic fractures were trac accidents (26%), assault

(20%), accidental falls (19%), sports injuries (10%),

home injuries (8%), and work accidents (6%)

, while

another reported retrospective review found that the most

common causes of zygomatic fractures were motor vehicle

accidents (40%), followed by assault (22%), motorcycle

accidents (12%), and all-terrain vehicle accidents (7%),

respectively.

e management of zygomatic fractures also vary,

depending on the institution or trauma center. Previous

research has reported that a high incidence of zygomatic

fractures (66%) could be managed non-operatively without

signicant complications.

Another report studied the

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451

variables related to the surgical and non-surgical treatment

of zygomatic complex fractures and found that the presence

of other facial fractures, alteration of occlusion, presence

of comminuted fractures, and infraorbital nerve sensory

disturbances were statistically associated with the surgical

treatment of zygomatic fracture.

Nowadays, the non-operative treatment of a fracture

of the facial skeleton is interesting, but there are few reports

in the published literature on the conservative treatment

of facial fractures.

A previous study reported that most

patients with facial fractures in their study population

were managed with non-operative treatment.

ey set

some criteria for the non-operative treatment of facial

fractures and found that an undisplaced/minimally

displaced fracture (57%) or minimal/no symptoms

(24%) resulted in the patient undergoing conservative

treatment.

However, data about the factors associated

with the decision to apply a non-operative management

of zygomatic fractures are lacking. Consequently, we

conducted this research to identify the factors associated

with the non-operative treatment of zygomatic fractures.

Moreover, we evaluated the patients’ age, etiology, type

of fracture, complications, and time of hospital arrival

in a level I trauma center in ailand.

MATERIALS AND METHODS

A retrospective observational study was performed

of patients with a zygomatic fracture who presented to

the Facial Fracture Clinic, Division of Trauma Surgery,

Siriraj Hospital, Mahidol University, ailand, during a

period of 5 years, from January 1, 2010, to December 31,

2014. is study was approved by the ethical committee

for human research of Mahidol University (Si 641/2559).

e inclusion criteria for this study were patients who

were diagnosed with a zygomatic fracture (based on ICD-

10) and who were treated at the Facial Fracture Clinic

(FFC Clinic), Division of Trauma Surgery, Department

of Surgery, Siriraj Hospital. e exclusion criteria were:

(1) patients who refused treatment, (2) patients who died

at arrival or during hospital admission, and (3) patients

who had incomplete medical records.

In this study, we classied a zygomatic fracture

into ve types, based on Siriraj Hospital’s classication

of zygomatic fractures, namely: (1) classical sutural

fracture of the zygoma (trimalar fracture), (2) comminuted

fracture of the zygoma, (3) zygomaticomaxillary complex

fracture, (4) isolated fracture of the zygomatic arch, and

(5) isolated fracture of the frontal process of the zygoma.

For data analysis, we used the Pearson chi-square test for

discontinuous data analysis, and the Mann–Whitney U-test

for continuous data analysis (not a normal distribution).

Simple and multiple logistic regressions were used to

investigate the factors associated with the non-operative

treatment of zygomatic fractures. We used the soware

PASW Statistics 18.0 (SPSS Inc., Chicago, IL, USA) for

the data analysis.

RESULTS

In total, there were 337 patients included in this

study. e patients overall demographic data are shown

in Table 1. e patients were split into two groups based

on treatment, with 161 patients (47.8%) placed in the

non-operative treatment group and 176 patients (52.2%)

placed in the operative group. e majority of the patients

were males, representing 261 patients (77.4%), while the

females accounted for 76 patients (22.6%). e median

patient age (overall) was 30 years old (Min–Max.: 11-

92). In the non-operative treatment group, the median

age was 41.0 years old (Min–Max.: 14-92), while in the

operative treatment group, the median age was 30.5 years

old (Min–Max.: 11-91). e most common age group

that suered from a zygomatic fracture was 21-40 years

old (128 patients, 38.0%), while the least frequent age

group to suer such a fracture was those more than 80

years old (14 patients, 4.2%) (Fig 1).

e most common types of zygomatic fracture

(based on Siriraj Hospital’s classication of zygomatic

fracture) were a trimalar fracture (272 patients, 80.7%),

isolated zygomatic arch fracture (27 patients, 8.0%),

zygomaticomaxillary complex fracture (25 patients, 7.4%),

isolated frontal process fracture (9 patients, 2.7%), and

the least common of fracture was comminuted zygomatic

arch fracture (4 patients, 1.2%) (Table 1).

The most common etiologies of the zygomatic

fractures were trac accident (219 patients, 65%), assault

(54 patients, 16%), sport injuries (4 patients, 1.2%),

occupational accidents (3 patients, 0.9%), and other

etiologies (57 patients, 16.9%) (Fig 2).

e most frequent times of hospital arrival were

within 6 hours (54.6%), more than 24 hours (31.8%), 6

to 12 hours (5.0%), 18 to 24 hours (4.7%), and 12 to 18

hours (3.9%) (Fig 3).

Data were analyzed using multiple logistic regression

to identify the factors associated with the non-operative

treatment of zygomatic fracture and it was found that

older age, no underlying disease (crude odds ratio (95%

CI); 2.99 (1.64-5.14), p-value < 0.001), no other facial

fracture disease (crude odds ratio (95% CI); 1.66 (1.08-

2.56), p-value = 0.022), no diplopia (crude odds ratio (95%

CI); 8.32 (2.45-28.19), p-value < 0.001), no infraorbital

nerve injury (crude odds ratio (95% CI); 3.54 (2.18-5.74),

p-value < 0.001), and a time of hospital arrival 6.01-

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Demographic data Non-operative Operative Total (%) P-value

treatment (%) treatment (%)

Age(year)

 Median(Min.-Max.) 41.0(14-92) 30.5(11-91) 36(11-92)

 1-20 26(16.1) 44(25) 70(20.8)

 21-40 53(32.9) 75(42.6) 128(38.0) <0.001

 41-60 45(28.0) 46(26.1) 91(27.0)

 61-80 25(15.5) 9(5.1) 34(10.1)

 >80 12(7.5) 2(1.1) 14(4.2)

Gender

Male 131(81.4) 130(73.9) 261(77.4) 0.100

Female 30(18.6) 46(26.1) 76(22.6)

Etiology

 Trafcaccident 99(61.5) 120(68.2) 219(65.0)

 Assault 22(13.7) 32(18.2) 54(16.0)

 Sport 2(1.2) 2(1.1) 4(1.2) 0.071

 Occupational 1(0.6) 2(1.1) 3(0.9)

 Others 37(23.0) 20(11.4) 57(16.9)

Typeoffracture(SirirajClassication)

 Classicalsuturalfractureofthezygoma 133(82.6) 139(78.9) 272(80.7)

 (Trimalarfracture)

 Comminutedfractureofthezygoma 1(0.6) 3(1.7) 4(1.2)

 Zygomaticomaxillarycomplexfracture 7(4.3) 18(10.3) 25(7.4) 0.085

 Isolatedfractureofthezygomaticarch 17(10.6) 10(5.7) 27(8.0)

 Isolatedfractureofthefrontalprocess 3(1.9) 6(3.4) 9(2.7)

 ofthezygoma

Complications

 Infra-orbitalnerve(ION)injury 33(20.5) 84(47.7) 117(34.7) <0.001

 Diplopia 3(1.9) 24(13.6) 27(8.0) <0.001

 Malocclusion 2(1.2) 5(2.8) 7(2.1) 0.304

 Cosmeticconcern 1(0.6) 37(21.0) 38(11.3) <0.001

Timeofhospitalarrival

 ≤6hr. 101(62.7) 83(47.2) 184(54.6)

 6.01-12hr. 10(6.2) 7(4.0) 17(5.0)

 12.01-18hr. 5(3.1) 8(4.5) 13(3.9) 0.014

 18.01-24hr. 8(5.0) 8(4.5) 16(4.7)

 >24hr. 37(23.0) 70(39.8) 107(31.8)

Associatedfacialfracture

 Nasalfracture 9(5.6) 14(8.0) 23(6.8) 0.390

 Maxillaryfracture 22(13.7) 29(16.5) 51(15.1) 0.472

 Mandibularfracture 2(1.2) 11(6.3) 13(3.9) 0.017

 Orbitalfracture 38(23.6) 54(30.7) 92(27.3) 0.145

 Otherfacialfracture 17(10.6) 21(11.9) 38(11.3) 0.691

Associatedotherorganinjury

 Headinjury 61(37.9) 53(30.1) 114(33.8) 0.132

 Orthopedicsfracture 23(14.3) 21(11.9) 44(13.1) 0.522

 Chestinjury 10(6.2) 1(0.6) 11(3.3) 0.004

 Abdominalinjury 5(3.1) 4(2.3) 9(2.7) 0.636

 Eyeinjury 67(41.6) 82(46.9) 149(44.3) 0.334

 Softtissueinjury 41(25.5) 45(25.7) 86(25.6) 0.958

 Otherinjury 34(21.1) 35(19.9) 69(20.5) 0.780

 Noneinjury 24(14.9) 31(17.6) 55(16.3) 0.502

TABLE 1. Demographic data of the patients with zygomatic fracture.

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Fig 1. Patients’ demographic data. e demographic

data of zygomatic fracture were demonstrated. e

numbers in the histogram represent age incidence

(years), the number of cases, the percentage of cases

from total 337 cases, respectively.

Fig 2. Etiology of injury. e etiology of zygomatic fracture was categorized in x axis, while the number of cases and the percentage of cases

from total 337 cases was demonstrated in each etiology.

Fig 3. Time of hospital arrival. e duration from time of injury to hospital visit of each patient with zygomatic fracture was recorded, and

categorized in x axis. e histogram demonstrated the time interval and the number and the percentage of cases in each interval.

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TABLE 2. Factors associated with non-operative treatment of zygomatic fracture

Factors Crude odd ratio P-value Adjusted odd ratio P-value

(95% CI) (95% CI)

Age   1.02(1.00-1.03) 0.049

Noneunderlyingdisease 2.99(1.64-5.14) <0.001 1.80(0.79-4.14) 0.165

Nonotherfacialfracture 1.66(1.08-2.56) 0.022 1.46(0.83-2.54) 0.187

Nodiplopia 8.32(2.45-28.18) 0.001 12.30(3.28-46.14) <0.001

Noinfra-orbitalnerveinjury 3.54(2.18-5.74) <0.001 6.76(3.81-11.99) <0.001

Nocosmeticconcern 42.59(5.77-314.46) <0.001 92.82(11.97-719.44) <0.001

Timeofhospitalarrival   

 <=6Hr. 0.53 0.002  0.440

 6.01-12Hr. 2.30(1.41-3.77) 0.001 1.07(0.32-3.58) 0.911

 12.01-18Hr. 2.70(0.95-7.68) 0.062 0.53(0.12-2.31) 0.401

 18.01-24Hr. 1.18(0.36-3.87) 0.782 0.98(0.26-3.65) 0.979

 >24Hr. 1.89(0.66-5.45) 0.237 0.57(0.31-1.06) 0.077

12 hours (crude odds ratio (95% CI); 2.30 (1.41-3.77),

p-value < 0.001) were the factors associated with the

non-operative treatment of a zygomatic fracture when

the analysis was performed using univariable analysis,

but when we used multivariable analysis, we found that

older age (adjusted odds ratio (95% CI); 1.02 (1.00-1.03),

p-value = 0.049), no diplopia (adjusted odds ratio (95%

CI); 12.30 (3.28-46.14), p-value < 0.001), no infra-orbital

nerve injury (adjusted odds ratio (95% CI); 6.76 (3.81-

11.99), p-value < 0.001), and no cosmetic concern (95%

CI); 92.82 (11.97-719.44), p-value < 0.001) were the only

factors associated with the non-operative treatment of

zygomatic fracture (Table 2).

DISCUSSION

Due to the dierences in the nature of each injury in

trauma patients, the analysis of management modalities

is dicult.

4,5

Non-operative treatment may be used in

any individual patient, but there are no denite criteria

for deciding on such treatment in the management of

zygomatic fracture.

3,4

Consequently, realizing which

factors are associated with the non-operative treatment

of zygomatic fracture should help the decision-making

for the treatment modalities.

In our study, most of the zygomatic fracture cases,

which were most common in males, were caused by trac

accidents. e mean patient age was 36.0 years old. ese

represent similar results, albeit with a little dierence in

percentages, when compared with another study that

reported that zygomatic complex fractures were more

common in men (80.1%) than women (19.9%), and the

average patient age was 35.3 years old.

High energy and

moderate energy mechanisms are associated with more

comminution and displacement of the fractures, and

this may need more operative intervention.

Despite the

dierence in ratios of the etiologies of the injury between

a previous study, which reported that the most common

causes of the injuries were due to personal aggression

(19.5%), followed by falls (18.8%)

, and our data, which

found that most the injuries due to trac accidents

(65%), the data from both studies showed similar results

in that there was no statistically signicant association

between the etiology and the decision made between

the surgical treatment or non-operative treatment of

zygomatic fracture.

In this study, the most common type of zygomatic

fracture was trimalar fracture and the most common

complication of the fracture was infraorbital nerve injury,

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respectively. Diplopia usually relates to an orbital wall

defect and intraorbital fat compromise and/or extraocular

muscles entrapment

and these patients need more

extensive evaluation and observation.

In our research,

27 patients (8.0 %) presented this sign and we found that

the lack of diplopia was statistically associated with the

non-operative treatment of zygomatic fractures (p-value

< 0.001). is was in contrast to the previous study,

which reported that only 8 cases out of 43 patients with

diplopia were in the operative treatment group, and

they concluded that there was no statistically signicant

association between diplopia and the operative treatment

of zygomatic fractures.

However, another study showed

that 7% of cases presented with diplopia, and all were in

the surgical group.

us, we concluded that the lack of

diplopia (no diplopia) was one of factors associated with

the non-operative treatment of zygomatic fracture.

e incidence of infraorbital nerve sensory disturbances

in zygomaticomaxillary complex (ZMC) fractures has

been reported to vary from 24% to 94%

10,11

, and it has

been found that infraorbital nerve sensory disturbances

were the most common sequelae aer ZMC fracture.

Previous studies reported that only 5.8–18% of cases

did not present infraorbital nerve sensory disturbances,

and most surgical patients showed this sign.

9,13

ese

previous studies concluded that patients with ZMC fracture

presenting infra-orbital nerve sensory disturbances were

highly correlated with operative treatment.

9,13

In this

study, we demonstrated that the presence of infraorbital

nerve injury was associated with operative treatment in

zygomatic fracture, and the lack of infraorbital nerve

injury was statistically signicantly associated with the

non-operative treatment of zygomatic fracture.

e presence of comorbidity may be correlated with

adverse peri-operative events and may increase the risk of

morbidity and mortality in surgical patients,

and here,

the ASA classications are the key predictors of major

complications in head and neck surgery.

In our study,

we found that the absence of comorbidity was correlated

with the non-operative treatment of zygomatic fracture

when we analyzed the data using univariable analysis,

but it was not statistically associated with non-operative

treatment when analyzed using multivariable analysis.

A previous study showed that the cosmetic or aesthetic

outcome was the dominant indicator for the treatment

of zygomatic fracture, and concluded that the aesthetic

result is predominantly the principal indication of surgical

xation in most zygomatic fractures.

Similarly, our

results demonstrated that having no cosmetic concern

was strongly statistically signicantly associated with the

non-operative treatment of zygomatic fracture. Many

studies have found that more complex facial fractures,

such as naso-orbito-ethmoidal fractures, maxillary

fractures, or mandibular fractures, are associated with

a high energy trauma mechanism.

3,6

Our data showed

some correlation, but not statistically signicant, between

other facial fractures and the non-operative treatment of

zygomatic fracture. Besides, other factors, such as time

of hospital arrival and the presence of associated other

organ injury, did not show any correlation with operative

management modalities. us, it may be assumed that

the etiology, time of hospital arrival, and the severity of

injury as well as the presence of other injuries and any

comorbidity did not aect directly the decision-making

in the management of zygomatic fractures. On the other

hand, some studies, which used radiographic ndings

of the facial anatomy in their classication, showed a

relationship between the etiology, or the severity of injury,

or other facial fractures, and the surgical management of

zygomatic complex fractures.

3,6,7

e dierences in these

relationships may be due to the dierent classications

of facial fractures. For example, when patients had a

radiographic diagnosis of a bilateral zygomatic complex

fracture and if presenting to our institute with fractures

around the midline components of the facial skeleton,

e.g. naso-orbital-ethmoid fractures, then the diagnosis

of Lefort fractures were given in these cases, and they

were not enrolled in this study. In summary, we could

summarize that patients who presented with zygomatic

fracture and had the following important factors, e.g.,

older age, no diplopia, no infraorbital nerve injury, and

no cosmetic concern, could be treated with non-operative

treatment, and in the future we may be set up denite

criteria for the non-operative treatment of zygomatic

fracture to ensure the best treatment for the patient

population.

ere were some limitations in this study to report:

(1) this study was a retrospective study and we did

not mention results concerning complications and the

duration of any complication that the patient suered

because of incomplete or a lack of data about this in this

study, (2) there were many surgeons in this study who

treated the patients and applied no standard guideline

treatment, leading to confounding factors and selection

bias that depended on the individualized treatment of the

surgeons. Further research is advised, especially regarding

the non-operative treatment of zygomatic fracture for

creating standard treatment guidelines and for setting

up criteria for this treatment group in the future.

Roeksomtawin et al.

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CONCLUSION

In our study, we found that the majority of the patients

were male, the most common type of zygomatic fracture

was a trimalar fracture, the most common etiologies of

zygomatic fracture were trac accidents and assault,

respectively, and the most frequent time of hospital

arrival was within 6 hours. Older age, no diplopia, no

infraorbital nerve injury, and no cosmetic concern were

the factors associated with the non-operative treatment

of zygomatic fracture.

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, Kittidumkerng W. Analysis of treatment for

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8. He D, Blomquist PH, Ellis E, 3

. Association between ocular

injuries and internal orbital fractures. J Oral Maxillofac Surg

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9. Kovacs AF, Ghahremani M. Minimization of zygomatic complex

fracture treatment. Int J Oral Maxillofac Surg 2001;30:380-3.

10. Pedemonte C, Basili A. Predictive factors in infraorbital sensitivity

disturbances following zygomaticomaxillary fractures. Int J

Oral Maxillofac Surg 2005;34:503-6.

11. De Man K, Bax WA. e inuence of the mode of treatment

of zygomatic bone fractures on the healing process of the

infraorbital nerve. Br J Oral Maxillofac Surg 1988;26:419-25.

12. Boano P, Roccia F, Gallesio C, Karagozoglu KH, Forouzanfar

T. Infraorbital nerve posttraumatic decit and displaced zygomatic

fractures: a double-center study. J Craniofac Surg 2013;24:2044-6.

13. Jungell P, Lindqvist C. Paraesthesia of the infraorbital nerve

following fracture of the zygomatic complex. Int J Oral Maxillofac

Surg 1987;16:363-7.

14. Eyelade O, Sanusi A, Adigun T, Adejumo O. Outcome of

anesthesia in elective surgical patients with comorbidities.

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15. Ferrier MB, Spuesens EB, Le Cessie S, Baatenburg de Jong RJ.

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in head and neck surgery. Arch Otolaryngol Head Neck Surg

2005;131:27-32.

16. Mahmoud SM, Liao HT, Chen CT. Aesthetic and Functional

Outcome of Zygomatic Fractures Fixation Comparison

WithResorbable Versus Titanium Plates. Ann Plast Surg

2016;76 Suppl 1:S85-90.

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ammawat Parakonthun, M.D.*, Chawisa Nampoolsuksan, M.D.*, Jirawat Swangsri, M.D., Ph.D.*, Anusak

Yiengpruksawan, M.D.**, Asada Methasate, M.D., Ph.D.*

*Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand, **Capital Health Cancer Center,

Pennington, New Jersey, USA.

Retrospective Analysis of the Outcomes in Elderly

Patients with Adenocarcinoma of the Stomach and

Esophagogastric Junction Following Three

Different Treatments

ABSTRACT

Objective: To compare survival outcomes and complications in elderly patients who underwent three dierent

treatments.

Methods: e data of patients aged 70 years old or older diagnosed with adenocarcinoma of the stomach and

esophagogastric junction (Siewert types II and III) between January 2005 and December 2016 were reviewed. e

results of dierent treatments and risk factors for post-treatment morbidity and mortality were analyzed.

Results: In total, 220 elderly patients were included: 102 (46.4%) who underwent curative intended gastrectomy

with radical lymphadenectomy (Curative group), 62 (28.2%) who underwent non-curative surgery or endoscopy

(Non-curative group), and 56 (25.4%) who received best supportive care (BSC group). Mean ages were 76.6, 78.1,

and 78.7 years old, respectively (p=0.596). Median overall survival was 32, 5, and 3 months, respectively (p<0.001).

In the curative group, overall survival was associated with the pathological stage (p=0.017), but not the resection

category (p=0.298). Concerning the curative and non-curative groups, severe post-treatment complications occurred

in 14 (8.5%) patients (7.8%, curative group; 9.7%, non-curative group). Severe post-treatment complication was

associated with age ≥80 years (p=0.023) and coronary artery disease (p<0.001); however, multivariate analysis

identied coronary artery disease as an independent risk factor for severe post-treatment complication. 5 (3%)

patients had in-hospital mortality, associated with age ≥80 years old (p=0.039) and coronary artery disease (p=0.005).

Conclusion: Curative and non-curative procedures can be safely performed in elderly patients. However, caution

should be taken with extreme elderly patients, especially those with coronary artery disease. Best supportive care

should be considered only for unt patients.

Keywords: Stomach neoplasms; gastrectomy; aged; mortality; esophagogastric junction (Siriraj Med J 2019; 71: 457-465)

Corresponding author: Asada Methasate

E-mail: teamsster@gmail.com

Received 30 August 2019 Revised 24 September 2019 Accepted 1 October 2019

ORCID ID: http://orcid.org/0000-0002-8726-365X

http://dx.doi.org/10.33192/Smj.2019.68

INTRODUCTION

e number of elderly cancer patients has increased

worldwide during the past few decades. According to the

National Cancer Institute of ailand

, 20% of gastric

cancer patients are aged over 70 years old. Realizing that

the older a patient is the more oen they may experience

comorbidities or poor treatment performance status

could help decide the proper care for each patient.

In gastric cancer, including esophagogastric junction

cancer, surgery is the main modality of treatment, and

Parakonthun et al.

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can be classied into curative and non-curative surgery.

For patients who cannot tolerate surgery and who do not

have metastatic disease, palliative and best supportive

care are the preferable choices.

From a recent study in elderly gastric cancer patients

over 80 years old, curative resection showed a signicant

better overall survival compared to supportive care.

2,3

ose who received non-surgical care mostly died from

gastric cancer.

Cancer-specic survival was 100% in

clinical stage I. which can imply that this group died

from non-cancer diseases.

Surgery with reduced nodal

dissection in stage I disease also oered no signicant

dierence in survival compared to standard surgery.

Furthermore, complications in patients who underwent

curative surgery were more common in older age,

especially medical complications, occurring in 7.4% of

patients aged 80 years old or older compared to 2.2% of

patients aged 60-64 years old

, particularly cardiac events

and pulmonary complications, such as pneumonia and

respiratory failure.

With older age, the mortality rate is

signicantly higher than for younger patients.

is study aimed to measure the survival outcome

of these elderly patients receiving curative surgery, non-

curative treatment, and best supportive care. Postoperative

complications and mortalities were reviewed and analyzed

by statistics. e results from this study may suggest

treatment guidance for elderly patients. Old age may

not be a contraindication for curative surgery in surgical

resectable diseases. Hopefully, elderly patients will receive

the appropriate treatment concerning the stage of the

disease and their performance status.

MATERIALS AND METHODS

Patient population

We retrospectively reviewed the records of a total of

220 patients aged over 70 years old with pathologically

diagnosed adenocarcinoma of the stomach and Siewert–Stein

types II and III adenocarcinoma of the esophagogastric

junction (EGJ)

treated between January 2005 and December

2016 at the Faculty of Medicine Siriraj Hospital, Mahidol

University, Bangkok, ailand. Of these patients, 102

patients who had underwent curative surgical resection,

which was dened as a curative intent surgical procedure

with the extent of gastric resection and lymph node

dissection as per the Japanese classication and treatment

guidelines for gastric carcinoma,

9,10

were assigned to the

Curative group; while 62 patients who had underwent

non-curative treatment, which referred to any kind of

surgical or endoscopic management for relieving patients’

symptoms, were assigned to the Non-curative group;

and 56 patients who had underwent best supportive

care alone were assigned to the BSC group. BSC was

dened as any non-invasive treatments that aimed to

relieve symptoms such as analgesics, antibiotics and

blood transfusion, and did not involve any interventions

as in the two previous groups. None of patients in the

BSC group received palliative chemotherapy. Patients

who received neoadjuvant chemotherapy, underwent

endoscopic resection for curative intention, underwent

cytoreductive surgery with or without hyperthermic

intraperitoneal chemotherapy, and a transthoracic approach

for surgical resection were excluded from this study.

e clinicopathological characteristics were reviewed

from the patients’ medical records, including the patients’

age, gender, active smoking, comorbidities, such as

diabetes mellitus, hypertension, cerebrovascular accident,

chronic obstructive pulmonary disease, coronary artery

disease, valvular heart disease, and chronic kidney disease

≥ stage IV, patient’s performance status using the Eastern

Cooperative Oncology Group performance status score

(ECOG), body mass index, preoperative serum albumin

level, American Society of Anesthesiologists physical

status classication (ASA grade), preoperative tumor

location, macroscopic Borrmann classication, tumor

dierentiation, and preoperative clinical staging using

TNM staging according to the American Joint Committee

on Cancer.

Outcome measurements

e primary objective of this study was to evaluate

the overall survival between these three groups. Overall

survival was dened as the time from the date of conrmed

pathological diagnosis at our center to the date of death

from any causes. We obtained the date of death from

the Bureau of Registration Administration of ailand

and from family members of the patients. Postoperative

complications, which were classied by the Clavien–

Dindo classication system

, in-hospital mortalities,

and 30-days postoperative mortalities in curative surgery

and non-curative treatment groups, were also reviewed

and analyzed. is study protocol was approved by the

Siriraj Institutional Review Board (Si 024/2018 EC1).

Statistical methods

All the statistical analyses were performed using SPSS

statistical soware version 18.0 for Windows (SPSS Inc.,

Chicago, IL, USA). Categorical variables were analyzed

by using the chi-square test, and continuous variables

were compared using the Student’s t-test. Quantitative

data was conducted using n%, mean ± SD, or median

(min, max). Survival analysis was performed using the

Kaplan–Meier method and log-rank test. Univariate

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Parakonthun et al.

and multivariate analysis were performed using the

logistic regression model. All the statistical results were

considered signicant when the p-value was less than

0.05.

RESULTS

Clinicopathological characteristics

All the patients in this study were over 70 years of

age and had pathologically diagnosed adenocarcinoma

of either the stomach or esophagogastric junction. eir

clinicopathological characteristics were analyzed and

the results are shown in Table 1. e average age of the

patients was 76.6 years old in the curative group, 78.1

years old in the non-curative group, and 78.7 years old

in the BSC group. ere was a higher proportion of only

hypertensive patients in the curative group, but no dierence

in the other comorbidities. A better performance status

according to the ECOG score and a higher preoperative

serum albumin level were found in the curative group.

e majority of patients in the curative group had an

ASA physical status grade 2, while the other two groups

had ASA physical status grade 3. In terms of the tumor

characteristics, there were similar preoperative tumor

locations, macroscopic Borrmann types, and tumor

dierentiations among the three groups. Preoperative

clinical metastasis was found to be positive in the non-

curative group and BSC group more oen than in the

curative group. Two positive clinical metastasis in the

curative group were suspected liver metastasis according

to preoperative computed tomography but were found

to be negative during operation.

In the curative group, there were 51 distal gastrectomy,

46 total gastrectomy including extended gastrectomy,

3 proximal gastrectomy, and 2 partial gastrectomy. All

the patients underwent standard lymph node dissection

according to the Japanese classication of gastric carcinoma.

In the non-curative group, the choice of treatments

was according to the clinical symptoms of the patients,

such as bleeding or obstruction. ere were a total of

40 operative surgical procedures and 22 endoscopic

treatments. For the surgical procedures, there were 15

gastric resections (9 distal gastrectomy, 5 total gastrectomy,

and 1 partial gastrectomy), 10 feeding jejunostomy, 6

surgical bypass with gastrojejunostomy, and 2 simple

sutures for perforated gastric cancer. e remaining 7

patient cases involved 6 laparoscopies and 1 laparotomy,

in which metastasis was found so the curative surgical

operations were terminated and changed to non-curative

intention instead. For the endoscopic treatments, there

were 10 stent placements, 8 nasojejunal tube insertions, 2

endoscopic treatments for bleeding control, 1 nasogastric

tube insertion, and 1 percutaneous endoscopic gastrostomy

by push technique.

erapeutic outcomes

Overall survival analysis was conducted using

Kaplan–Meier survival curves. Comparing all the treatment

groups, there was a signicant better overall survival

in the curative group (p < 0.001) and the 5-year OS

survival was 22.5%. e median survival times were 32

months (95%CI 10.7-53.3), 5 months (95%CI 3.2-6.8), and

3 months (95%CI 2.2-3.8) aer diagnosis for the curative

group, non-curative group, and BSC group, respectively

(Fig 1). Although the non-curative group was treated for

palliative intention, they also had a signicantly better

overall survival compared with best supportive care alone

(p = 0.020). For all three types of treatment, no statistically

signicant dierence in overall survival (p = 0.079) was

found for the extremely old patients, classied as 80 years

old or over, compared to the younger patients, although

the median survival time was better in the younger group

(5 months vs. 12 months). In addition, pathological

staging aer curative surgery showed signicantly better

survival for the earlier stage than more advanced stage

of the disease (p = 0.02) as the median survival times

were 82, 34, 26, and 24 months for stages I, II, III, and

IV, respectively (Fig 2). ere were ve patients who had

underwent macroscopically curative resection but had

a positive peritoneal cytology, so they were considered

as being in stage IV of the disease. However for the nal

resection category, either R0 or R1 resection, there was

no statistical dierence in overall survival (p = 0.298).

Postoperative and treatment complications from

the curative group and non-curative group were detected

and classied by Clavien–Dindo classication

for both

surgical-related and non-surgical-related complications.

e surgical-related complications were gastroparesis

(16.5%), superficial surgical site infection (7.3%),

pancreatic fistula (3.7%), intraabdominal collection

(3%), bleeding (2.4%), anastomotic leakage (1.8%), and

intestinal obstruction (0.6%). e non-surgical-related.

complications were renal (15.9%); acute kidney injury

and volume overload, respiratory (11.6%); atelectasis

and pneumonia, cardiovascular (5.5%); myocardial

infarction, cardiac arrhythmia and heart failure, and

infection (4.3%); urinary tract infection, catheter-related

blood stream infection and septicemia, and neurologic

complications (3%); ischemic stroke and delirium Severe

complication was dened as Clavien–Dindo grade 3b

or higher. ere were 14 (8.5%) patients with severe

complications from these two groups. e postoperative

mortality rate was 3%. e clinical details are shown in

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Variables Curative Non-curative BSC P-value

n = 102 n = 62 n = 56

Age,(years) 76.63±4.93 78.05±5.92 78.73±5.39 0.596

Gender    0.075

 Male 64(62.7) 29(46.8) 27(48.2)

 Female 38(37.3) 33(53.2) 29(51.8)

Activesmoking 6(5.9) 6(9.7) 5(8.9) 0.628

Comorbidities

 DM 24(23.5) 16(25.8) 16(28.6) 0.783

 HT 70(68.6) 24(38.7) 27(48.2) <0.001

 CVA 12(11.8) 2(3.2) 6(10.7) 0.162

 COPD 6(5.9) 3(4.8) 2(3.6) 0.814

 CAD 11(10.8) 7(11.3) 3(5.4) 0.464

 VHD 6(5.9) 1(1.6) 0(0) 0.093

 CKD(≥stage4) 9(8.8) 3(4.8) 7(12.5) 0.333

ECOG    <0.001

 0-2 98(96.1) 49(79) 35(62.5)

 3-4 4(3.9) 13(21) 21(37.5)

Bodymassindex(kg/m

)    0.872

 <18.5 23(22.5) 16(25.8) 8(14.3)

 18.5-24.9 54(52.9) 31(50.0) 16(28.6)

 25-29.9 17(16.7) 7(11.3) 2(3.6)

 ≥30 5(4.9) 2(3.2) 1(1.8)

 Unknown 3(2.9) 6(9.7) 29(51.8)

Albumin(g/dL) 3.61±0.47 3.23±0.65 2.94±0.67 <0.001

ASAgrade    0.344

 I 1(1) 1(1.6) 1(1.8)

 II 62(60.8) 27(43.5) 27(48.2)

 III 38(37.3) 33(53.2) 28(50)

 IV 1(1) 0(0) 0(0)

 V 0(0) 1(1.6) 0(0)

Preoperative    0.828

Tumordifferentiation

 Well 9(8.8) 6(9.7) 4(7.1)

 Moderately 32(31.4) 16(25.8) 20(35.7)

 Poorly 52(51.0) 37(59.7) 31(55.4)

 Unknown 9(8.8) 3(4.8) 1(1.8) 

Preoperative    0.204

Tumorlocation

 EGJ 17(16.7) 15(24.2) 17(30.4)

 Upper1/3 7(6.9) 2(3.2) 6(10.7)

 Middle1/3 15(14.7) 10(16.1) 10(17.9)

 Lower1/3 57(55.9) 30(48.4) 19(33.9)

 Diffuse 3(2.9) 4(6.5) 4(7.1)

 Anastomosis 2(2.0) 0(0) 0(0)

Borrmannclassication    0.039

 I 11(10.8) 6(9.7) 10(17.9)

 II 35(34.3) 25(40.3) 15(26.8)

 III 43(42.2) 18(29.0) 15(26.8)

 IV 11(10.8) 11(17.7) 16(28.6)

 Unknown 2(2.0) 2(3.2) 0(0)

ClinicalTstaging    <0.001

 cT1 10(9.8) 2(3.2) 0(0)

 cT2 58(56.9) 18(29.0) 22(39.3)

 cT3 26(25.5) 26(41.9) 17(30.4)

 cT4 7(6.9) 14(22.6) 10(17.9)

 Unknown 1(1) 2(3.2) 7(12.5)

ClinicalNstaging    <0.001

 Negative 79(77.5) 32(51.6) 20(35.7)

 Positive 21(20.6) 25(40.3) 24(42.9)

 Unknown 2(2.0) 5(8.1) 12(21.4)

ClinicalMstaging    <0.001

 Negative 99(97.1) 33(53.2) 11(19.6)

 Positive 2(2.0) 23(37.1) 38(67.9)

 Unknown 1(1.0) 6(9.7) 7(12.5)

TABLE 1. Clinicopathological characteristics.

Abbreviations: DM = Diabetes mellitus; HT = Hypertension; CVA = Cerebrovascular accident; COPD = Chronic obstructive pulmonary

disease; CAD = Coronary artery disease; VHD = Valvular heart disease; CKD = Chronic kidney disease; ECOG = Eastern Cooperative

Oncology Group performance status score; ASA = American Society of Anesthesiologists physical status score.

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Parakonthun et al.

Fig 1. Kaplan-Meier overall survival

curves of the curative surgery, non-

curative treatment and best supportive

care groups.

Fig 2. Kaplan-Meier overall survival

curves of the dierent pathological stages

in the curative surgery group.

Table 2. e risk factors for severe complications in these

two groups were extremely old age over 80 years old

and the presence of coronary artery disease according

to the univariate analysis (Table 3). Multivariate analysis

showed that only the presence of coronary artery disease

(OR 7.65, 95%CI 2.2-26.6; p = 0.001) was an independent

risk factor. In the subgroup analysis of curative surgery

group, severe complications were found to be signicantly

higher in distal gastrectomy than in total gastrectomy

(11.8% vs. 4.3%; p = 0.033). We found that there was a

similar proportion of coronary artery disease patients

in both types of surgery, but a higher proportion of

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Abbreviation: EGD = Esophagogastroduodenoscopy

TABLE 2. Clinical details of the fourteen patients with severe complications.

No Age Procedure Complications Grade Management Result

Surgical related Non-surgical related (IIIb–V)

Curative surgery

1 71 Distalgastrectomywith Gastroparesis Myocardialinfarction, IIIb Nasojejunaltubeplacement, Improved

  wedgeliverresection  acutekidneyinjury,  medicaltreatment

    volumeoverload  

2 80 Distalgastrectomy Intestinalobstruction None IIIb Segmentaljejunalresection Improved

3 81 Distalgastrectomy Gastroparesis None IIIb DiagnosticEGD,intravenous Improved

      prokinetics,parenteralnutrition

4 80 Distalgastrectomy Gastroparesis None IIIb Nasojejunaltubeplacement Improved

5 74 Robotic-assistedlaparoscopic Gastroparesis None IIIb Nasogastrictubeplacement Improved

  distalgastrectomy    underuoroscopy

6 79 Robotic-assistedlaparoscopic Accidentallyclipped Pneumonia,myocardial IVb Repairhepaticartery,hemodialysis, Improved

  totalgastrectomy hepaticarteryproper infarction,acutekidneyinjury,  mechanicalventilation,blood

    volumeoverload  transfusion,medicaltreatment

7 85 Extendedgastrectomy Anastomoticleakage, Pneumonia,cardiac V Abdominaltoiletwithfeeding Deathfrom

   intraabdominalcollection arrhythmia,catheter-related  jejunostomy,mechanicalventilation, severesepsis

    bloodstreaminfection  tracheostomy,intravenousantibiotics onday49

8 92 Distalgastrectomy Bleedingfromanterior Cardiacarrhythmia, V Reexplorelaparotomytostop Deathfrom

   pancreaticoduodenal acutekidneyinjury,  bleeding,massivebloodtransfusion, severemeta

   arteryandanterior liverfailure,coagulopathy  medicaltreatment bolicacidosis

   surfaceofpancreas    onday2

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Parakonthun et al.

TABLE 2. Clinical details of the fourteen patients with severe complications.

No Age Procedure Complications Grade Management Result

Surgical related Non-surgical related (IIIb–V)

Non-curative treatment

1 76 Simplesuturewithomental Supercialsurgicalsite Atelectasis,volumeoverload, IVa Mechanicalventilation,medical Improved

  graftwithfeedingjejunostomy infection delirium,septicshock  treatment,intravenousantibiotics,

      wounddressing

2 75 Simplesuturewithomental None Pneumonia,cardiacarrhythmia, IVa Mechanicalventilation, Improved

  graft  volumeoverload,catheter-  tracheostomy,medicaltreatment,

    relatedbloodstreaminfection  intravenousantibiotics

3 86 Palliativedistalgastrectomy None Pneumonia,acutekidneyinjury, IVb Mechanicalventilation,hemodialysis, Improved

    volumeoverload  intravenousantibiotics

4 92 Laparoscopicfeeding Bowelileus Septicemia V Intravenousprokinetics, Deathfrom

  jejunostomy    intravenousantibiotics septicemia

       onday24

5 71 Diagnosticlaparoscopy None Myocardialinfarction, V Mechanicalventilation, Deathfrom

    congestiveheartfailure,  medicaltreatment myocardial

    volumeoverload   infarctionon

       day19

6 83 Diagnosticlaparoscopy None Pneumonia,volumeoverload, V Intravenousantibiotics, Deathfrom

  withfeedingjejunostomy  ischemicstroke  oxygensupplement respiratory

       failureon

       day24

Abbreviation: EGD = Esophagogastroduodenoscopy

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extremely old aged patients over 80 years underwent

distal gastrectomy surgery (66.6% vs. 50%). In contrast,

there was no statistically signicant dierence in the

severe complications in the subgroup analysis of the

various treatment options for the Non-curative group

(p = 0.137). ere were ve in-hospital mortalities and

four 30-days-postoperative mortalities, which are also

shown in Table 2. e signicant risk factors for in-hospital

mortalities were extremely old age over 80 years old

(OR 10.36, 95%CI 1.1-95.3; p = 0.039) and the presence

of coronary artery disease (OR 14.30, 95%CI 2.2-92.5;

p = 0.005). For the 30-days-postoperative mortalities, the

only signicant risk factor was the presence of coronary

artery disease (OR 9.00, 95%CI 1.2-68.3; p = 0.034).

e mean hospital length of stay from the curative and

non-curative groups was 12 days. e risk factors for

prolonged hospitalization were an extremely old age over

80 years old, the presence of hypertension, the presence

of coronary artery disease, and patients who had severe

complications according to the univariate analysis, but

severe complications was the only independent risk

factor (OR 22.84, 95%CI 4.9-107.4; p < 0.001) identied

from the multivariate analysis.

DISCUSSION

Life expectancy has been increasing globally, paralleling

the advancement in holistic medical care. e extent of

comorbidities and decline of functional status increase

with age, and these also aect morbidity and mortality

in cancer patients. A better understanding of frailty

in an oncology population may assist in identifying

older adults who are candidates for palliative therapy

as well as those patients who may benet from standard

treatment.

In 2006, Gretschel et al.

Reported the higher

mortality rate of curative surgery for gastric cancer in

a more elderly age group. With the improvement of

surgical techniques and postoperative care over time,

recent studies have revealed a signicant better survival

outcome in curative surgical resection regardless of older

age,

with no signicance dierences in postoperative

morbidity and mortality.

5,14

In the present study, curative surgery showed

signicantly better overall survival compared to non-

curative treatment and best supportive care despite

the more advanced age. is result corresponded to a

previous study by Choo et al.

e better survival outcomes

might be from unavoidable selection bias in choosing

curative surgery for patients who tend to have a better

performance status, relatively higher nutritional status,

and the absence of clinical metastasis at the time of the

treatment decision. Only four patients in our curative

surgery group had a poor performance status, and none of

them had severe postoperative complications. A previous

study at our center showed that positive microscopic

TABLE 3. Factors aecting severe postoperative complications.

Variables Univariate Multivariate

OR (95% CI) P-value OR (95% CI) P-value

Age≥80 3.667(1.19-11.22) 0.023 3.173(0.98-10.28) 0.054

Sex 1.344(0.45-4.02) 0.597 

ASA≥3 1.744(0.58-5.27) 0.325 

Comorbidities

 DM 1.267(0.37-4.28) 0.704

 HT 1.964(0.59-6.55) 0.272

 CAD 8.625(2.57-28.98) <0.001 7.652(2.20-26.60) 0.001

 CKD(≥stage4) 2.333(0.46-11.89) 0.308

ECOG≥3 1.500(0.31-7.35) 0.617 

Albumin<3 0.378(0.05-3.07) 0.363 

Abbreviations: ASA = American Society of Anesthesiologists physical status score; DM = Diabetes mellitus; HT = Hypertension; CAD =

Coronary artery disease; CKD = Chronic kidney disease; ECOG = Eastern Cooperative Oncology Group performance status score.

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Parakonthun et al.

residual tumor aer standard gastrectomy seemed to

have a downward tendency for the survival outcome

and this was relevant to the results from the present study.

For the remaining patients beyond this curative group,

they were treated as having incurable gastric cancer based

on physicians and patients’ reasons. Hsu et al.

found

that palliative gastrectomy still oered a better median

survival time than the non-resection procedure. In serious

symptomatic patients, stent placement for obstruction

has been shown to be clinically eective

, and endoscopic

hemostasis for bleeding associated gastric cancer achieved

an initial successful for 83% of patients.

ese evidences

support our various options for non-curative treatment,

which depended on the clinical symptoms and yielded

a signicantly better survival result compared to best

supportive care alone.

Due to the lack of complete follow-up data and

the recurrence rate from our retrospective study design,

disease-specic survival could not be clearly interpreted.

As the mortality rate in our study was relatively low,

the risk factors for postoperative mortality could not be

analyzed. Hopefully, further research and progression

in treatment would provide better survival outcomes

and less morbidities.

Severe complications in our series occurred in 7.8%

of patients in our curative surgery group and 9.7% in

the non-curative treatment group (p = 0.77). e only

predictive risk factor for severe complications was the

presence of coronary artery disease, which diered from

the previous study, which reported a low serum albumin

level and male sex as risk factors

From all the severe

complication cases in the non-curative group, there was

none from endoscopic management. is might be from

it being a less invasiveness and quicker procedure.

CONCLUSION

Elderly gastric cancer patients are still candidates

for curative surgical resection in spite of their more

advanced age and comorbidities. Surgery oers a better

survival outcome than best supportive care alone. e

possibility of severe postoperative complications should

be considered, especially in coronary artery disease

patients.

ACKNOWLEDGMENTS

We are thankful to Dr. Saowalak Hunnangkul for

her assistance with the statistical analysis.

REFERENCES

1. National Cancer Institute DoMS, Ministry of Public Heath of

ailand. Hospital-Based Cancer Registry 2016;2016:1-94.

2. Choo JW, Ju Y, Lim H, Youn SH, Soh JS, Park JW, et al. Is it

benecial to perform surgical resection in elderly patients more

than 80 years old with advanced gastric cancer? Scand J

Gastroenterol 2017;52:1057-64.

3. Endo S, Shimizu Y, Ikenaga M, Ohta K, Yamada T. Survival

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years old: A retrospective propensity score-matched analysis.

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4. Konishi H, Ichikawa D, Itoh H, Fukuda K, Kakihara N, Takemura

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6. Yang JY, Lee HJ, Kim TH, Huh YJ, Son YG, Park JH, et al.

Short- and Long-Term Outcomes Aer Gastrectomy in Elderly

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7. Zhou CJ, Chen FF, Zhuang CL, Pang WY, Zhang FY, Huang

DD, et al. Feasibility of radical gastrectomy for elderly patients

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8. Siewert JR, Stein HJ. Classication of adenocarcinoma of the

oesophagogastric junction. Br J Surg 1998;85:1457-9.

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carcinoma: 3

English edition. Gastric Cancer 2011;14:101-12.

10. Japanese Gastric Cancer A. Japanese gastric cancer treatment

guidelines 2014 (ver. 4). Gastric Cancer 2017;20:1-19.

11. Dindo D, Demartines N, Clavien PA. Classication of surgical

complications: a new proposal with evaluation in a cohort of

6336 patients and results of a survey. Ann Surg 2004;240:205-13.

12. Pal SK, Katheria V, Hurria A. Evaluating the older patient

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CA Cancer J Clin 2010;60:120-32.

13. Gretschel S, Estevez-Schwarz L, Hunerbein M, Schneider U,

Schlag PM. Gastric cancer surgery in elderly patients. World

J Surg 2006;30:1468-74.

14. Kim MS, Kim S. Outcome of Gastric Cancer Surgery in Elderly

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15. Parakonthun T, Parichardsombat N, Paredes HSR, Phalanusittheph

C, Taweerutchana V, Trakarnsanga A, et al. Signicance of

Microscopic Residual Tumor in Adenocarcinoma of Stomach and

Esophagogastric Junction after Gastrectomy with D2

Lymphadenectomy. Siriraj Med J 2018;70:95-102.

16. Hsu JT, Liao JA, Chuang HC, Chen TD, Chen TH, Kuo CJ, et al.

Palliative gastrectomy is benecial in selected cases of metastatic

gastric cancer. BMC Palliat Care 2017;16:19.

17. Kim JH, Song HY, Shin JH, Hu HT, Lee SK, Jung HY, et al.

Metallic stent placement in the palliative treatment of malignant

gastric outlet obstructions: primary gastric carcinoma versus

pancreatic carcinoma. AJR Am J Roentgenol 2009;193:241-7.

18. Song IJ, Kim HJ, Lee JA, Park JC, Shin SK, Lee SK, et al. Clinical

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Cancer 2016;16:43-50.

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Pholasith Sangserestid, M.D., Chutwichai Tovikkai, M.D., Yongyut Sirivatanauksorn, M.D., Prawat Kositamongkol,

M.D., Prawej Mahawithitwong, M.D., Wethit Dumronggittigule, M.D., Somchai Limsrichamrern, M.D.

Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.

The Malignant Potential in Adult Choledochal

Cysts; an Awareness Issue

ABSTRACT

Objective: Although still uncommon, choledochal cysts (CCs) are more frequently found in Asians than Caucasians.

e incidence of malignancy associated with these cysts and the surgical outcomes have not been reported in ailand.

Methods: A retrospective review was performed of 48 adult CC patients who underwent surgery January 2005–

December 2015. eir clinical data and outcomes were analyzed.

Results: ere were 31 (64.6%) female patients, with a female-to-male ratio of 1.8:1. e mean age ± SD at diagnosis

was 40.5 ± 17.4 years. Using the modied Todani classication, 32 patients (66.7%) had a type I CC, one (2.1%)

had type II, twelve (25.0%) had type IV, and three (6.3%) had type V. Twelve patients (25%) had a malignant

tumor: eleven had synchronous cancer at surgery, while one with CC type I developed metachronous intrahepatic

cholangiocarcinoma during the follow-up. e cholangiocarcinoma was inside the CC in 6 cases, intrahepatic in

three, perihilar in two, and distal in one. e 5-year overall survival of the cohort was 68%. e factor aecting the

overall survival was the coexisting cancer (p < 0.001). e 1-year and 5-year overall survival rates were 58.3% and

20%, respectively, for patients with cancer, but 96.7% and 88.4% for patients without cancer.

Conclusion: e adult choledochal cysts had a high incidence of associated malignancy. Factors predicting coexisting

malignancy were an age above 40 years and a signicant weight loss. If cancer occurred, the overall survival was

signicantly poor. Even aer denitive surgery, patients still need life-long surveillance for cancer.

Keywords: Cholangiocarcinoma; choledochal cyst; malignancy; prognosis factors; risk factors (Siriraj Med J 2019;

71: 466-471)

Corresponding author: Yongyut Sirivatanauksorn

E-mail: ysirivat@gmail.com

Received 31 May 2019 Revised 10 October 2019 Accepted 11 November 2019

ORCID ID: http://orcid.org/0000-0001-7520-8832

http://dx.doi.org/10.33192/Smj.2019.69

INTRODUCTION

Choledochal cysts (CCs) are an uncommon congenital

anomaly of the bile duct that present as an abnormal

cystic dilatation of the intra and/or extra hepatic bile

ducts. In 1959, Alonso-Lej et al. rst described and

proposed a classication of CCs into 3 types.

is was

modied in 1977 by Todani et al. by adding types IV and V.

e Todani system is currently the most widely used

classication scheme for CCs. e incidence of CCs is

approximately 1 in 100,000 to 150,000 live births in the

Western population, but it has been reported to be as

high as 1 in 13,500 live births in the United States and

1 in 15,000 in Australia.

In Asia, CCs are more commonly

reported, especially in Japan, with an incidence of up to

1 in 1,000 live births.

CCs are usually diagnosed in childhood; however

about 20% of patients present in adulthood.

In adult

patients, CCs commonly present with abdominal pain,

jaundice, and a palpable mass. e patients may also

present with severe complications, such as cholangitis,

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Sangserestid et al.

pancreatitis, secondary biliary cirrhosis, and cancer. Cancer

associated with CC is one of the dire complications of CC

and drastically aects the outcome. Carcinoma arising in

CC can be found within the cyst or any part of the biliary

system. e incidence of cholangiocarcinoma arising

with CCs varies and depends on the CC subtype and the

patient’s age.

6-11

Moreover, the risk of malignancy is not

reduced in patients with inadequate treatment, such as

a cystoenterostomy and/or incomplete cyst excision.

10,11

In ailand, little data regarding CCs

12-16

have been

reported as case reports or small case series. erefore,

this study aimed to analyze the clinical data, operative

procedures, surgical outcomes, and risk factors associated

with cancer in a large series of CC patients.

MATERIALS AND METHODS

A total of 48 consecutive patients diagnosed with

CCs who underwent surgery between January 2005

and December 2015 at the Hepatopancreatobiliary and

Transplant Surgery Unit, Department of Surgery, Faculty

of Medicine Siriraj Hospital, Mahidol University, were

enrolled. We obtained the demographic data, medical

comorbidities, laboratory information, operative outcomes,

and long-term survival of the patients from a retrospective

chart review. All of the patients were above 18 years of

age at the time of denitive surgery. e type and extent

of the surgery were based on a clinical assessment by

a consultant surgeon. is study was approved by the

Institutional Review Board of the Faculty of Medicine

Siriraj Hospital, Mahidol University (Si 089/2016).

Statistical analysis

Continuous variables are expressed as mean and

standard deviation (± SD), and comparisons were made

using Student’s t-test. Categorical variables were compared

using a chi-squared or Fisher’s exact test, as appropriate.

A logistic regression model was used to identify factors

predicting a coexisting malignancy. e overall survival

rates were analyzed with the Kaplan–Meier method and

log-rank tests. All statistical analyses were performed using

Stata for Macintosh, version 15.0 (StataCorp, College

Station, TX, USA). e level of statistical signicance

was set at a p-value of ≤ 0.05.

RESULTS

Forty-eight consecutive patients diagnosed with

CCs underwent operations in the Hepatopancreatobiliary

and Transplant Surgery Unit at Siriraj Hospital between

January 1, 2005 and December 31, 2015. ere were 31

(64.6%) female and 17 (35.4%) male patients, with a

female-to-male ratio of 1.8:1. e mean age (± SD) of

the patients at diagnosis was 40.5 (± 17.4) years. Most

of the patients had at least one symptom. e most

common presentation was abdominal pain (93.8%),

followed by obstructive jaundice (45.8%) and cholangitis

(45.8%). Choledocholithiasis and hepatolithiasis were also

observed in 52.1% and 14.6% of patients, respectively. As

to the treatments, preoperative endoscopic retrograde

cholangiopancreatography and percutaneous transhepatic

biliary drainage were performed in 15 (31.3%) and 5

(10.4%) patients, respectively. Fourteen patients (29.2%)

had previously undergone a cholecystectomy before

definitive surgery. The mean time between the first

presenting symptoms and denite surgery was 49.7

months. e demographic data of the cohort are detailed

in Table 1.

Based on the modied Todani classication

, 32

patients (66.7%) had a type I cyst, one (2.1%) had type II,

twelve (25.0%) had type IV, and three (6.3%) had type V.

Of note, there was no CC type III in this cohort. CC type

IV was signicantly associated with hepatolithiasis (33% ;

p = 0.02). A CC excision with a hepaticojejunostomy was

the most frequently performed operation (24 patients;

50%). e detail of the operations and the CC types are

presented in Table 2.

In this series, there were 12 patients (25%) with a

malignant tumor. Eleven patients had cancer at the time

of the surgery. Of the eleven, ve underwent curative

surgery, while six only had a palliative bypass or a biopsy.

Thirty-six patients had no cancer at the beginning.

irty-one patients had no symptoms aer surgery,

with a mean follow-up time of 31.4 months. However,

2 patients died from liver abscess and massive upper

gastrointestinal bleeding, and another 3 patients had to

undergo reoperation. Moreover, one patient with CC

type I developed intrahepatic cholangiocarcinoma 18

months aer the cyst excision and hepaticojejunostomy.

e malignancy most oen associated with the CCs

was cholangiocarcinoma. Patients with CC type V had

the highest incidence of malignancy (66.7%), following

by types I and IV at 25% and 16.7%, respectively. One

patient with CC type II had no cancer at the beginning

or during the follow-up. e cholangiocarcinoma was

inside the CC in 6 cases, intrahepatic in three, perihilar

in two, and distal in one. e other cancer types that

occurred in our patients were pancreatic adenocarcinoma

in the pancreatic head and the body of the pancreas, and

adenocarcinoma in the sigmoid colon.

Three patients had 2 concomitant cancers, but

they were dierent types. e rst patient had distal

cholangiocarcinoma and pancreatic adenocarcinoma

in the body of the pancreas. e second had perihilar

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TABLE 1. Patient characteristics and clinical manifestations of patients with and without malignancy.

Characteristics Total % Non-CA % CA % P

Number 48 100.0 36 75.00 12 25.00

Sex       0.60

 Male 17 35.4 12 70.6 5 29.4

 Female 31 64.6 24 77.4 7 22.6

Age(mean±SD;years) 40.5±17.4  35.8±15.7  54.9±14.2  0.001

Clinicalmanifestation      

RUQpain,epigastricpain 45 93.8 33 91.7 12 100.0 0.40

Jaundice 22 45.8 17 47.2 5 41.7 0.74

Cholangitis 22 45.8 15 41.7 7 58.3 0.31

Signicantweightloss 6 12.5 2 5.6 4 33.3 0.01

Palpablemass 6 12.5 3 8.3 3 25.0 0.13

Pancreatitis 4 8.3 4 11.1 0 0.0 0.22

Cholecystitis 3 6.3 2 5.6 1 8.3 0.73

Liverabscess 1 2.1 1 2.8 0 0.0 0.56

Asymptomatic 2 4.2 2 5.6 0 0.0 0.40

ConcurrentCBDstone 25 52.1 18 50.0 7 58.3 0.62

ConcurrentIHDstone 7 14.6 5 13.9 2 16.7 0.81

Priorcholecystectomy 14 29.2 9 25.0 5 41.7 0.08

CA19-9(mean±SD;ng/ml) 422.8±1,573.9  47.1±70.1  736.0±2,119.0  0.32

CEA(mean±SD;U/ml) 4.00±5.3  2.3±3.6  5.9±6.3  0.13

Timetosurgery 49.7±71.1  48.0±76.3  54.6±54.7  0.80

(mean±SD;months)

Abbreviations: Non-CA: no malignancy; CA: malignancy; RUQ: right upper quadrant; CBD: common bile duct; IHD: intrahepatic duct

TABLE 2. Choledochal cyst type and operative procedure.

Operation Choledochal cyst type

I II IV V

CE+HJ 24  7

CE   1 

CE+HJ+LR 1  3

CE+HJ+PD 2  1

LR 2

Palliative 4  1 1

Other 1  

Total 32 1 12 3

Abbreviations: CE: cyst excision; HJ: hepaticojejunostomy; LR: liver resection; PD: pancreaticoduodenectomy; Palliative: palliative surgical

bypass

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cholangiocarcinoma and sigmoid colon cancer. e

last patient had intrahepatic cholangiocarcinoma and

cholangiocarcinoma arising in the CC (type I).

Despite undergoing curative surgery, the patients

with cancer had a poor overall survival. Four patients

(80%) died at 2, 20, 35, and 40 months aer surgery

due to disease recurrence. Only one patient survived

without evidence of disease aer 67 months of follow-

up. Furthermore, all patients who had an unresectable

disease died within a year of surgery. In the case of the

patient who developed intrahepatic cholangiocarcinoma

during surveillance, she had not experienced any disease

recurrence as at 12 months aer a right hepatectomy.

e patients with cancer were signicantly older

than those without cancer (mean age ± SD: 54.9 ± 14.2

vs 35.8 ± 15.7 years; p < 0.001). e levels of CA 19-9

and CEA in the patients with cancer were also higher

than in those without cancer, but the dierences were not

statistically signicant. A univariable analysis identied

that the two risk factors associated with cancer in these

patients was an age above 40 years and a signicant

weight loss before surgery.

e operations were mostly performed in an elective

setting. However, six patients (12.5%) had urgent surgery

after improvement of acute cholangitis in the same

admission. ese patients had signicantly more blood

loss (1,064 ml vs 465 ml; p = 0.034) and usually required

more blood transfusion (1.2 units vs 0.2 units; p = 0.013).

On the other hand, the urgent operations did not aect

the patients’ post-operative morbidity or long-term

survival.

e overall post-operative complication rate was

around 54%, with half of the complications being minor

(such as surgical site infection, at 23%). A comparison

of the patients with and without cancer revealed that

the overall complications were quite similar, except that

there was a signicantly higher rate of intrabdominal

collection in the cancer group (33% vs 8%; p = 0.03). e

complication rates and surgical outcomes of the patients

with and without cancer are presented in Table 3.

e 5-year overall survival rate of the cohort was

68%. e factor aecting the overall survival was the

coexisting cancer (p < 0.001). In the case of the patients

with cancer, the 1-year and 5-year overall survival rates

were 58.3% and 20%, respectively, whereas for the patients

without cancer, the corresponding rates were 96.7% and

88.4% (Fig 1).

TABLE 3. Surgical outcomes and post-operative complications of patients with and without malignancy.

Parameters Total % Non-CA % CA % P

Operationtype       0.94

 Elective 42 87.5 31 86.1 11 91.7

 Urgent 6 12.5 5 13.9 1 8.3

Cystsize(mean±SD;cm) 4.6±3.6  4.8±4.1  4.1±2.2  0.55

Operativetime(mean±SD;min) 235±14  235±13  234±44  0.96

EBL(mean±SD;ml) 541±95  575±118  431±125  0.52

PRCtransfusion(mean±SD;units) 0.36±0.87  0.42±0.94  0.18±0.60  0.44

Lengthofstay(mean±SD;days) 11.5±9.0  10.5±6.4  14.7±14.5  0.18

Complications 26 54.2 6 50 8 66.7

 Anastomosisstricture 4 8.3 4 11.1 0 0.0 0.23

 Bileleakage 5 10.4 5 13.9 0 0.0 0.17

 Vascularinjury 4 8.3 3 8.3 1 8.3 1.0

 Woundinfection 11 22.9 8 22.2 3 25.0 0.84

 Intra-abdominalcollection/abscess 7 14.6 3 8.3 4 33.3 0.03

 Cholangitis 6 12.5 4 11.1 2 16.7 0.61

 Pancreatitis 2 4.2 2 5.6 0 0.0 0.40

 Pseudoaneurysm 1 2.1 0 0.0 1 8.3 0.08

 Pancreaticstula 4 8.3 2 5.6 2 16.7 0.23

Abbreviations: Non-CA: no malignancy; CA: malignancy; EBL: estimated blood loss; PRC: packed red blood cells

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DISCUSSION

In this single-center study, we describe a series of

CCs, which is not a common disease, especially in adults.

Patients usually present with recurrent, self-limited,

abdominal discomfort at the beginning without any

other symptoms. erefore, they are oen misdiagnosed

with dyspepsia until they develop more obvious clinical

symptoms related to, for example, obstructive jaundice

or cholangitis. As abdominal ultrasonography sometimes

misses the identication of a cystic dilatation of bile duct,

there were some patients in our series who had undergone

a cholecystectomy before denitive surgery (29.2%).

Moreover, the average time to denite surgery was quite

long at about 49.7 months. Due to the late diagnosis,

the patients in the current study had a high incidence

of CBD and IHD stones; this was in concordance with

many previous studies comparing CCs in adults and

children.

8,9,18

Many previous studies have reported that the

malignancies occurring in CC patients are cholangiocarcinoma

and gallbladder cancer.

10,11,17-23

e reported incidence

rate of synchronous biliary tract malignancy ranges

from 7% to 23.5%.

6,10,11,17-23

Our series saw a similar high

incidence of concomitant cancer (25%), especially in

patients aged more than 40 years, which may result from

late diagnosis. Our results support previous studies that

found a higher age is associated with a higher cancer

incidence.

7,23

It is noteworthy that our series found no

coexisting gallbladder cancer, which may be due to the

high incidence of prior cholecystectomy.

Cholangiocarcinoma can subsequently develop in

about 0.6%-5.4% of cases, even aer curative surgery, as

described in numerous other reports.

6,10,11,17,18,20

is is

consistent with our nding that one patient (2%) with

a type I CC developed intrahepatic cholangiocarcinoma

18 months aer cyst excision and hepaticojejunostomy.

erefore, continued surveillance is advocated in every

patient aer denitive surgery. Interestingly, we also found

some CC patients presented with pancreatic adenocarcinoma

and colonic carcinoma. CCs may increase the risk for

other types of cancer without a clear pathogenesis. is

issue warrants further investigation.

e management of a CC type IVa is more complex

and still controversial. At our institution, it is managed

in two ways: cyst excision and hepaticojejunostomy,

with or without a hepatectomy. e indications for

hepatectomy in unilobar disease are hepatolithiasis,

atrophy, or suspected malignancy. A unilobar cystic

dilation only is not an indication for hepatectomy. As to

bilobar involvement, hepatectomy is performed only on

liver segments that have hepatolithiasis, lobar atrophy, or a

suspected malignancy. During surveillance, three patients

with additional liver resection were symptom-free aer

a mean follow-up of 63 months. Seven patients without

an indication for hepatectomy also had no symptoms

aer a mean follow-up of 15.6 months. Nevertheless, it

was dicult to compare the outcomes of the two groups

because of the markedly dierent mean follow-up times.

is study has some limitations due to its retrospective

nature and the small patient population. e follow-up

duration was not long enough to enable conclusions to be

drawn on the cumulative risk of cancer and hepatolithiasis

developing aer surgery. A larger series with a long-term

follow-up, such as a multi-center study or a national

registry, is therefore still needed.

Fig 1. Overall survival estimates of all patients (A), and a comparison between patients with and without cancer (B).

A B

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CONCLUSION

e adult CCs had a high incidence of associated

malignancy. e factors predicting a coexisting malignancy

were an age above 40 years and a signicant weight loss.

If cancer occurred, the overall survival was signicantly

poor. Even aer denitive surgery, patients still need

life-long surveillance for cancer.

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cyst, with a report of 2, and an analysis of 94, cases. Int Abstr

Surg 1959;108:1-30.

2. Todani T, Watanabe Y, Narusue M, Tabuchi K, Okajima K.

Congenital bile duct cysts: Classication, operative procedures,

and review of thirty-seven cases including cancer arising from

choledochal cyst. Am J Surg 1977;134:263-9.

3. Gigot J, Nagorney D, Farnell M, Moir C, Ilstrup D. Bile duct

cysts: A changing spectrum of disease. J Hepatobiliary Pancreat

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4. O’Neill JA Jr. Choledochal cyst. Curr Probl Surg 1992;29:361-

410.

5. Singham J, Yoshida EM, Scudamore CH. Choledochal cysts:

part 1 of 3: classication and pathogenesis. Can J Surg 2009;52:

434-40.

6. Watanabe Y, Toki A, Todani T. Bile duct cancer developed

aer cyst excision for choledochal cyst. J Hepatobiliary Pancreat

Surg 1999;6:207-12.

7. Voyles CR, Smadja C, Shands WC, Blumgart LH. Carcinoma in

choledochal cysts: age-related incidence. Arch Surg 1983;118:

986-8.

8. Chaudhary A, Dhar P, Sachdev A, Kumar N, Vij JC, Sarin SK,

et al. Choledochal cysts‐dierences in children and adults. Br

J Surg 1996;83:186-8.

9. Bhavsar MS, Vora HB, Giriyappa VH. Choledochal cysts: a

review of literature. Saudi J Gastroenterol 2012;18:230-6.

10. Ohashi T,Wakai T,Kubota M,Matsuda Y,Arai Y,Ohyama T,

et al. Risk of subsequent biliary malignancy in patients undergoing

cyst excision for congenital choledochal cysts. J Gastroenterol

Hepatol 2013;28:243-7.

11. Ten Hove A, de Meijer VE, Hulscher JB, de Kleine RH. Meta‐

analysis of risk of developing malignancy in congenital choledochal

malformation. Br J Surg 2018;105:482-90.

12. Khieocharoen S. Adult Choledochal Cyst in Buddhachinaraj

Phitsanulok Hospital. Buddhachinaraj Med J 2010;24:200-7.

13. Treepongkarunar S. Adult choledochal cyst: report of four

cases. Khon Kaen Med J 1993;17:27-38.

14. Akaraviputh T, Boonnuch W, Watanapa P, Lert-Akayamanee

N, Lohsiriwat D. Surgical management of adult choledochal

cysts. J Med Assoc ai 2005;88:939-43.

15. Singhavejsakul J, Ukarapol N. Choledochal cysts in children:

epidemiology and outcomes. World J Surg 2008;32:1385-8.

16. Boonyongsunchai P, Kongphanich C, Srikoch Y. Malignant

Choledochal Cyst: A Case Report and Reviews. ai J Surg

2011;32:80-83.

17. Lee SE, Jang JY, Lee YJ, Choi DW, Lee WJ, Cho BH, et al.

Choledochal cyst and associated malignant tumors in adults:

a multicenter survey in South Korea. Arch Surg 2011;146:1178-

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18. Edil BH, Cameron JL, Reddy S, Lum Y, Lipsett PA, Nathan H,

et al. Choledochal cyst disease in children and adults: a 30-

year single-institution experience. J Am Coll Surg 2008;206:

1000-5.

19. Tsuchiya RY, Harada NO, Ito TO, Furukawa MA, Yoshihiro

IT. Malignant tumors in choledochal cysts. Ann Surg 1977;186:

22-28.

20. Mizuguchi Y, Nakamura Y, Uchida E. Subsequent biliary

cancer originating from remnant intrapancreatic bile ducts

aer cyst excision: a literature review. Surg Today 2017;47:

660-7.

21. He XD, Wang L, Liu W, Liu Q, Qu Q, Li BL, et al. e risk of

carcinogenesis in congenital choledochal cyst patients: an

analysis of 214 cases. Ann Hepatol 2014;13:819-26.

22. Sastry AV, Abbadessa B, Wayne MG, Steele JG, Cooperman

AM. What is the incidence of biliary carcinoma in choledochal

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Suparauk Geanphun, M.D., Pranya Sakiyalak, M.D.

Division of Cardiothoracic Surgery, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand.

Survival and Factors Predictive of Survival in

Patients with Thymic Carcinoma

ABSTRACT

Objective: ymic carcinoma is a rare malignancy that has a poor prognosis and low 5-year survival. e rarity

of this disease and the variety of histologic subtypes has limited the evidence needed to establish disease-specic

staging and treatment guidelines. e aim of this study was to investigate overall survival, the factors that predict

survival, and the treatment modalities that inuence survival in patients with thymic carcinoma.

Methods: All thymic carcinoma cases diagnosed and treated at Siriraj Hospital (Bangkok, ailand) during 1997-

2013 were retrospectively reviewed. Univariate and multivariate analyses were performed to identify factors that

predict survival, and overall survival was estimated by Kaplan-Meier method.

Results: Of the 45 patients diagnosed during the study period, 8 were lost to follow-up. e remaining 37 patients

were included in our analysis. e median survival time was 2.5 years, with 5-year and 10-year survival of 40% and

16%, respectively. In univariate analysis, tumors >10 cm (p=0.017), high-grade histologic subtypes (p=0.014), and

high Masaoka stage (p=0.011) were signicant determinants of survival. Multivariate analysis revealed tumor size

(HR: 3.594, 95% CI: 1.103-11.714; p=0.034) and high-grade histologic subtypes (HR: 8.175, 95% CI: 1.689-39.566;

p=0.009) to be independent predictors of survival. Patients who underwent tumor removal had signicantly longer

median survival time than those who didn’t (3.85 vs. 0.63 years; p=0.005).

Conclusion: ymic carcinoma patients have low 5-year and 10-year survival. Tumor size and high-grade histologic

subtype were identied as independent predictors of survival, and surgical therapy was found to be signicantly

associated with longer median survival time.

Keywords: ymic carcinoma; malignant thymoma; invasive mediastinal tumor (Siriraj Med J 2019; 71: 472-479)

Corresponding author: Pranya Sakiyalak

E-mail: pranya.sak@mahidol.ac.th

Received 30 August 2019 Revised 9 October 2019 Accepted 15 October 2019

ORCID ID: http://orcid.org/0000-0003-1716-1225

http://dx.doi.org/10.33192/Smj.2019.70

INTRODUCTION

ymic tumors are the most common primary

neoplasms located at the anterior mediastinum, with

an incidence of less than 0.13 per 100,000 person-years

in the USA. However, thymic carcinoma is a very rare

malignancy that accounts for only 0.06% of all thymic

neoplasms.

1-5

ymic carcinoma is an invasive, aggressive,

metastasis-prone malignancy that has a poor prognosis

with an estimated 5-year survival of 30%.

e classication

and clinical staging of thymic carcinomas has not been

conclusively established due to the rarity of this condition

and the variety of histologic subtypes and their dissimilar

characteristics.

8,9,10

e clinical staging system that is

currently most appropriate for the evaluation of thymic

carcinomas is Masaoka staging due to its prognostic

value.

e aim of this study was to investigate overall

survival, the factors that predict survival, and the treatment

modalities that inuence survival in patients with thymic

carcinoma.

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MATERIALS AND METHODS

is retrospective chart review included patients

diagnosed with and treated for thymic carcinoma at

the Division of Cardiothoracic Surgery, Department of

Surgery, Faculty of Medicine Siriraj Hospital, Mahidol

University, Bangkok, ailand during the January 1997

to December 2013 study period. e following patient

data were collected and analyzed: patient demographics;

clinical presentations; preoperative diagnosis; Masaoka

stage; tumor size; surgical procedure, including no surgery,

local therapy only, (including excisional biopsy), thymic

excision (including debulking and/or simple, total, and

radical excision); radiation therapy; histologic subtype;

recurrence; and, survival data. Patients with missing

treatment and/or follow-up data were excluded. In case

of the patients were deceased, they or their families would

be contacted by telephone to determine whether they

were alive or not.

e protocol for this study was approved by the

Siriraj Institutional Review Board (Si 609/2014(EC2)].

e customary requirement to obtain patient written

informed consent was waived due to the retrospective

nature of this study.

Statistical analysis

Continuous data variables were analyzed using Student’s

t-test. Nominal data were analyzed using crosstabs and

Pearson’s chi-square test. Data are reported as mean and

range or frequency and percentage. Kaplan-Meier survival

curves were generated, and they were compared using

log-rank test. A Cox proportional hazard model was used

to identify the variables that signicantly impact overall

survival. e proportionality of hazards was evaluated

using Cox regression analysis with time-dependent

covariates. e assumption of proportionality of hazards

was tested, and was not to be broken in any of the Cox

regression models. Statistical analysis was performed

with SPSS statistical soware package version 18.0 (SPSS,

Inc., Chicago, IL, USA). Statistical signicance was set

at a probability value less than 0.05.

RESULTS

Of the 45 cases diagnosed with thymic carcinoma

during the study period, 8 patients were excluded due

to loss to follow-up aer the rst hospital visit (Fig 1).

e remaining 37 patients were included. e gender

proportion breakdown was 24 males and 13 females, with

a mean age of onset of 47.59 years (range: 20-71). e

mean tumor size was 8.41 cm, and 25 patients (67.57%)

had tumor size less than 10 cm. e majority of patients

were in Masaoka Stage III and had high-grade histologic

subtypes. Half of all the patients (51.35%) had great vessel

tumor invasion, and 7 patients (18.92%) had metastasis,

which involved liver and/or bone in most cases (Table 1).

e number of patients that underwent radiation therapy

(RT) and chemotherapy (CMT) was 16 (43.24%) and

22 (59.46%), respectively. Eight patients (21.62%) had

recurrent tumor. e major histologic subtypes were

well-dierentiated squamous cell carcinoma (32.43%)

and undierentiated carcinoma (16.21%) (Fig 2).

Fig 1. Flow diagram describing enrollment of thymic carcinoma patients and the gender proportions of the 37 enrolled patients.

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Characteristics n (%)

Ageofonset(years),mean(range) 47.59(20-71)

Gender

 Male 24(64.86%)

 Female 13(35.14%)

Tumorsize(mean:8.41cm)

 ≤10cm 25(67.57%)

 >10cm 12(32.43%)

MasaokaStaging

 IandII 7(8.10%)

 III 15(40.54%)

 IV 12(32.43%)

Tumorremovalsurgeryperformed 28(75.68%)

Resection

 R0 8(21.62%)

 R1 10(20.02%)

 R2 10(20.02%)

SVCinvasion 19(51.35%)

Histologicsubtypes

 Low-grade 15(40.54%)

 High-grade 22(59.46%)

Metastasis(liverand/orbone) 7(18.92%)

CMT 22(59.46%)

RT  16(43.24%)

Recurrence 8(21.62%)

TABLE 1. Demographic and clinical characteristics of 37 thymic carcinoma patients.

Abbreviations: SVC = superior vena cava; CMT = chemotherapy; RT = radiation therapy

Fig 2. Histologic subtypes

among thymic carcinoma

patients.

Geanphun et al.

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e median survival time among all thymic carcinoma

patients was 2.5 years (95% condence interval [CI]:

2.676-5.225), with 5-year survival of 40% and 10-year

survival of 16% (Fig 3). In univariate analysis (Table 2),

size of tumor greater than 10 cm (p=0.017), high-grade

histologic subtype (p=0.014), and Masaoka Stage IV

(p=0.011) were variables found to signicantly aect

survival (Fig 4). In multivariate analysis (Table 3), size

of tumor greater than 10 cm (p=0.034) and high-grade

histologic subtype (p=0.009) were identied as independent

predictors of survival in patients with thymic carcinoma.

Regarding treatment, patients that underwent surgical

therapy had signicantly better survival (p=0.005) (Fig 5)

and longer median survival time than those who did not

receive surgical therapy (3.85 vs. 0.63 years). Comparisons

between patients that did or did not undergo RT or CMT

revealed no signicant inuence on survival for either

treatment modality (p=0.187 and p=0.296, respectively).

N 2 years 5 years 10 years

Patients at risk 37 22 17 12

Fig 3. Overall survival in patients with thymic carcinomas. Median survival time was 2.5 years (95% condence interval: 2.676-5.225), with

5-year survival of 40% and 10-year survival of 16%.

TABLE 2. Univariate analysis for factors that signicantly inuence survival of patients with thymic carcinoma.

Factors P-value HR 95% CI

Age 0.147 0.978 0.945-1.008

Malegender 0.169 0.550 0.235-1.288

Size≥10cm 0.017 2.734 1.194-6.260

High-gradehistology 0.014 3.529 1.297-9.604

MasaokaStageIV 0.011 7.393 1.573-34.734

Surgery 0.372 1.631 0.558-4.770

SVCinvasion 0.956 1.022 0.463-2.259

CMT0.187 0.585 0.284-1.298

RT 0.296 0.648 0.287-1.462

Recurrence 0.489 1.416 0.533-3.732

A p-value<0.05 indicates statistical signicance

Abbreviations: HR= hazard ratio; CI= condence interval; SVC= superior vena cava; CMT= chemotherapy; RT= radiation therapy

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Size of tumors 0 year 2 years 5 years 10 years

<10cm 25 17 15 11

≥10cm 11 4 1 1

0 year 2 years 5 years 10 years

Low-grade 15 11 11 8

High-grade 22 11 6 4

0 year 2 years 5 years 10 years

StageI-II 7 7 6 5

StageIII 15 10 8 6

StageIV 12 5 2 1

Fig 4. Overall survival curve according to (A) size of tumor >10 cm [p=0.013], (B) high-grade histologic subtype [p<0.001], and (C) Masaoka

Stage IV [p=0.014].

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0 year 2 years 5 years 10 years

Surgery 28 19 15 11

Nosurgery 9 3 2 1

Fig 5. Overall survival compared between patients who were and were not treated with surgical tumor removal (p=0.005).

TABLE 3. Multivariate analysis for factors that signicantly inuence survival of patients with thymic carcinoma.

Factors P-value HR 95% CI

Size>10cm 0.034 3.594 1.103-11.714

High-gradehistology 0.009 8.175 1.689-39.566

Surgery 0.957 1.033 0.319-3.344

Recurrence 0.963 0.974 0.329-2.887

A p-value<0.05 indicates statistical signicance

Abbreviations: HR= hazard ratio; CI= condence interval

DISCUSSION

ymic carcinoma is a rare disease with variety

in classication and treatment modality. We analyzed

data to identify factors that impact prognosis and to

determine the treatment modality that confers the most

survival benet. e main ndings of our study were, as

follows: (1) tumor size, high-grade histologic subtype,

and Masaoka Stage IV were found to be signicant

predictors of survival in univariate analysis; (2) tumor

size and high-grade histologic subtype were identied as

independent predictors of survival in multivariate analysis;

and, (3) patients who underwent surgical intervention for

tumor removal had a median survival time signicantly

greater than that of patients who did not receive surgery

for tumor removal. e largest cohort study in thymic

carcinoma that included 290 patients also found surgical

tumor removal to be signicantly associated with longer

median survival time.

From previous studies – resectability, histology,

tumor stage, and tumor size were identied as prognostic

factors for survival in patients with thymic carcinoma.

this study, size of the tumor, Masaoka staging, histologic

subtype, SVC invasion, metastatic behavior, surgical

intervention, and other modalities, such as CMT and

RT, were investigated.

e 5-year cumulative survival rates reported in the

literature vary widely (14.5%

, 27.5%

, 30.0%

, 38.8%

and 61.1%

). In our study, the 5-year survival rate was

40%, and the 10-year survival rate was 16%, which is

higher than the previously reported rate of 12.1%.

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e median survival times reported in the literature

also vary widely (15.6 months

, 35.6 months

, 48.0

months

, 53.0 months

, and 66.7 months.

e median

survival time in our study was 30 months. e observed

dierences among studies may be due to dierences in

patient selection, treatment modalities, and the number

of cases that were included in the study (some studies

had a very small study population).

Previous studies found Masaoka stage to be a factor

that signicantly predicts survival thymic carcinoma.

7,23,19

In the present study, Masaoka stage was not only a

prognostic factor, but it was also the strongest independent

predictor of survival in multivariate analysis.

e Tumor-

Nodes-Metastasis (TNM) staging system

was recently

proposed; however, that system has not yet been widely

accepted for general use in routine clinical practice. To

date, Masaoka staging is the system that is most commonly

used to stage patients with thymic carcinoma.

Regarding histologic subtypes, we found 12 dierent

subtypes in our study, all of which were previously dened

as being part of a subgroup of thymic carcinoma according

to a previous literature review6 and previous clinico-

pathological studies.

10-14

Hosaka, et al.

reported that the

prognostic values of histologic subtypes were dierent for

dierent combinations of histologic subtypes. Due to the

limited number of cases included in our study, we divided

the histology into low-grade and high-grade histologic

subtype as a denition of classication.

3,6,9-14

Levine and

Rosai

dened the histologic features of thymic tumors,

and the subsequent revisions culminated in the widely

accepted classication system that was proposed by the

World Health Organization (WHO) in 1999.

In our

study, univariate analysis showed histologic subtype

to be a prognostic factor for survival (p<0.001, Fig 4b).

Subsequent multivariate analysis revealed histologic

subtype to be an independent signicant prognostic

factor for overall survival (p=0.009, HR: 8.175, 95%

CI: 1.689-39.566), which is consistent with previous

reports.

13,15,19,21,27

Multivariate analysis also revealed tumor size to

be an independent predictor of survival (p=0.034, HR:

3.594, 95% CI: 1.103-11.714), which is consistent with

the findings of two previous studies.

7,27

Specifically,

tumor size less than or equal to 10 cm was associated

with signicantly longer overall survival when compared

to tumor size greater than 10 cm (Fig 4a). A previously

published review of the literature

suggested a cut point

of 8 cm for determining patient prognosis, but that value

applied to thymomas. Since not cut point currently exists

for thymic carcinoma, we included 8 cm, 9 cm, and 10

cm tumor size values in our statistical analysis, and we

found 10 cm to be the cut point that was associated

with a signicant dierence in survival. However and

given our small study population, additional study is

needed to conrm the tumor size cut point threshold

for determining patient prognosis.

All of the studies in thymic carcinoma that have

been reported to date found surgical treatment to be

signicantly associated with improved survival, which

explains why surgical therapy is the preferred treatment in

thymic carcinoma.

2,28

Consistent with previous studies, we

found the same survival benet of surgical intervention.

Patients who underwent tumor removal had a signicantly

longer median survival time than those who did not

receive surgical therapy (3.85 vs. 0.63 years; p=0.005)

(Fig 5). In comparison, an analysis of survival in 154

patients with thymic carcinoma by Kondo and Monden

revealed 5-year survival rates of 67% aer total resection,

30% aer subtotal resection, and 24% with no operation.

Complete resection was analyzed in our study; however,

no signicant dierences were observed among the in

the R0, R1, and R2 subgroups. is may be explained

by the small number of cases enrolled in our study.

However, our data support the widely adopted opinion

that surgery is the preferred modality of treatment for

patients with thymic carcinoma.

Limitations

is study has some mentionable limitations. First,

the retrospective nature of this study makes it vulnerable

to missing or incomplete data. Second, all of the data

included in this study was collected from a single center.

ird, we included a small number of patients due to the

relative rarity of thymic carcinoma. is small sample

size may have limited the strength of our study to identify

all signicant dierences and associations. Fourth, our

center is a national tertiary referral center, which means

that we are oen referred cases that are too complicated

to be treated in other care settings. is suggests that our

ndings may not be immediately generalizable to thymic

cancer cases in other care settings. e strength of this

study is that we included patients that were diagnosed,

treated, and followed at our center during a 17-year study

period. Moreover, the data from our study broaden our

understanding of this rare disorder, and will contribute

to the development of thymic carcinoma-specic staging

and treatment guidelines in the future.

CONCLUSION

ymic carcinoma is a rare and invasive mediastinal

tumor with low 5-year and 10-year survival. Univariate

analysis revealed size of tumor, high-grade histologic

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479

subtype, and Masoaka Stage IV as factors that signicantly

inuence survival. Of those, tumor size and high-grade

histologic subtype were identied as independent predictors

of survival in multivariate analysis. Patients who underwent

surgical therapy had a signicantly longer median survival

time.

ACKNOWLEDGMENTS

e authors gratefully acknowledge to Ms. Julaporn

Pooliam of the Division of Clinical Epidemiology, Research

Department, Faculty of Medicine Siriraj Hospital, Mahidol

University for assistance with statistical analysis.

Conict of interest declaration: Both authors declare

no personal or professional conicts of interest relating

to any aspect of this study.

Funding disclosure: is was an unfunded study.

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Original Article

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Vutthipong Sanphasitvong, M.D.*, Loh Yee Jim, M.D.**, Kriangkrai Tantiwonglkosri, M.D.*

*Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand, **Cardiothoracic Surgery Service, KK

Women’s and Children’s Hospital, 100 Bukit, Singapore.

Impact of Accuracy of Preoperative Transthoracic

Echocardiography on Complex Congenital Heart

Surgery in Pediatrics

ABSTRACT

Objective: In simple congenital heart disease, transthoracic echocardiography for the diagnosis and preoperative

evaluation is an eective investigation. But its role in complex congenital heart disease is yet to be proven. e aim

of this study was to nd an accuracy ratio of preoperative echocardiography in complex congenital heart disease

and the eect of non-equivalent ndings to surgical plan and outcomes.

Methods: Medical records of complex congenital heart disease patients who underwent open heart surgery during

2013 -2015, including echocardiographic reports, operative notes, in-patient and out-patient data were retrospectively

reviewed. Patients who underwent palliative shunt procedure, age > 15 year and missing data were excluded. A

total of 300 patients were included in the study. We used intraoperative ndings as a gold standard to compare with

preoperative transthoracic echocardiography. en, we analyzed data comparing between groups of patients who

had concordant and non-concordant echocardiographic nding. Aer that we compared between groups of patients

who had surgery changed from the preoperative plan and those who had not. SPSS version 18 was used to analyze.

Results: e concordance of preoperative echocardiography was 77.7%. In the non-concordant data group, approximately

one third had to change the plan of operation and about one tenth had to change cannulation technique. Most

of non-concordance were that of systemic venous drainage and coronary artery pattern. But it had no signicant

eect to surgical outcomes including operative time, cardiopulmonary bypass time, morbidity and mortality rate.

Conclusion: Transthoracic echocardiography is valuable tool that give a lot of details on anatomical and physiological

data in congenital heart disease. However, some complex congenital heart patients may need additional investigations

such as cardiac catheterization, CT scan, Cardiac MRI in order to obtain adequate anatomical and physiological

data for surgical planning.

Keywords: Preoperative; transthoracic echocardiography; complex congenital heart surgery (Siriraj Med J 2019;

71: 480-485)

Corresponding author: Kriangkrai Tantiwongkosri

E-mail: kae814@yahoo.com

Received 13 May 2019 Revised 16 September 2019 Accepted 25 September 2019

ORCID ID: http://orcid.org/0000-0002-8926-6715

http://dx.doi.org/10.33192/Smj.2019.71

INTRODUCTION

In congenital heart surgery, anatomical and

physiological data are important in planning the surgical

procedure. In the past, cardiac catheterization was used to

obtain the information. However, cardiac catheterization

is an invasive procedure with some procedural risks.

Nowadays, echocardiography as an imaging modality has

improved tremendously. We can obtain many anatomical

and physiological data from this non-invasive procedure.

In simple congenital heart diseases such as atrial septal

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defect (ASD), ventricular septal defect (VSD) and patent

ductus arteriosus (PDA), we can do surgery based solely

on preoperative echocardiography.

1-6

During recent years,

there has been many studies suggested that we can also

perform complex congenital heart surgery based on

preoperative echocardiographic nding alone without

increasing the risk of the complication and overall

outcome.

7-13

However, this had to be proven and is

still not a standard practice in our institute. We usually

have both preoperative echocardiography and cardiac

catheterization in complex congenital heart patients.

e aim of this study is to nd out the proportion

of complex congenital heart patients with concordant

data between preoperative echocardiogram and surgical

ndings and its impact on surgical plan and outcomes.

Complex congenital heart disease in this study

includes all congenital heart disease except atrial septal

defect (ASD), ventricular septal defect (VSD) and patent

ductus arteriosus (PDA).

Objectives

Primary Objective

1. To assess the proportion of patients with concordant

data between preoperative echocardiography and intra-

operative ndings.

Secondary Objectives

2. To study the impact of non-concordance ndings on

surgical outcome (morbidity, mortality rate).

3. To study the impact of non-concordance ndings on

surgical plan.

MATERIALS AND METHODS

is is a descriptive study. Data of complex congenital

heart patients who had undergone heart surgery during

2013-2015 at Siriraj Hospital were retrospectively reviewed.

We excluded palliative surgery cases (systemic to pulmonary

shunt, PA banding), patients over 15 years old and missing

data patients. A total of 300 patients were reviewed. e

rst stage palliative surgery cases were excluded because

this procedure underwent without cardiopulmonary

bypass support and we performed systemic to pulmonary

shunt through thoracotomy incision which might limit

intraoperative nding. e adult complex congenital heart

patients were excluded because this group of patients

have higher risk due to delay in surgery.

We reviewed inpatient and outpatient documents,

operative notes and preoperative transthoracic

echocardiographic reports. Preoperative echocardiogram

was performed by pediatric cardiologist and/or fellow

in pediatric cardiologist under the supervision of a

certied pediatric cardiologist. Preoperative transthoracic

echocardiographic reports were assessed on their

concordance based on the intraoperative ndings. Data

that is deemed concordant must have all the data as

listed in Fig 1 and correlate with intraoperative ndings.

In the non-concordance data group, the percentages of

procedural change from preoperative plan due to the new

ndings were calculated. Procedural change is dened

as change of cannulation technique from preoperative

planning or having additional procedure performed.

For example, persistent le sided superior-vena cava

(SVC) that was found intra-operatively and additional

le SVC cannulation that had to be performed. is was

considered a change of cannulation technique. For change

of intraoperative decisions that were not the result of

dierent preoperative echocardiographic report, these

were not included in this study. e concordance data

and non-concordance data groups were analyzed to nd

the dierences between demographic data, morbidity

and mortality rate, cardiopulmonary bypass time and

aortic cross clamp time.

Quantitative data was presented in median and

range. Qualitative data was presented in number and

percentage. In inferential statistics, Chi-square test was

used for qualitative data and t-test/Mann Whitney U-test

were used for quantitative data. P-value < 0.05 was used

as a cut-o point of statistical signicance. SPSS

V18.0 was used to analyze data.

Ethical approval for our clinical study was obtained

by human research protection unit of Siriraj Hospital.

(Si 248/2016)

RESULTS

300 cases were included in the study. Median age

of patients is 21.5 months ranging from 2 days to 15

years old. Most cases were Tetralogy of Fallot (TOF),

Univentricular heart disease and double outlet of right

ventricle as shown in Table 1.

Among these patients, 77.7% (233 patients) of

preoperative transthoracic echocardiography correlated

to the intra-operative ndings. In 22.3% of patients

(n= 67), transthoracic echocardiographic ndings diered

from intraoperative ndings. Systemic venous drainage

(i.e. missing le superior vena cava (SVC), abnormal

SVC drainage) were found to be the most common

non-concordant ndings. Second most common non-

concordant ndings were that of the coronary artery

pattern (Table 2) which was found in all our patients

with transposition of great arteries (TGA). So in TGA

patients, echocardiography had accurately report type

Sanphasitvong et al.

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Total Echo concordant Echo non- p-value

(n=300) group concordant

(n=233) group (n=67)

Age,months 21.5(.07,180) 22(.07,175) 20(.27,180) 0.878

Median(Min,Max)

PreoperativeDiagnosis,n(%)  

     0.293

TOF  86(28.7%) 68(29.2%) 18(26.9%)

TGA 21(7%) 13(5.6%) 8(11.9%)

DORV 25(8.3%) 16(6.9%) 9(13.4%)

PA/IVS 3(1%) 3(1.3%) 0(0%)

Truncus 15(5%) 10(4.3%) 5(7.5%)

TAPVR 14(4.7%) 11(4.7%) 3(4.5%)

PAPVR 7(2.3%) 5(2.1%) 2(3.0%)

AVcanel 27(9%) 17(7.3%) 10(14.9%)

Ebstein 1(0.3%) 1(4%) 0(0%)

APWindow 1(0.3%) 1(4%) 0(0%)

CoA  14(4.7%) 12(5.2%) 2(3.0%)

ALCAPA 3(1%) 3(1.3%) 0(0%)

HLHS 8(2.7%) 8(3.4%) 0(0%)

TA  17(5.7%) 16(6.9%) 1(1.5%)

UVH 40(13.3%) 33(14.2%) 7(11.4%)

Others 18(6%) 16(6.9%) 2(3.0%) 0.731

Urgentsurgery,n(%) (n=294) (n=228) (n=66)

 Elective 263(89.5%) 204(89.5%) 59(89.4%)

 Urgent 29(9.9%) 22(9.6%) 7(10.6%)

 Emergency 2(0.7%) 2(0.9%) 0(0%)

Redooperation (n=300) (n=233) (n=67) 0.013

  32(10.7%) 31(13.3%) 1(1.5%)

TABLE 1. Patient characteristics.

Abbreviations: TOF=Tetralogy of Fallot, TGA=Transposition of great artery, DORV=Double outlet right ventricle, PA/IVS=pulmonary

atresia/intact ventricular septum, Truncus=Truncus arteriosus, TAPVR=total anomalous pulmonary venous return, PAPVR=partial

anomalous pulmonary venous return, AV canal=Common AV canal, AP window=Aortopulmonary window, CoA=Coarctation of aorta,

ALCAPA=anomalous le coronary origin from pulmonary artery, HLHS=hypoplastic le heart syndrome,TA=Tricuspid atresia,

UVH=univentricular heart disease

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TABLE 2. Preoperative TTE anatomical non-concordance.

TABLE 3. Non-concordance by pre-operative TTE.

Types of non-concordance N = 54 Percent

Systemicveindrainage 19 35.19%

Coronaryarterypattern 17 31.48%

Pulmonaryveindrainage 6 11.11%

RVOT 3 5.56%

 ValvularPSGoodsizepulmonicvalve 2

 SubvalvePSNosubvalvularobstruction 1

Others 9 16.67%

 MissedASDsecundum 1

43leaetstruncalvalve 1

 Missedcortiratum 1

 Left-sidedRight-sidedarch 1

 MildSeverehypoplasticLV 1

 MissedAPwindow 1

 MissedvegetationinRVOT 2

 MildSeverMR,TR 1

of coronary artery 62 % (13 patients from total 21).

In non-concordant data group, 24 from 67 patients

(35.8%) had their operative procedures changed from the

preoperative plan. Cannulation technique was changed

in 6 patients (9%).

Most common non-concordant diagnosis between

preoperative echocardiographic reports and intraoperative

ndings was complete atrioventricular canal defects

(complete AV canal) and followed by TOF as show in

Table 3.

Demographic data between the two groups were

similar, No statistical dierences were found except for

rates of redo-operation which was higher in concordant

data group (13.3% VS 1.5%) as shown in Table 1. Redo-

operation in this study mean that patient who underwent

operation through previous incision.

For the analysis of intraoperative data, cardiopulmonary

bypass time was found to be longer in non-concordant

data group but p-value did not meet statistical signicance.

Morbidity, 30-day mortality, overall mortality were not

dierent between two groups (Table 4).

Wrong diagnosis Intraoperative diagnosis N = 14 Percent

(Preoperative diagnosis)

 5

TOF DORV 4 35.71%

 VSD/PS 1

CompleteAVcanal  6

 PartialAVcanal 4 42.86%

 TypeCTypeA 2

TransitionalAVcanal  1 7.14%

Truncusarteriosus  2 14.29%

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TABLE 4. Clinical outcome between echo groups.

Echo concordant group Echo non-concordant group p-value

(n=233) (n=67)

Optime,min (n=229) (n=65)

Median(Min,Max) 175(55,565) 190(90,410) 0.095

CPBtime (n=222) (n=67)

Median(Min,Max) 95(23,394) 110(41,215) 0.056

AoXtime (n=187) (n=63)

Median(Min,Max) 62(7,237) 74(19,164) 0.141

Complicationrate,n(%) 90(38.8%) 25(37.3%) 0.939

Deathrate,n(%) 13(5.6%) 5(7.5%) 0.565

30daysmortality,n(%) 10(4.3%) 3(4.5%) 1.000

1. Situsposition/Atrial-ventriclerelationship/ventricle–greatvesselrelationship

2. Systemicveindrainage

3. Pulmonaryveindrainage

4. Atrioventricularvalveanatomyandfunction

5. Aorticandpulmonicvalveanatomyandfunction

6. Truncalvalveanatomyandfunction(inTruncusarteriosus)

7. Shuntinatriallevel/ventricularlevel/Greatvessellevel

8. RVoutowtract

9. McGoonratio(inTOF,PA/VSD,Univentricularheart)

10. LVoutowtract

11. Coronaryanatomy(inTGA,TOFandPA/VSD)

12. Greatvesselsrelationship

13. Aorticarchanatomyandposition

14. LVandRVfunction

15. Assessmentofpulmonaryhypertension

16. Proximaldescendingaortaanatomyandgradientacrossstenosislesion(inCoarctationofaorta)

Abbreviations: TOF=Tetralogy of Fallot, TGA=Transposition of great artery

Fig 1. Criteria for completeness of echocardiography report.

DISCUSSION

Preoperative transthoracic echocardiography provided

concordant data in 77.7% of our study group. Approximately

one third of patients (32.3%) who had non-concordant

data, did not undergo surgery as planned preoperative and

approximately one tenth of patients (9%) had to change

the cannulation technique. e most common diering

data was information on systemic venous drainage such

as Lt SVC. Second most common non-concordant data

were details of the coronary artery pattern. All non-

concordant data found in our TGA patients were error in

coronary artery pattern. However, diering preoperative

data from transthoracic echocardiography did not aect

the morbidity and mortality rates of patients.

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Although no statistical signicant eect of non-

concordant preoperative data was found, there was

one Tetralogy Of Fallot (TOF) patient who underwent

total repair and preoperative echocardiography did

not demonstrate any le ventricular hypoplasia. Aer

the operation, he needed extracorporeal membrane

oxygenation (ECMO) insertion and reoperation.

Compared to other studies, Our study showed

higher ratio of non-concordant data (32.3 % VS 2-7%).

11-14

is may be because our study was a retrospective study

and we used only 2D transthoracic echocardiography.

Furthermore, some of primary investigators were fellows

who have less experience compared to certied pediatric

cardiologist. With respect to non-concordance data to

surgical procedure,

11-14

our result was comparable with

other studies with the rate of changed procedure about

30-40% without eect to surgical outcome, such as study

by Tworetzky W which was discovered in 42.1% (8 in

19 cases)

or study by Pfammatter JP in 33.3% (4 in 12

cases).

Our study found a high rate of non-concordant

data in coronary artery pattern dierent from other

studies which suggested that coronary anatomy could be

accurately assessed by preoperative echocardiogram (62%

VS 86%).

is nding may be aected by retrospective

design. Improvement of technology in echocardiography

machine may be ameliorate this problem.

We also noticed that patients who required staged

procedures tend to have a higher rate of concordant

preoperative echocardiographic data. is may be due

to the fact that these cases have had some data from

previous intraoperative ndings and may have also gotten

multiple echocardiographies before surgery. Cardiologists

might also pay more attention to those redo cases due

to awareness of its complexity in surgery.

Limitations of this study were its retrospective

design and high distribution of diseases. So it is dicult to

compare between groups of patients. Secondly, changing

surgical procedures were also decided subjectively by

individual surgeons. Lastly, Interpersonal variability

between surgeons performing the operation is another

uncontrolled factor in our study. Future study should

be more disease specic and prospective design.

CONCLUSION

Transthoracic echocardiography is valuable tool that

provides a lot of details on anatomical and physiological

data. However, in some complex congenital heart diseases

especially in TGA patients whom we not sure about

coronary artery anatomy, patients may still need additional

investigations such as cardiac catheterization, CT scan,

cardiac MRI in order to get adequate anatomical and

physiological data for planning the surgical procedure

and counselling purposes.

REFERENCES

1. Huhta JC, Glasow P, Murphy DJ, Jr., Gutgesell HP, Ott DA,

McNamara DG, et al. Surgery without catheterization for

congenital heart defects: management of 100 patients. J Am

Coll Cardiol 1987;9:823-9.

2. Carotti A, Marino B, Bevilacqua M, Marcelletti C, Rossi E,

Santoro G, et al. Primary repair of isolated ventricular septal defect

in infancy guided by echocardiography. Am J Cardiol 1997;79:1498-

501.

3. Shub C, Tajik AJ, Seward JB, Hagler DJ, Danielson GK. Surgical

repair of uncomplicated atrial septal defect without “routine”

preoperative cardiac catheterization. J Am Coll Cardiol 1985;6:49-54.

4. Freed MD, Nadas AS, Norwood WI, Castaneda AR. Is routine

preoperative cardiac catheterization necessary before repair of

secundum and sinus venosus atrial septal defects? J Am Coll

Cardiol 1984;4:333-6.

5. Lipshultz SE, Sanders SP, Mayer JE, Colan SD, Lock JE. Are

routine preoperative cardiac catheterization and angiography

necessary before repair of ostium primum atrial septal defect?

J Am Coll Cardiol 1988;11:373-8.

6. Gutgesell HP, Huhta JC, Latson LA, Hunes D, McNamara

DG. Accuracy of two-dimensional echocardiography in the

diagnosis of congenital heart disease. Am J Cardiol 1985;55:514-8.

7. Santoro G, Marino B, Di Carlo D, Formigari R, de Zorzi A,

Mazzera E, et al. Echocardiographically guided repair of tetralogy

of Fallot. Am J Cardiol 1994;73:808-11.

8. Zellers TM, Zehr R, Weinstein E, Leonard S, Ring WS, Nikaidoh

H. Two-dimensional and Doppler echocardiography alone can

adequately dene preoperative anatomy and hemodynamic

status before repair of complete atrioventricular septal defect

in infants < 1 year old. J Am Coll Cardiol 1994;24:1565-70.

9. Marek J, Skovranek J, Hucin B, Chaloupecky V, Tax P, Reich O,

et al. Seven-year experience of noninvasive preoperative diagnostics

in children with congenital heart defects: comprehensive

analysis of 2,788 consecutive patients. Cardiology 1995;86:488-95.

10. Pfammatter JP, Berdat PA, Carrel TP, Stocker FP. Pediatric

open heart operations without diagnostic cardiac catheterization.

Ann orac Surg 1999;68:532-6.

11. Pfammatter JP, Berdat P, Hammerli M, Carrel T. Pediatric

cardiac surgery after exclusively echocardiography-based

diagnostic work-up. Int J Cardiol 2000;74:185-90.

12. Tworetzky W, McElhinney DB, Brook MM, Reddy VM,

Hanley FL, Silverman NH. Echocardiographic diagnosis alone

for the complete repair of major congenital heart defects. J

Am Coll Cardiol 1999;33:228-33.

13. Sohn S, Kim HS, Han JJ. Pediatric cardiac surgery with

echocardiographic diagnosis alone. J Korean Med Sci 2002;17:463-7.

14. Lopes LM, Damiano AP, Moreira GN, Azevedo TJ, Nagamatsu

CT, Tavares GM, et al. e role of echocardiography as an

isolated method for indicating surgery in patients with congenital

heart disease. Arq Bras Cardiol 2005;84:381-6.

15. Fundora MP, Aregullin EO, Wernovsky G, Welch EM, Muniz

JC, Sasaki N, et al. Echocardiographic and Surgical Correlation

of Coronary Artery Patterns in Transposition of the Great

Arteries. Congenit Heart Dis 2016;11:570-7.

Sanphasitvong et al.

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KaninPruekprasert, M.D.*, Chanean Ruangsetakit, M.D.*, Chumpol Wongwanit, M.D.*, Khamin Chinsakchai,

M.D.*, Kiattisak Hongku, M.D.*, Nattawut Puangpanngam, M.D.*, Jutapim Khayankit, M.D.*, Tze Tec Chong,

M.D.**, Nuttawut Sermsathanasawadi, M.D.*

*Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand, **Department of Vascular Surgery,

Singapore General Hospital, Singapore.

Presence of Residual Venous Thrombus at Warfarin

Withdrawal: a Predictor for Recurrence after a

First Episode of Symptomatic Provoked Proximal

Deep Venous Thrombosis in Thai Population?

ABSTRACT

Objective: To assess the risk for venous thromboembolism (VTE) recurrence by presence of residual venous

thrombus (RVT) at warfarin withdrawal following symptomatic rst provoked proximal DVT.

Methods: Medical records of 45 consecutive patients with symptomatic rst provoked proximal DVTs who had

undergone warfarin surveillance for ≥ 3 months were reviewed retrospectively. Altogether, 22 patients discontinued

anticoagulation aer ≥ 3 months regardless of duplex ultrasonography results of RVT diagnosed by compression

ultrasonography. Another 23 patients discontinued anticoagulation aer the RVT disappeared. Primary outcome

was recurrent VTE.

Results: Four of the 45 patients experienced recurrent VTE (8.89%), including 2 (9.00%) of 22 patients who

had discontinued anticoagulant regardless of duplex ultrasonography results and 2 (8.70%) of 23 patients who

discontinued anticoagulation aer RVT disappearance (p = 0.963). All of the recurrent VTE were recurrent DVT.

Conclusion: RVT at warfarin withdrawal was not a predictor for recurrence VTE following a rst symptomatic

provoked proximal DVT.

Keywords: Deep vein thrombosis; duplex ultrasound; VTE management (Siriraj Med J 2019; 71: 486-490)

Corresponding author: Nuttawut Sermsathanasawadi

E-mail: nuttawut@gmail.com

Received 1 July 2019 Revised 6 November 2019 Accepted 8 November 2019

ORCID ID: http://orcid.org/0000-0002-0262-1438

http://dx.doi.org/10.33192/Smj.2019.72

INTRODUCTION

Because the recurrent rate of a proximal deep venous

thrombosis (DVT) of the leg that had been provoked by

surgery or by nonsurgical transient risk factors is high

during the rst 3 months, the American College of Chest

Physicians recommends treatment with anticoagulation for

3 months aer the diagnosis.

In patients with provoked

proximal DVTs, the estimated 5-year cumulative risk

of recurrent venous thromboembolism (VTE) after

discontinuing anticoagulant treatment was reported to

be 3% for surgery-provoked VTEs and 15% for VTEs

provoked by nonsurgical, reversible risk factors.

e

risk of recurrence of a provoked DVT is considered

low enough not to warrant prolonged anticoagulation,

although the risk of recurrence is not negligible in the

long term. In addition, the risk of recurrence associated

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487

with provoked VTE varies among reports. Patients

with VTE due to reversible risk factors have a 10-year

cumulative recurrence rate of 22.5%: surgically provoked

VTE 11.4%, patients with medical illness 31.8%, women

with pregnancy-related or hormonal therapy 20.3%.

e presence of residual venous thrombus (RVT)

has been associated with an increased risk of thrombotic

recurrence in patients with provoked venous thrombosis.

Recurrent DVT occurs not only in previously thrombosed

veins but also at other sites.

RVT may indicate an underlying

prothrombotic state for the initial DVT.

The role of RVT as a predictor for a recurrent

proximal provoked DVT remains unclear. e DACUS

study showed that RVT was predictive of recurrence of

a provoked DVT. e AESOPUS study showed that the

advantage of prolonging warfarin treatment on the basis

of persistent RVT was more signicant aer unprovoked

DVTs than provoked DVTs.

Methods for measuring

RVTs in the AESOPUS and DACUS studies diered,

however, which might have aected the results of those

studies.

4,5

ere are no reported clinical studies on the relation

between RVT and the risk of recurrent DVT aer a rst

provoked proximal DVT in an Asian population. e

specic objective of the study was to assess the risk for

DVT recurrence conferred by RVT aer anticoagulant

withdrawal in a cohort of consecutive Asian patients

with symptomatic provoked proximal DVT.

MATERIALS AND METHODS

is study is based on a retrospective review of cohort

data. Consecutive patients attending a vascular surgery

clinic because of a rst episode of symptomatic proximal

provoked DVT of a lower extremity who were on warfarin

anticoagulation for at least 3 months between January

2011 and December 2013 were included. Patients with

unprovoked DVT requiring indenite anticoagulation,

patients with antiphospholipid syndrome, and those

with cancer were excluded.

Provoked DVT was dened as a DVT caused by

reversible risk factors, including immobilization for >

30 min during surgery with general anesthesia, history

of trauma during the previous 3 months, current use of

oral contraception or hormonal therapy, recent fracture

or plaster casting of a leg, connement to bed for 3 days

during the previous 3 months, pregnancy or puerperium,

and/or prolonged travel (> 4 h) during the previous 4

weeks.

Aer at least 3 months of treatment, some of the

vascular surgeons stopped warfarin following the American

College of Chest Physicians Guideline, neither duplex

ultrasonography (DUS) nor the D-dimer test was performed

in these patients. Although, some vascular surgeons prefer

to evaluate the patients with compression ultrasonography

and stopped warfarin aer the patients were free of residual

vein thrombus (RVT). e examination was performed

with the patient in supine position and the aected leg

externally rotated and slightly exed at the knee. CUS

images were obtained in transverse sections. Lumen

compressibility was then evaluated by gentle pressure

exerted using the ultrasound probe. e RVT diameter

was determined by measuring the distance between the

anterior and posterior walls of the vein before and aer

compression with the ultrasound probe.

Measurements of the common femoral vein diameter

were obtained 1 cm below the inguinal ligament. ose

of the popliteal vein were obtained at the most prominent

crease in the mid-popliteal fossa.

RVT was evaluated

following the techniques described in the DACUS and

AESOPUS studies.

4,5

In the DACUS study, the percentage

of the RVT was the ratio between the vein’s diameter before

and during compression.

Patients were considered not

to have an RVT when a persisting thrombus was ≤ 40%

of the venous measurement. Patients were considered

to have an RVT when a persisting thrombus of > 40%

was present in at least one of the two examined venous

segments.

In the AESOPUS study, RVT was dened as

being present if the vein’s transverse diameter was > 2

mm at maximum compression or absent if the transverse

diameter was ≤ 2 mm.

In this study, an RVT was considered present when

the RVT measured by at least one technique was deemed

positive. An RVT was considered absent when both

techniques produced negative results.

In patients who performed to measure RVT, warfarin

was stopped aer no RVT was found. Patients in whom

RVT was considered present continued to receive warfarin.

ese patients underwent CUS evaluation every 3 months

until the RVT had disappeared. CUS was performed

whenever a DVT was suspected to have recurred.

e study outcome was recurrent VTE. In cases of

recurrence, CUS results were compared with those of the

previous examination. Recurrent DVT was diagnosed if

a previously fully compressible segment (contralateral

or ipsilateral) was no longer compressible or there was a

≥ 4 mm increase in the diameter of the residual thrombus

during compression. In dicult cases, CUS was repeated

(aer 5-7 days) or computed tomography venography was

performed. e lower limb veins were evaluated using

a GE LOGIC 9 system (GE Healthcare, Milwaukee, WI,

USA) with 5- to 10-MHz linear transducers. Recurrent

PE (pulmonary embolism) was diagnosed if clinical

Pruekprasert et al.

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suspicious, with conrmation by computed tomography

pulmonary angiography.

e ethics committee of the Siriraj Institutional

Review Board approved this study (Si 002/2019).

For the statistical analyses, continuous variables are

described as the mean and standard deviation (SD) or the

median and range, as appropriate. Categorical variables

are described as the number and percentage. e t-test or

Mann-Whitney U test was used to compare continuous

variables, as appropriate. e χ

test or Fisher’s exact test

was used to compare categorical variables. e Kaplan-

Meier method was used to estimate the recurrence-free

survival curve and the recurrence rate. Cox regression

analysis was used to investigate the association between

RVT status (assessed by DUS) and recurrence of DVT.

ose associations were evaluated using the hazard ratio

and corresponding 95% condence intervals. All p values

were two-tailed with a signicance level of 0.05. Data

were recorded and analyzed using PASW Statistics 18.0

soware (SPSS Inc., Chicago, IL, USA).

RESULTS

ere were 45 patients with provoked DVT in this

study. ere were 35 (77.78%) women and 10 (22.22%) men.

Twenty-two patients with provoked DVTs discontinued

the anticoagulant aer ≥3 months of treatment without

DUS evaluation. e other 23 patients discontinued it aer

the RVT had disappeared. e mean age was 60.0 ± 18.9

years in patients who discontinued anticoagulant without

DUS and 63.9 ± 19.4 years in patients who discontinued

it aer RVT disappearance. e mean follow-up time

was 121.2 ± 40.2 weeks (range 50.0-207.0 weeks) for

patients who discontinued the anticoagulant without

DUS and 118.3 ± 38.8 weeks (range 52-243 weeks) for

patients who discontinued it aer RVT disappearance.

Factors that provoked the DVT are shown in Table 1.

During the follow-up period, four recurrent DVTs

(8.89%) were recorded from among 45 patients with

a provoked DVT. Two of these patients (9.00%) had

discontinued anticoagulant without DUS and two (8.70%)

had discontinued anticoagulant aer RVT disappearance

(p =0.963) (Fig 1). ere was no recurrent PE in this

study.

TABLE 1. Demographic data from Asian patients with their rst symptomatic provoked DVT who discontinued

anticoagulation.

Patients discontinued anticoagulant

Without DUS After no RVT P-value

(n = 22) (n = 23)

Age

Mean±SD,year 60.0±18.9 63.9±19.4 0.502

Sex

Female,n(%) 18(81.8) 17(79.9) 0.722

Anticoagulantduration,week  

Median(range) 30.5(13.4-87.0) 32.9(13.0-75.7) 0.901

Mean±SD 36.9±21.4 36.6±18.8

Provokedfactors  

Surgery/Trauma 11(50) 11(47.8)

 Immobilization/Illness 7(31.8) 9(39.1)

 Hormonalused 2(9.1) 2(8.7) 0.520

Prolongedtravel 0(0) 1(4.3)

 Pregnancy 2(9.1) 0(0)

Abbreviations: DVT = deep vein thrombosis; DUS = Duplex ultrasonography; RVT = residual vein thrombus

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Fig 1. Kaplan-Meier curves for recurrent deep vein thrombosis (DVT) in patients who stopped taking an anticoagulant (warfarin) aer no

residual vein thrombosis (RVT) was detected and those who stopped the anticoagulant without duplex ultrasonography (DUS) conrmation.

DISCUSSION

Patients who develop a DVT associated with a

transient surgical procedure (surgically provoked DVT)

have a low rate of recurrence, estimated at 0.7% per year

for the 2 years aer stopping anticoagulation therapy.

Patients who develop a non-surgically provoked DVT

(e.g., due to immobilization, pregnancy, use of estrogen-

containing contraception) have a slightly higher risk of

recurrence, estimated at 4.2% per year for the same 2-year

period aer discontinuing anticoagulation therapy.

e

risk of recurrence aer the appearance of a provoked

DVT is considered low enough not to warrant prolonged

anticoagulation, although the risk of recurrence is not

negligible in Asian populations.

In our study of ai patients with provoked DVTs,

the annual risk of recurrence aer warfarin withdrawal was

6.77%. is risk was somewhat higher than the reported

annual risk of recurrence in subjects with provoked

DVTs in Caucasian populations.

DVTs provoked by a major reversible risk factor,

such as recent surgery, had a low risk of recurrence.

Although the risk of recurrence in patients with DVTs

provoked by a nonsurgical trigger was higher than that

for patients with DVTs provoked by surgery, the risk

was still low.

Provoked DVTs in a ai population were at a

suciently low risk of recurrence to recommend stopping

anticoagulants at 3 months. If the provoking factor is

incompletely resolved, however, it is appropriate to treat

the patients longer than 3 months.

Our results were in line with those of the AESOPUS

study and a study by Cosmi et al. in which an RVT was

not predictive for recurrence aer provoked DVT.

5,7

Our results, however, were dierent from those of the

DACUS study in which RVT was predictive of recurrence

following a provoked DVT.

e reproducibility of RVT measurements could

be an issue across studies because of the lack of widely

accepted criteria for dening vein recanalization.

For

example, the AESOPUS study adopted the method of

Prandoni et al.,

3,5

whereas the RVT in the DACUS study

was dened as a residual thrombus occupying more

than 40% of the vein’s area calculated in the absence of

compression.

4,5

Although measurements of RVT in the

AESOPUS and DACUS studies were dierent, which

could aect the results of the study, our center uses

Pruekprasert et al.

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both techniques to dene the presence of an RVT, with

a positive result from at least one of them indicating the

need to continue anticoagulation.

Even though the presence of an RVT was not a risk

factor for recurrence in ai patients experiencing their

rst symptomatic provoked proximal DVT at the time

of warfarin withdrawal, DUS should be performed to

dene the baseline characteristics of the vein’s lumen

for detecting a new thrombus in the future.

e small number of patients limits the statistical

power of this study. Larger series are needed to clarify the

relation between the presence of an RVT and recurrence of

a DVT in Asian patients with a rst episode of symptomatic

provoked proximal DVT.

CONCLUSION

e presence of an RVT at the time of warfarin

withdrawal was not a predictor for recurrence of the

VTE in ai patients with a rst episode of symptomatic

provoked proximal DVT.

ACKNOWLEDGMENTS

e authors thank Miss Supaporn Tunpornpituk

and Dr. Sasima Tongsai for statistical assistance and

Miss Phakawan Phutthakunphithak for data collection.

Declaration of Conicting Interests: e authors declared

no potential conicts of interest with respect to the

research, authorship, and/or publication of this article.

Funding: is study was supported by the Faculty of Medicine

Siriraj Hospital, Mahidol University. KaninPruekprasert,

Chanean Ruangsetakit, Chumpol Wongwanit, Khamin

Chinsakchai, Kiattisak Hongku, Nattawut Puangpanngam,

and Nuttawut Sermsathanasawadi are supported by

Chalermphrakiat grants, Faculty of Medicine Siriraj

Hospital, Mahidol University.

REFERENCES

1. Kearon C,Akl EA,Ornelas J,Blaivas A,Jimenez D,Bounameaux

H,et al. Antithrombotic erapy for VTE Disease: CHEST

Guideline and Expert Panel Report. Chest 2016;149:315-52.

2. Kearon C,Akl EA,Comerota AJ,Prandoni P,Bounameaux

H,Goldhaber SZ,et al. Antithrombotic therapy for VTE

disease: Antithrombotic erapy and Prevention of rombosis,

ed: American College of Chest Physicians Evidence-Based

Clinical Practice Guidelines. Chest 2012;141:e419S-94S.

3. Prandoni P,Noventa F,Ghirarduzzi A,Pengo V,Bernardi E,

Pesavento R,et al. e risk of recurrent venous thromboembolism

aer discontinuing anticoagulation in patients with acute

proximal deep vein thrombosis or pulmonary embolism. A

prospective cohort study in 1,626 patients. Haematologica

2007;92:199-205.

4. Siragusa S,Malato A,Anastasio R,Cigna V,Milio G,Amato C,

et al. Residual vein thrombosis to establish duration of

anticoagulation aer a rst episode of deep vein thrombosis: the

Duration of Anticoagulation based on Compression

UltraSonography (DACUS) study. Blood 2008;112:511-5.

5. Prandoni P,Prins MH,Lensing AW,Ghirarduzzi A,Ageno

W,Imberti D,et al. Residual thrombosis on ultrasonography

to guide the duration of anticoagulation in patients with deep

venous thrombosis: a randomized trial. Ann Intern Med 2009;

150:577-85.

6. Iorio A,Kearon C,Filippucci E,Marcucci M,Macura A,Pengo

V,et al. Risk of recurrence aer a rst episode of symptomatic

venous thromboembolism provoked by a transient risk factor:

a systematic review. Arch Intern Med 2010;170:1710-6.

7. Cosmi B,Legnani C,Cini M,Guazzaloca G,Palareti G. D-dimer

and residual vein obstruction as risk factors for recurrence

during and aer anticoagulation withdrawal in patients with

a rst episode of provoked deep-vein thrombosis. romb

Haemost 2011;105:837-45.

8. Linkins LA, Stretton R, Probyn L, Kearon C. Interobserver

agreement on ultrasound measurements of residual vein

diameter, thrombus echogenicity and Doppler venous ow in

patients with previous venous thrombosis. romb Res 2006;

117:241-7.

9. Kearon C, Akl EA. Duration of anticoagulant therapy for deep

vein thrombosis and pulmonary embolism. Blood 2014;123:

1794-801.

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INTRODUCTION

Arteriovenous hemodialysis access facilitates a

connection between the patient and the hemodialysis

system in end-stage renal disease patients. Current

Nattawut Puangpunngam, M.D.*, Nathakorn Supokaivanich, M.D.*, Chanean Ruangsetakit, M.D.*, Chumpol

Wongwanit, M.D.*, Nuttawut Sermsathanasawadi, M.D., Ph.D.*, Khamin Chinsakchai, M.D.*, Suteekhanit

Hahtapornsawan, M.D.*, Kiattisak Hongku, M.D.*, Pramook Mutirangura, M.D.*, Somrach amtorawat,

M.D.**, Satit Rojwatcharapibarn, M.D.**, Walailak Chaiyasoot, M.D.**, Jirawadee Yodying, M.D.**, Trongtum

Tongdee, M.D.**

*Department of Surgery, **Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand

Endovascular Thrombectomy versus Open

Surgical Thrombectomy for Thrombosed

Arteriovenous Hemodialysis Graft

ABSTRACT

Objective: e aim of this study was to investigate the procedure success rate, one-year primary patency rate,

one-year secondary patency rate, and complications compared between endovascular therapy and open surgical

thrombectomy for treatment of thrombosed arteriovenous hemodialysis gra.

Methods: is retrospective chart review included patients with thrombosed arteriovenous hemodialysis gra

who were treated at the Division of Vascular Surgery, Department of Surgery, Faculty of Medicine Siriraj Hospital,

Mahidol University, Bangkok, ailand during January 2012 to December 2016. Demographic, gra type, time

before treatment, thrombus removal technique, additional technique, procedure success rate, operative, primary

and secondary patency, follow-up time, and complication data were collected.

Results: Seventy-four thrombosed dialysis gras were included. Twenty-ve and 49 gras underwent endovascular

therapy and open surgical thrombectomy, respectively. ere was no signicant dierence in demographic data,

gra type, or adjunct procedure between groups. e procedure success rate was 92% and 98% in the endovascular

group and thrombectomy group, respectively (p=0.262). e one-year primary patency rate was 26% in the

endovascular group, and 33% in the thrombectomy group (p=0.054). One-year secondary patency rate was 82.6%

in the endovascular group, and 56.3% in the thrombectomy group (p=0.122).

Conclusion: No signicant dierences were observed between groups for procedure success rate or 1-year primary

patency rate; however, the one-year secondary patency rate in the endovascular group was signicantly better than

in the thrombectomy group. No dierence in complications was observed between groups.

Keywords: Endovascular thrombectomy; open surgical thrombectomy; thrombosed arteriovenous hemodialysis

gra (Siriraj Med J 2019; 71: 491-498)

Corresponding author: Nattawut Puangpunngam

E-mail: nattawut.pua@mahidol.ac.th

Received 22 May 2019 Revised 21 November 2019 Accepted 22 November 2019

ORCID ID: http://orcid.org/0000-0002-4874-5285

http://dx.doi.org/10.33192/Smj.2019.73

guideline

recommends the use of native arteriovenous

stula (AVF) as the rst choice for hemodialysis access.

However, arteriovenous hemodialysis gra (AVG) is

still preferred in many patients due to vessel-related

Puangpunngam et al.

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limitations, and the fact that some patients in need of

urgent hemodialysis cannot wait for AVF maturation

aer surgery. Although AVG does not require time for

maturation, it is easier to puncture than AVF and it has

a higher likelihood of complications. One of the most

important complications of AVG is acute thrombosis

that leads to gra blockage that results in loss of function

and access.

Restoration of thrombosed hemodialysis AVG can be

managed by either endovascular therapy or open surgical

thrombectomy. Several studies have compared outcome

of treatment between endovascular therapy and open

surgical thrombectomy. A 2002 meta-analysis review by

Green, et al.

found that open surgical thrombectomy

had a signicantly better outcome relative to both failure

rate and 90-day patency rate.

Another meta-analysis review by Tordior, et al.

in 2009 analyzed 78 studies that included 8 randomized

controlled trials and 1 meta-analysis. at group found

results similar to those reported by Green, et al. except

that a comparison between studies conducted before

and after 2002 revealed no significant difference in

outcome between the two treatment groups in studies

conducted aer 2002. is dierence may be explained

by improvements in endovascular techniques over time.

e most recent retrospective study in ailand was

published in 2015 by Hongsakul, et al.

at group also

found no signicant dierence in outcomes between

the two treatment options.

Objective

e aim of this study was to investigate the procedure

success rate, one-year primary patency rate, one-year

secondary patency rate, and complications compared between

endovascular therapy and open surgical thrombectomy

for treatment of thrombosed arteriovenous hemodialysis

gra.

MATERIALS AND METHODS

Population

is retrospective chart review included patients

(age >18 years) with acute thrombosed arteriovenous

hemodialysis gra (onset 0-14 days) who were treated

at the Division of Vascular Surgery, Department of

Surgery, Faculty of Medicine Siriraj Hospital, Mahidol

University, Bangkok, ailand during the January 2012 to

December 2016 study period. Demographic, gra type, time

before treatment, thrombus removal technique, adjunct

procedure, procedure success rate, operative, primary

and secondary patency, follow-up time, and complication

data were collected, recorded, and analyzed. Included

data were retrieved from the databases of the Division of

Vascular Surgery of the Department of Surgery and the

Division of Interventional Radiology of the Department

of Radiology at our center. Only patients who were

follow-up for at least one year were included. Patients

who had thrombosis of AVG related to infected gra

or aneurysm were excluded. e treatment method was

determined by the patient’s attending vascular surgeon

or nephrologist. e protocol for this study was approved

by the Siriraj Institutional Review Board (Si 603/2559).

Open surgical thrombectomy

e procedure was performed by vascular surgeons

under general or local anesthesia. e only thrombus

removal technique used in this group was surgical

thrombectomy with Fogarty catheter. In the operating

room, the hemodialysis gra was opened directly at

the venous limb and thrombectomy was performed

by advancing the Fogarty thrombectomy catheter

through the gra into the native venous outow. e

same thrombectomy technique was also performed on

the arterial limb. Angiography was then performed

to evaluate for residual thrombus, and to investigate

for underlying stenotic lesions of arteries and veins in

every cases. Surgical thrombectomy would be repeated

if residual thrombus was observed in the gra. Aer

adequate thrombus removal was conrmed, then any

needed adjunct procedure was selected according to

angiographic nding. If underlying lesion was revealed,

balloon angioplasty was performed to correct luminal

stenosis of vessels. Stent was deployed if there was residual

stenosis greater than 30% aer balloon angioplasty. In

case of recurrent stenosis of venous outow, gra revision

using a short bypass gra to more central venous outow

was performed in selected cases. Final angiogram was

performed to assess the patency of gra and anastomosis.

Fig 1. Open surgical thrombectomy

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493

Fig 2. (A) Angiogram aer thrombus removal showing long stenosis at venous outow. (B, C) Angioplasty with stent was performed and

nal angiogram revealed improvement in lumen stenosis.

A B C

Endovascular therapy

All endovascular procedures were performed by

interventional radiologists. e majority of these procedures

were performed under local anesthesia. A needle was used

to puncture the gra, aer which an introducer sheath

was inserted into the gra. In this group, three dierent

endovascular thrombus removal techniques were used, as

follows. Method 1: Catheter aspiration technique using

5-6 Fr. catheter to aspirate thrombus from the AVG

until the thrombus was removed. Method 2: Mechanical

thrombectomy technique that uses a thrombectomy device

that generates mechanical force to dissolve the thrombus

and aspirate clot fragments into a catheter. Method 3:

Catheter-directed thrombolysis (CDT) technique that

uses a catheter to directly infuse a thrombolytic agent

(recombinant tissue plasminogen activator [rt-PA]) into

the thrombus. For all methods, angiography was performed

aer thrombus removal to check for residual thrombus

and to reveal underlying stenotic lesions of arteries and

veins. Adjunct procedure was selected according to

angiographic nding. If residual thrombus was found,

the same thrombus removal technique could be repeated,

or another of the 3 techniques could be used to ensure

adequate thrombus removal. en underlying lesion was

revealed, balloon angioplasty was performed to correct

luminal stenosis of vessels. Stent was deployed if there

was residual stenosis greater than 30% aer balloon

angioplasty. Aer the aforementioned procedures were

completed, nal angiogram was performed to conrm

the patency of gra and anastomosis.

Follow-up

All patients were clinically followed-up at the outpatient

vascular surgery clinic or nephrology clinic at 1 month,

3 months, and then every 3 months thereaer. If we found

any problem in dialysis or physical examination, duplex

ultrasound was used to evaluate gra function. Gra

dysfunction was conrmed before further correction

by duplex ultrasound in all cases. Decision to abandon

gra was maded by vascular surgeon who performed

ultrasound and we abandoned it only very poor patency

aer restoration of ow (less than 1 months).

Denitions

According to standard practice guideline published

by the Society of Intervention Radiology

, procedural

success is dened as restoration of ow in the dialysis

gra and palpable thrill. Primary patency is dened as

the time interval aer the procedure until the next access

thrombosis or rst subsequent intervention. Secondary

patency is dened as the time interval aer the procedure

until the access was surgically revised or abandoned.

Major complication is dened as complication that

requires additional treatment or that results in permanent

sequelae or death.

Statistical analysis

We compared demographic data, clinical data,

procedure-related data, complications, and outcomes

of procedures between groups. Paired-samples t-test

was used to compare continuous variables, and chi-

square test was used to compare categorical variables.

Normally and non-normally distributed continuous

data are reported at mean ± standard deviation and

median and range, respectively. Categorical data are

shown as frequency and proportion. Survival analysis

was performed using Kaplan-Meier method and log

rank test was used to compare patency. A p-value less

than 0.05 indicates statistical signicance. SPSS Statistics

data analysis program (SPSS, Inc., Chicago, IL, USA)

was used to perform all data analyses.

Puangpunngam et al.

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RESULTS

Of the 74 patients that were included in this study,

25 were in the endovascular group, and 49 were in the

open thrombectomy group. e mean age of patients was

60.68±14.37 years in the endovascular therapy group,

and 64.33±14.81 years in the open thrombectomy group.

All patients had hypertension as a comorbidity, and

diabetes was the second most common comorbidity in

both groups. Loop forearm and loop upper arm AVG

were the most common gra types in the endovascular

and open thrombectomy groups, respectively.

ere was no signicant dierence between groups

for time of gra function aer creation, time since last

gra revision, or number of prior gra thrombectomies.

Eighty percent of patients in the endovascular group and

55% of patients in the open thrombectomy group that

developed failure of hemodialysis access presented with

clinical signs and symptoms of thrombosis. Mostly of

patients had total gra thrombosis, only 11 of 25 patients

in the endovascular group presented with clinical partial

gra thrombosis. Median time from gra thrombosis to

treatment was 2 days (range: 1-14) in the endovascular

group, and 1 day (range: 1-14) in the open thrombectomy

group (p=0.078). A summary of patient and gra data

is shown in Table 1.

All endovascular procedures were performed under

local anesthesia. Eighty percent of the cases used catheter

aspiration as the thrombus removal technique. Mechanical

thrombectomy and catheter-directed thrombolysis were

also used as single or combined thrombus removal

technique. e vast majority (96%) of procedures required

angioplasty for stenosis lesion correction. Stent was

required in 1 case.

In the open thrombectomy group, 73.5% of procedures

were performed under local anesthesia, and additional

angioplasty was needed in 90% of cases. Aer angioplasty,

stent was required in 2 cases, and jump gra procedure

was required in 3 cases due to failure of angioplasty

(Table 2). e most common gra stenotic lesions in both

groups were venous anastomosis and venous outow.

ere was no signicant dierence between the

endovascular and open thrombectomy groups relative to

procedure success rate (92% vs. 98%; p=0.262). Median

operative time was signicantly shorter in the endovascular

group than in the open thrombectomy group (17 vs. 120

minutes; p=0.001). ere was no mortality in this study,

and both groups had a median hospital stay of 3 days.

ere was no signicant dierence between groups for

minor procedure-related complications (Table 3).

Data Endovascular Open P value

(n=25) (n=49)

Age (years), mean±SD 60.68±14.37 64.33±14.81 0.315

Gender, n (%)   0.083

Male 8(32.0%) 26(53.1%)

Female 17(68.0%) 23(46.9%)

Graft type, n (%)   0.207

Loopforearm 10(43.5%) 13(27.1%)

Loopupperarm 11(47.8%) 28(58.3%)

Straightupperarm 2(8.7%) 2(4.2%)

Femoral 0(0.0%) 5(10.4%)

Time before treatment (days),  2(1-14) 1(1-7) 0.078

median (min-max)

TABLE 1. Patient demographic and gra data.

A p-value<0.05 indicates statistical signicance

Abbreviation: SD = standard deviation

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TABLE 2. Procedure-related data.

TABLE 3. Operative, follow-up, patency, and complication data.

Data Endovascular Open P value

(n=25), n (%) (n=49), n (%)

Thrombus removal technique

 Openthrombectomy 0(0.0%) 49(100%)

 Mechanicalthrombectomy 8(34.8%) 0(0.0%)

 CDT 3(13.0%) 0(0.0%)

 Catheteraspiration 20(80.0%) 0(0.0%)

Adjunct procedure after thrombus removal

 Angioplasty 25(100%) 44(89.8%) 0.098

 Stent 1(4.0%) 2(4.1%) 0.987

 rt-PA 0(0.0%) 0(0.0%)

 Jumpgraft 0(0.0%) 3(6.1%) 0.207

A p-value <0.05 indicates statistical signicance

Abbreviations: CDT = catheter-directed thrombolysis, rt-PA = recombinant tissue plasminogen activator

Operative data Endovascular Open P value

(n=25) (n=49)

Proceduresuccessrate,n(%) 23(92.0%) 48(98.0%) 0.262

Medianoperativetime(minutes) 17 120 0.001

Follow-uptime(months),mean±SD 24.0±3.9 17.6±4.0 0.111

Primarypatencytime(months),median(min-max) 6.37(0.79-54.47) 6.37(0.13-43.04) 0.703

Secondarypatencytime(months),median(min-max) 25.75(1.58-54.47) 14.48(0.13-57.56) 0.037

Minorcomplication,n(%) 2(8.6%) 5(9.5%) 0.546

A p-value <0.05 indicates statistical signicance

Abbreviation: SD = standard deviation

As shown in Table 3, the median average primary

patency times in the endovascular and open thrombectomy

groups were the same at 6.37 months (p=0.703). In contrast,

the median secondary patency time was signicantly

longer in the endovascular group (25.75 months) than in

the open thrombectomy group (14.48 months) (p=0.037).

e 1-year primary patency rate was 26.1% in the

endovascular group, and 33.3% in the open thrombectomy

group (p=0.875) (Fig 3). e 1-year secondary patency

rate was 82.6% in the endovascular group, and 56.3% in

the open thrombectomy group (p=0.028) (Fig 4). e

mean follow-up time was 24 months and 17.6 months

in the endovascular group and open thrombectomy

group, respectively (p=0.111).

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Fig 3. Kaplan-Meier curve for primary patency rate

Fig 4. Kaplan-Meier curve for secondary patency rate

DISCUSSION

AVG is preferred as permanent hemodialysis access

in end-stage renal disease patients with limited time to

rst hemodialysis, but access thrombosis is a common

complication. Endovascular therapy for thrombosed

hemodialysis gra is now used worldwide as an alternative

to open surgical thrombectomy. Early studies found

open surgical thrombectomy to have better outcome

than endovascular therapy. Green, et al.

reviewed 7

randomized controlled trials and found that open surgical

thrombectomy had signicantly better outcome for both

failure rate (risk ratio [RR]: 1.90, 95% condence interval

[CI]: 1.32-2.73; p=0.0005) and 90-day patency rate (RR:

1.22, 95% CI: 1.05-1.40; p=0.007) than endovascular

therapy. However, a 2009 meta-analysis review by Tordior,

et al.

and a 2015 retrospective study by Hongsakul, et al.

both reported equivalent outcome between groups.

e 92% and 98% procedure success rates in the

endovascular and open thrombectomy groups, respectively,

in our study were comparable to the rates reported in the

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aforementioned meta-analysis (92-95% and 79-100%,

respectively) and retrospective study (94% and 93.8%,

respectively).

e time interval from gra thrombosis to intervention

is one of the factors that signicantly inuences the

procedure success rate. In the present study, the median

duration before treatment was longer in the endovascular

group than in the open thrombectomy group (2 days vs.

1 day), and there was some dierence in the procedure

success rate (92% vs. 98%), but the dierence for both

comparisons failed to achieve statistical signicance.

Our comparative analysis revealed operative time

to be one of the variables most dierent between groups.

Open thrombectomy had a signicantly longer operative

time than endovascular method. is may be explained

by additional gra open and closure steps, and the need

for general or regional anesthesia in some patients.

Although, longer operative time was required, open

thrombectomy still had similar procedural success rate

and primary gra patency compared to endovascular

procedure. Moreover, the rate of complications was

non-signicantly dierent between groups.

Mechanical thrombectomy and catheter-directed

thrombolysis were reported to be effective and safe

techniques for endovascular gra thrombectomy.

4,6-10

Catheter aspiration, which accounted for 80% of the

endovascular procedures performed in our study, is a

simple and eective technique that requires no expensive

surgical devices, but it yields comparable results relative

to procedure success rate and gra patency.

We found signicant lesions aer open thrombectomy

that need intervention to correct lesions more than 90%

of cases. ese data near the result in previous report

(78%) from Kuma, et al.

Regarding one-year primary patency rate, the

26% and 33% rates of one-year primary patency in the

endovascular and open thrombectomy groups in our

study were near the upper end of the range reported by

Tordoir, et al. (8-29% and 10-30%), and similar to the

rate reported by Hongsakul, et al. (28% and 30%).

Concerning the one-year secondary patency rate,

the 82.6% and 56.3% rates of one-year secondary patency

in the endovascular and open thrombectomy groups in

the present study are in some ways dierent and in some

ways comparable to the results reported by Tordoir, et al.

(23-62% and 27-65%) and Hongsakul, et al. (54.3% and

57%). Recent study from Koraen-Smith, et al.

show the

same results that thrombolysis group had better assist

primary patency.

Our study showed markedly better one-year

secondary patency compared to previous studies due

to selection bias and dierent severity of thrombosis in

the endovascular group. We found that 11 of 25 patients

in the endovascular group presented with clinical partial

gra thrombosis, so lower severity of gra thrombosis

may lead to better secondary patency rate. Furthermore,

early follow-up at 1 and 3 months in our study resulted

in early additional endovascular therapy for partial gra

stenosis before complete gra thrombosis occurred.

To summarize, our study found advantage of

endovascular therapy to open thrombectomy in thrombosed

AVBG, with signicantly better one-year secondary

patency, signicantly shorter operative time, and all

endovascular procedures could be performed under

local anesthesia.

Limitations

is study has some limitations. First, the retrospective

design of our study suggests the potential for missing or

incomplete data. Second, our center is a national tertiary

referral hospital that is oen referred complex cases. As

such, our results may not reect or be generalizable to

other care settings. ird, our overall study population was

relatively small, and we had a small number of patients

in the endovascular group. ese factors suggest the

possibility that our study may have lacked the statistical

power to identify all signicant dierence and associations

between groups. Fourth, we were not able to include detail

relating to improvement in lumen stenosis from post-

procedure angiogram, which could inuence gra patency.

Further randomized controlled study is recommended

to determine the advantage of endovascular therapy

over open thrombectomy in patients with thrombosed

AVBG.

CONCLUSION

No signicant dierences were observed between

groups for procedure success rate or 1-year primary patency

rate; however, the one-year secondary patency rate in the

endovascular group was signicantly better than in the

thrombectomy group. No dierence in complications

was observed between groups. ese results suggest

endovascular treatment as a safe and ecacious treatment

alternative in patients with thrombosed arteriovenous

hemodialysis gra.

ACKNOWLEDGMENTS

e authors gratefully acknowledge Dr. Sasima

Tongsai of the Division of Clinical Epidemiology,

Department of Research, Faculty of Medicine Siriraj

Hospital, Mahidol University, Bangkok, ailand for

assistance with statistical analysis.

Puangpunngam et al.

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Conict of interest declaration

All authors declare no personal or professional

conicts of interest, and no nancial support from the

companies that produce and/or distribute the drugs,

devices, or materials described in this report.

Funding disclosure

is was an unfunded study.

REFERENCES

1. Gilmore J. KDOQI clinical practice guidelines and clinical practice

recommendations--2006 updates. Nephrol Nurs J 2006;33:

487-8.

2. Green LD, Lee DS, Kucey DS. A metaanalysis comparing surgical

thrombectomy, mechanical thrombectomy, and pharmacomechanical

thrombolysis for thrombosed dialysis gras. J Vasc Surg 2002;

36:939-45.

3. Tordoir JH, Bode AS, Peppelenbosch N, van der Sande FM, de

Haan MW. Surgical or endovascular repair of thrombosed dialysis

vascular access: is there any evidence? J Vasc Surg 2009;50:

953-6.

4. Hongsakul K, Rookkapan S, Sungsiri J, Boonsrirat U, Kritpracha

B. Pharmacomechanical Thrombolysis versus Surgical

rombectomy for the Treatment of rombosed Haemodialysis

Gras. Annals of the Academy of Medicine, Singapore. 2015;

44(2):66-70.

5. Aruny JE, Lewis CA, Cardella JF, Cole PE, Davis A, Drooz AT,

et al. Quality improvement guidelines for percutaneous

management of the thrombosed or dysfunctional dialysis

access. J Vasc Interv Radiol 2003;14(9 Pt 2):S247-53.

6. Dougherty MJ, Calligaro KD, Schindler N, Raviola CA, Ntoso A.

Endovascular versus surgical treatment for thrombosed

hemodialysis gras: A prospective, randomized study. J Vasc

Surg 1999;30:1016-23.

7. Sofocleous CT, Hinrichs CR, Weiss SH, Contractor D, Barone

A, Bahramipour P, et al. Alteplase for hemodialysis access

gra thrombosis. J Vas Interv Radiol 2002;13:775-84.

8. Karatepe C, Aldemir M, Cinar B, Onalan A, Issever H, Goksel OS.

Midterm Results Following Percutaneous Rotational rombectomy

for Acute rombotic Occlusions of Prosthetic Arteriovenous

Access Gras. Int Surg 2015;100:1249-54.

9. Chan PG, Goh GS. Safety and ecacy of the AngioJet device

in the treatment of thrombosed arteriovenous stula and gras:

A systematic review. J Vasc Access 2018;19:243-51.

10. Marcelin C, D’Souza S, Le Bras Y, Petitpierre F, Grenier N, van

den Berg JC, et al. Mechanical Thrombectomy in Acute

rombosis of Dialysis Arteriovenous Fistulae and Gras

Using a Vacuum-Assisted rombectomy Catheter: A Multicenter

Study. J Vasc Interv Radiol 2018;29:993-7.

11. Kumar SD, Jain KM, Jain S, Munn JS, Rummel MC. Fistulogram

aer arteriovenous dialysis gra thrombectomy should be

mandatory. Am Surg 2008;74:1154-8.

12. Koraen-Smith L, Krasun M, Bottai M, Hedin U, Wahlgren

CM, Gillgren P. Haemodialysis access thrombosis: Outcomes

aer surgical thrombectomy versus catheter-directed thrombolytic

infusion. J Vasc Access 2018;19:535-41.

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Banjerd Praditsuktavorn, M.D., Chumpol Wongwanit, M.D., Tiwa Chaisongrit, M.D., Chanean Ruangsetakit,

M.D., Kiattisak Hongku, M.D., Nattawut Puangpunngam, M.D.

Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.

Outcomes of Autogenous Snuffbox Radiocephalic

Arteriovenous Fistula-First Strategy for

Hemodialysis Access

ABSTRACT

Objective: An autogenous arteriovenous stula (AVF) has been recommended as the rst-line hemodialysis access

option. A distal radiocephalic (snuox) arteriovenous stula (SBAVF), the most distally located AVF, provides an

extended vascular access area, allows future AVF correction in the proximal part, and oers relatively easy surgical

access. is study aimed to evaluate the outcomes of patients who had SBAVFs as their rst option for dialysis access.

Methods: e medical-record electronic database of Siriraj Hospital, Bangkok, ailand, was retrospectively reviewed

to evaluate the outcomes of patients receiving SBAVFs July 2013-December 2016 with over 12 months of follow-up.

Results: Of 39 patients, SBAVFs were successfully created in 33 patients (84.6%). Early thrombosis was observed in

1 patient. Steal syndrome, distal thrombosis, and complications of high-venous ow were not detected. e primary,

primary-assisted, and secondary patency rates at 12 months were 60.6%, 81.8%, and 100%, respectively, and at 24 months

were 51.5%, 72.7%, and 97.0%, respectively. Diabetes showed a signicant correlation with failed AVF maturation, and

venous diameters under 2.5 mm signicantly reduced the 1-year primary patency. SBAVFs were successfully created in 9/12

patients who had a borderline venous size (< 2.5 mm), resulting in the AVF creation rate improving from 66.7% to 89.7%.

Conclusion: Autogenous distal radiocephalic (snuox) arteriovenous stula is a feasible rst-line option, especially

for young, non-diabetic patients who are not in urgent need of hemodialysis. is strategy could also enhance the

possibility of autogenous AVF creation in patients with a borderline venous size.

Keywords: Arteriovenous stula; snuox arteriovenous stula; hemodialysis; vascular access for hemodialysis;

AVF (Siriraj Med J 2019; 71: 499-505)

Corresponding author: Nattawut Puangpunngam

E-mail: nattawut.pua@mahidol.edu

Received 14 August 2019 Revised 30 August 2019 Accepted 27 September 2019

ORCID ID: http://orcid.org/0000-0002-4874-5285

http://dx.doi.org/10.33192/Smj.2019.74

INTRODUCTION

According to a report on renal replacement therapy

in ailand, the number of patients requiring treatment

for renal replacement therapy has been increasing. ere

were twice as many patients in 2015 as in 2010, and

hemodialysis was implemented in the majority of cases

(65.2%).

As to the hemodialysis modalities, an autogenous

arteriovenous stula (AVF) has been recommended as

the rst-line approach over arteriovenous gra (AVG)

and central venous catheter-based hemodialysis (CVC)

by both the National Kidney Foundation Kidney Disease

Outcomes Quality Initiative (NKF-KDOQI) guideline

recommendations of 2006

and the Society for Vascular

Surgery clinical practice guidelines of 2008.

is was

because of AVF’s comparatively lower complication rates;

superior long-term functions; and favorable survival

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outcomes

4-5

, evidenced by fewer high-ow or ischemic

complications (especially in the distal-location). It also

oers the possibility of a new, proximal, AVF creation.

Distal radiocephalic arteriovenous fistula for

hemodialysis at the anatomical snuox (SBAVF) is

considered the most distally located AVF. It is created

by an anastomosis between the dorsal branch of the

radial artery in the anatomical snuox region and the

cephalic vein at the base of the thumb. Because the two

vessels lie in parallel and are in close proximity, SBAVF

creation provides a favorable angle and allows for ease

of surgical access. Further advantages of SBAVF are its

wider vascular access area and its potential for the later

creation of a wrist radiocephalic AVF.

6–7

Despite the

advantages of an AVF in the wrist or snuox region,

many patients are not feasible candidates for SBAVF

creation. is is mainly because of the relatively small

vessel size in this area, which is challenging for a distal

AVF-rst strategy. However, several authors have reported

favorable outcomes for SBAVFs in patients with borderline

vessel size.

7-9

e aim of this study was to evaluate the outcomes

of SBAVFs, including factors aecting maturation and

patency in patients with borderline vessel size, in order

to enhance the creation of an autogenous arteriovenous

stula-rst protocol for patients requiring long-term

hemodialysis.

MATERIALS AND METHODS

e medical-record electronic database of Siriraj

Hospital was retrospectively reviewed to identify all

patients who had undergone an autogenous distal

radiocephalic (snuox) arterio-venous stula creation

for hemodialysis between July 2013 and December 2016.

Excluded were patients who had incomplete data, were

unable to attend follow-ups, or had an abandoned

arterio-venous stula within 12 months of the stula

creation. Kidney transplantations, elective changes to

dierent renal replacement therapies, or death were

considered to be censored events. Demographic data

(such as age, gender, and co-morbidities like diabetes

mellitus and coronary artery disease), factors related

to the hemodialysis management (including the serum

creatinine level), and the status of the hemodialysis were

recorded. Patient management and follow-ups were

conducted as per the Division of Vascular Surgery’s

protocols, which encompassed a preoperative assessment

with duplex ultrasonography, the operative procedures,

and the postoperative follow-ups (comprising an initial

1- to 2-week postoperative period for wound care and

subsequent 1- to 3-monthly assessments of the stula

maturation and complications). Preoperative duplex

ultrasonography was used to assess both the arterial and

venous size (using the tourniquet technique), continuity

of the vessel, and potential sites for a proximal AVF and

AVG. Patients who had a history of coronary artery disease

were evaluated by cardiologists before undergoing the

AVF procedure.

Surgical procedures: All arteriovenous stulas were

created through a 2-cm longitudinal incision under local,

regional, or general anesthesia by vascular surgeons.

Radiocephalic stulas were accomplished in a side-to-

end fashion, and 6-8 mm radial artery arteriotomies were

anastomosed with cephalic veins using polypropylene

no. 6/0 or 7/0, according to the vessel size (Fig 1).

Outcome measures: e primary outcome was

stula maturation, which was determined by vascular

surgeons based on physical examinations and evidence of

adequate venous ow in duplex ultrasonography (Fig 2).

Primary maturation was dened as an arteriovenous stula

maturing without any additional intervention. Assisted

primary maturation was dened as an arteriovenous stula

needing additional surgical or endovascular intervention

to mature. Secondary (cumulative) maturation was dened

as an arteriovenous stula maturing regardless of a prior

thrombosis or the need for a surgical or endovascular

intervention.

Fig 1. e photographs of (A) incision and cephalic vein dissection of le distal radio-cephalic arteriovenous stula and (B) completion of

le snuox radio-cephalic anastomosis.

A B

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Fig 2. Postoperative assessment of anastomosis size.

e secondary outcomes were the time when the

stulas were accessed and the patency of the arteriovenous

stulas. In detail, primary patency was dened as the time

to achieve a functioning arteriovenous stula without

any additional intervention. Primary-assisted patency

was dened as the time to achieve an uninterrupted

functioning arteriovenous in the case of those stulas

needing a surgical or endovascular intervention to maintain

patency. Secondary (cumulative) patency was dened as

the time to achieve a functioning arteriovenous stula

regardless of interventions or thrombosis. is study was

approved by the Ethics Committee of the Institutional

Review Board of the Faculty of Medicine Siriraj Hospital,

Mahidol University, ailand (Si 783/2559).

Statistical analysis: All data were analyzed using

IBM SPSS Statistics for Windows, version 24 (IBM

Corp., Armonk, NY, USA). e analyses comprised

descriptive statistics, outcomes analysis by Chi-square,

logistic regression, and survival analysis by Kaplan–Meier

survival plots for patency rates.

A total of 39 distal radiocephalic arteriovenous

stula creations were included in this study. e patients’

median age was 58 years (range, 25–80 years). Twenty-

ve patients (64.1%) were male; 21 (53.8%) had diabetes

mellitus; 8 (20.5%) had received a coronary artery

intervention; while one (2.6%) had lower extremity

arterial occlusive disease (Table 1). Eighteen patients

(46.2%) were receiving catheter-based hemodialysis,

and of those without hemodialysis, the mean serum

creatinine level was 5.84 ± 1.97 mg/dL.

e preoperative vascular assessment found that

the mean radial artery diameter was 2.41 mm (standard

deviation, ± 0.46 mm) and the mean cephalic vein diameter

was 2.29 mm (standard deviation, ± 0.50 mm).

Fistula creations were performed under local, regional,

and general anesthesia on 32 (82.0%), 4 (10.3%), and

3 (7.7%) patients, respectively. Anastomoses were performed

by running polypropylene number 7/0 in 34 patients

(87%) and number 6/0 in 5 patients (13%). ere were

no reports of wound complications (infections and

hematomas), steal syndrome, or distal ischemia. One

patient developed thrombosis within the rst 24 hours,

while another two complained of reversible numbness at

the le thumbs, both of which were completely recovered

within 3 and 6 months post operation.

TABLE 1. Demographic data and chronic kidney disease parameters.

Clinical variable No. of patients (%)

Total n = 39

Age(years)

 Median 58

 Range 25-80

  <50years 14(35.9%)

  50-70years 16(41.0%)

  >70years 9(23.1%)

Gender

 Male 25(64.1%)

 Female 14(35.9%)

Comorbidities

 Diabetesmellitus 21(53.8%)

 Coronaryarterydisease 8(20.5%)

 Lowerextremityarterialocclusivedisease 1(2.6%)

Praditsuktavorn et al.

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The primary, primary-assisted, and secondary

(cumulative) maturation responses were 59%, 64.1%, and

84.6%, respectively (Table 2). All 10 patients who failed

to achieve primary maturation required transposition

to wrist radiocephalic stula creations. e maturation

times ranged from 2 to 12 months (median, 3 months).

Diabetic patients had a significant correlation with

maturation failure. Male patients and patients younger

than 50 years of age demonstrated a tendency to higher

maturation rates aer correlations with diabetes were

adjusted. On the other hand, venous size and a history

of coronary artery disease did not display signicant

correlations with maturation rates.

e follow-up periods ranged from 12 to 50 months

(median, 29 months). e patency results are presented

as Kaplan–Meier Plots in Fig 2. It was found that the

primary, primary-assisted, and secondary patency rates

at 12 months were 60.6%, 81.8%, and 100%, respectively,

and at 24 months were 51.5%, 72.7%, 97.0%, respectively.

A Cox regression analysis evaluating the clinical factors

(age group, gender, diabetes, and vein size) and the

1-year primary patency rates revealed signicantly lower

primary patency rates in patients whose cephalic venous

size was less than 2.5 mm.

DISCUSSION

A distal radiocephalic arteriovenous stula at the

anatomical snuox (SBAVF) has been recommended as

the rst-line approach over other types of AVF, including

wrist AVF, by several authors.

6–10

However, its popularity

and the number of reported cases have been low relative

to the other AVF types. is could be the result of limited

vessel-size feasibility and varied outcomes. Wolowczyk

et al. reported that 14% (30/208) of stulas failed within

6 weeks and that the 1-year patency rate was 65%7; by

comparison, other authors have reported 1-year patency

rates ranging from 61%

7–8

to over 90%.

6,11

TABLE 2. Correlation between cephalic vein size and maturation of arterio-venous stulas.

Clinical factors No. of patients Maturation (%) P-value

(%) Primary vs primary-assisted

vs secondary

Gender    0.09

 Male 25(64.1%) 68.0%vs72.0%vs92.0%

 Female 14(35.9%) 42.9%vs50.0%vs71.4%

Agegroup   0.05

 <50years 14(35.9%) 78.6%vs78.6%vs100%

 50-70years 16(41.0%) 43.8%vs56.3%vs75.0%

 >70years 9(23.1%) 55.5%vs55.5%vs77.7%

Diabetesmellitus   <0.05

 DM 21(53.8%) 47.6%vs47.6%vs71.4%

 Non-DM 18(46.2%) 72.2%vs83.3%vs100%

CAD   n.s.

 CAD 8(20.5%) 50%vs50%vs75%

 Non-CAD 31(79.5%) 61.3%vs67.7%vs87.1%

Veinsize(mm)   n.s.

 <2.0 9(23.1%) 44%vs55%vs77%

 2-2.4 16(41.0%) 63%vs69%vs94%

 2.5-2.9 10(25.6%) 60%vs60%vs80%

 >3.0 4(10.3%) 75%vs75%vs75%

Abbreviation: n.s.= no statistical signicance

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Our autogenous snuox AVF-rst approach resulted

in an 84.6% success rate and a 1-year patency of 60.6%,

both of which were comparable to other studies

12–13

well as the outcomes of wrist radiocephalic arteriovenous

stula creations at our center.

Of the 6 patients (15.4%)

who had a failed AVF, two underwent an AVG, two

were given brachiocephalic arteriovenous stulas, and

two received catheter-based hemodialysis due to having

borderline cardiac functions. However, of those who had

a failed AVF, three had no suitable site for an AVF as

they had a small venous diameter (< 2.5 mm); a small

venous size was also observed in 9 patients for whom

autogenous AVFs were successfully created.

Regarding vascular size as a determining factor for

autogenous AVF creation, the results of the present study

indicated that the SBAVF-rst approach enhanced the

autogenous AVF creation from 66.7% (26/39) to 89.7%

(35/39).

e major disadvantages of this approach were its

relatively long maturation time (mean, 3 months) and

a high incidence of juxta-anastomosis stenosis at the

wrist level, which frequently required transposition to a

wrist radiocephalic arteriovenous stula as a secondary

procedure. Nonetheless, that procedure was able to be

performed simply under local anesthesia due to the

vessels being enlarged aer the rst stula creation

(Fig 3).

Diabetes had a signicant association with failed

SBAVF maturations, while being female and a patient age

of over 50 years tended towards lower maturation rates.

Although venous size was not signicantly correlated with

the maturation rate, a venous diameter of 3 mm or more

did not require any intervention to assist maturation.

A venous size of less than 2.5 mm signicantly correlated

with a reduction in the 1-year patency rate. However,

our sample size was relatively small and contained only

a few patients who had a large venous diameter.

ere are several measures to determine the factors

aecting snuox AVF outcomes. In 2012, Twine et al.

developed a DISTAL score by combining 6 factors (each

factor representing 1 score) aecting stula failure, namely,

diabetes, ischemic heart disease, stroke, two snuox

procedures, an age > 70 years, and a venous diameter of

< 2 mm.

is DISTAL scoring system was used in our

study (Table 4), and it revealed a signicant correlation

with the maturation rates but not with the patency rates.

is can be explained by the DISTAL scoring system’s

use of a dierent cut-point for signicant venous size

(< 2 mm versus < 2.5 mm in the current study) and

a patient age of > 70, which tended to lead to higher

patency rates in our study (Fig 4).

Fig 3. Transposition of le radio-cephalic arteriovenous stula (Le)

and Transposed le radio-cephalic arteriovenous stula (Right).

Fig 4. Outcomes of autogenous snuox radiocephalic AVF (Le)

Early postoperative period, (Middle) in a 47 year-old male patient,

and (Right) a 79 year-old female patient.

CONCLUSION

e study results suggest that an autogenous snuox

radiocephalic arteriovenous stula (SBAVF)-rst strategy

is feasible because of its relative ease of surgical access,

its comparatively extended venous access area, and the

provision of options for future AVF correction, especially

in the case of young patients without diabetes and not

in urgent need of hemodialysis. SBAVF could also be

considered in cases of borderline venous size in order

to enhance the rate of autogenous arteriovenous stula

for hemodialysis.

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TABLE 3. Correlation between clinical factors and 1-year primary patency rates.

Clinical factors No. of patients Patency rates (%) P-value

(n = 33)*

Gender   n.s.

 Male 23(69.7%) 65.2%

 Female 10(30.3%) 50.0%

Agegroup   0.056

 <50years 14(42.4%) 57.1%

 50-70years 12(36.4%) 50.0%

 >70years 7(21.2%) 85.7%

Diabetesmellitus   n.s.

 DM 15(45.4%) 73.3%

 Non-DM 18(54.5%) 50.0%

CAD   n.s.

 CAD 6(18.2%) 83.3%

 Non-CAD 27(81.8%) 55.6%

Venoussize(mm)   <0.05

 <2mm 7(21.2%) 28.6%

 2-2.4mm 15(45.4%) 53.3%

 2.5-2.9mm 8(24.3%) 87.5%

 >3mm 3(9.1%) 100%

*Patients in whom the AVF failed to mature were excluded.

Abbreviation: n.s.= no statistical signicance

e follow-up period range was 12–50

months (median, 29 months). e patency

results are demonstrated in Kaplan–Meier

plots in Fig 2; the primary, primary-assisted,

and secondary patency rates at 12 months

were 60.6%, 81.8%, and 100%, respectively;

and at 24 months were 51.5%, 72.7%, and

97.0%, respectively. A Cox regression analysis

evaluating the clinical factors (age group,

gender, diabetes, and vein size) and 1-year

primary patency rates demonstrated signicantly

lower primary patency rates in patients whose

cephalic venous size was < 2.5 mm.

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REFERENCES

1. Nephrology Society of ailand. Nephrothaiorg. [Online].

Available from: http://www.nephrothai.org/images/Final_

TRT_report_2015_edited.pdf [Accessed 20 Nov 2018].

2. NKF-K/DOQI Clinical Practice Guidelines for Vascular Access:

Update 2006. Guideline 2: Selection and placement of hemodialysis

access, 2.1 e order of preference for placement of stulae,

2.1.1 Preferred: stulae.

3. Sidawy AN,Spergel LM, Besarab A, Allon M,Jennings

WC,Padberg FT Jr,et al. e Society for Vascular Surgery:

clinical practice guidelines for the surgical placement and

maintenance of arteriovenous hemodialysis access. J Vasc Surg

2008; 48:2S-25S.

4. Xue JL, Dahl D, Ebben JP, Collins AJ. e association of initial

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5. Ravani P,Palmer SC,Oliver MJ,Quinn RR,MacRae JM,Tai

DJ,et al. Associations between hemodialysis access type and

clinical outcomes: a systematic review. J Am Soc Nephrol

2013;24:465-73.

6. Bonalumi U, Civalleri D, Rovida S, Adami GF, Gianetta E,

Grianti-Bartoli F. Nine years’ experience with end-to-end

arteriovenous stula at the ‘anatomical snuox’ for maintenance

haemodialysis. Br J Surg 1982;69:486-8.

7. Wolowczyk L, Williams AJ, Donovan KL, Gibbons CP. e

snuox arteriovenous stula for vascular access. Eur J Vasc

Endovasc Surg 2000;19:70-6.

8. Twine CP, Haidermota M, Woolgar JD, Gibbons CP, Davies

CG. A scoring system (DISTAL) for predicting failure of snuox

arteriovenous stulas. Eur J Vasc Endovasc Surg 2012;44:

88-91.

9. Letachowicz K, Gołębiowski T, Kusztal M, Letachowicz W,

Weyde W, Klinger M. e snuox stula should be preferred

over the wrist arteriovenous stula. J Vasc Surg 2016;63:436-

40.

10. Mehigan LT, McAlexander RA. Snuox arteriovenous stula

for haemodialysis. Am J Surg 1982;143:252-3.

11. Horimi H, Kusano E, Hasegawa T, Fuse K, Asano Y. Clinical

experience with an anatomic snu box arteriovenous stula

in hemodialysis patients. ASAIO J 1996;42:177-80.

12. Al-Jaishi AA, Oliver MJ, omas SM, Lok CE, Zhang JC, Garg

AX, et al. Patency rates of the arteriovenous stula for hemodialysis:

a systematic review and meta-analysis. Am J Kidney Dis

2014;63:464-78.

13. Almasri J, Alsawas M, Mainou M, Mustafa RA, Wang Z, Woo

K, et al. Outcomes of vascular access for hemodialysis: A

systematic review and meta-analysis. J Vasc Surg 2016;64:236-

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14. Ruangsetakit C, Chuemor P, Hongku K, Hahtapornsawan S,

Chinsakchai K, Sermsathanasawadi N, et al. Outcomes of

Autogenous Hemodialysis Access at Siriraj Hospital. J Med

Assoc ai 2017;100(Suppl 3):S193-8.

TABLE 4. Correlations between distal scores, maturation rates, and 1-year patency rates.

Distal score No. of patients Maturation rate* No of AVFs 1-year primary

(n=39) (n=33) patency rate

n.s.

0 10(25.6%) 100% 10 50%

1 17(43.6%) 88.2% 15 50.0%

2 4(10.3%) 75% 3 66.7%

3 8(20.5%) 62.5% 5 80.0%

*p < 0.05,

Abbreviation: n.s.= no statistical signicance

Praditsuktavorn et al.

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Original Article

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Nutthawut Akaranuchat, M.D., Jongdee Aojanepong, M.D.

Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.

Formulaic Prediction of Z-Plasty Outcomes Relative

to Z Scar Lengthening, Z Flap Tension, and Area

of Distortion, and Determination of the Multiple

Z-Plasty Congurations that Optimally Increase Z

Scar Length, Decrease Z Flap Tension, and

Decrease Area of Distortion

ABSTRACT

Objective: To generate mathematical formulas to predict Z-plasty outcomes relative to Z scar lengthening, Z ap

tension, and area of distortion, and to determine the multiple Z-plasty congurations that optimally increase Z scar

length, decrease Z ap tension, and decrease area of distortion.

Methods: Each Z-plasty conguration was evaluated for highest percent Z scar lengthening, lowest tension to

close Z ap, and lowest area of distortion. For part 1 of the study, conventional one-ap, two-ap, four-ap, and

eight-ap Z-plasties were created, aer which relocation of the Z aps was performed. e outcomes were analyzed

and formulas were generated to predict Z-plasty outcomes. In part 2, the following modications to the four-ap

Z-plasty were made: modication of Z ap angle, modication of Z ap limb size, and addition of a gap between

each Z ap. Outcomes were evaluated to identify the conguration that produced the optimal outcome for each

outcome measure.

Results: irty-six pig skins were incised and sutured under controlled condition. For part 1, one-ap Z-plasty was

best for Z scar lengthening, and 8-ap Z-plasty was best for reducing both tension to close and area of distortion.

ree formulas were generated to predict the studied outcomes of Z-plasty. For part 2, the conguration that added

a gap of 75% of the central limb length yielded the best outcome for scar length and also work very well for reducing

the tension to close. e conventional design was the best for minimizing area of distortion.

Conclusion: Mathematical formulas were generated to predict Z scar percent lengthening, Z ap tension to close, and

area of distortion. Addition of a gap 75% of the central limb length was the most ecacious Z-plasty conguration

for increasing Z scar length.

Keywords: Mathematical prediction; Z-plasty outcomes; Z scar lengthening; Z ap tension; area of distortion;

multiple Z-plasty congurations (Siriraj Med J 2019; 71: 506-514)

Corresponding author: Nutthawut Akaranuchat

E-mail: nutthawut.joe@gmail.com

Received 27 May 2019 Revised 22 September 2019 Accepted 25 September 2019

ORCID ID: http://orcid.org/0000-0003-1798-8484

http://dx.doi.org/10.33192/Smj.2019.75

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INTRODUCTION

Z-plasty is a valuable technique for plastic surgeons.

Z-plasty is an eective surgical treatment to manage scar

contracture

2,3,5,6

, and it is incorporated in many plastic

surgery procedures. e four fundamental functions of

Z-plasty are: 1) To lengthen a scar or release a contracture;

2) To realign a scar within relaxed skin tension lines

(RSTLs); 3) To move tissue from one area to another; and,

4) To obliterate or create a web or cle.

Modications of

Z-plasty were developed to serve dierent purposes

, and

one of the most popular variations is multiple Z-plasty

or compound Z-plasty technique. Multiple Z-plasty is

dened as the linkage of two or more Z aps. Multiple

Z-plasty is an eective alternative for the management

of large scars that would not respond well to the use

of a single (one-ap) Z-plasty, because the large aps

of a single Z ap would eectuate more distortion and

tension to the adjacent area than multiple smaller Z

aps. Many studies were conducted to understand and

predict the eect of Z-plasty on adjacent tissue in both

animal models1 and computer simulations.

4,9,10

However,

methods to predict the surgical outcomes of Z-plasty,

and data relating to the Z-plasty congurations that

yield the best surgical outcomes are scarce. Accordingly,

the aims of this study were to generate mathematical

formulas to predict Z-plasty outcomes relative to Z scar

lengthening, Z ap tension, and area of distortion, and

to determine the multiple Z-plasty congurations that

optimally increase Z scar length, decrease Z ap tension,

and decrease area of distortion.

MATERIALS AND METHODS

Fresh pig skins, including the epidermis, dermis, and

subcutaneous layer were prepared. All specimens were

cut to 16.0 x 16.0 cm in size, and to between 1.3 to 1.5

cm in thickness. Specimen temperature was maintained

within the range of 25-30 degrees Celsius using an infrared

thermometer. Skin surface tension was set within 0.07-

0.08 newton/m (N/m)

by using digital manometer

before commencement of the experiment.

Specimens were marked with colored dots located

0.5 cm apart, aer which Z-plasty and multiple Z-plasty

aps were drawn then marked the reference point of

both end of Z flap as point A and point B (After Z

ap was relocated these points will be point A’ and

point B’ respectively). Aer that incisions were made.

Part 1

e conventional design of 1-ap, 2-ap, 4-ap,

and 8-ap Z-plasties was performed, which consisted of

60 degree angle size and equality among all Z ap limb

lengths (Fig 1A-D).

Fig 1. (A) One-ap Z-plasty, (B) Two-ap Z-plasty, (C) Four-ap

Z-plasty, (D) Eight-ap Z-plasty.

Part 2

Modications to the conventional 4-ap Z-plasty

were designed. First, we modied the angle of each Z

ap to 75 and 45 degrees (Fig 2A), and to 90 and 30

degrees (Fig 2B). Second, we modied the size of Z ap

limb length to 2.5 cm and 1.5 cm (Fig 2C), and also to

alternating unequal Z ap peripheral limb size of 2.5

cm and 1.5 cm, and central limb size 2.0 cm (Fig 2D).

ird, we added a gap between each Z ap, as follows:

1. Gap 0.5 cm (25% of central limb length; Fig 2E)

2. Gap 1.0 cm (50% of central limb length; Fig 2F)

3. Gap 1.5 cm (75% of central limb length; Fig 2G)

4. Gap 2.0 cm (100% of central limb length; Fig 2H)

Z aps were then relocated to their nal position

and the following outcomes were measured: 1) actual

scar length (centimeter, cm); tension to close (newton,

N); and, area of distortion (square centimeter, cm2).

A descriptive analysis was performed, and the results

are presented as mean, and as frequency and percentage

for categorical variables. SPSS Statistics version 18 (SPSS,

Inc., Chicago, IL, USA) was used to analyze the data.

Akaranuchat et al.

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RESULTS

Part 1

is experimental study was performed on 36 pig

skin specimens (12 designs, 3 per each design), and post-

procedure measurements were taken and recorded.

For one-ap Z plasty, it increased the length about

46.875%, need tension to close the Z ap about 5.283 N,

and create area of distortion about 208.0 cm

. For two-

ap Z plasty, it increased the length about 31.25%, need

tension to close the Z ap about 5.913 N, and create area

of distortion about 122.375 cm

. For four-ap Z plasty, it

increased the length about 18.75%, need tension to close

the Z ap about 6.433 N, and create area of distortion

about 84.5 cm

. For eight-ap Z plasty, it increased the

length about 17.5%, need tension to close the Z ap

about 3.255 N, and create area of distortion about 37.5

e results of each design were compared (Table 1),

and we found that 1-ap Z-plasty yielded the best result

in terms of scar lengthening, followed by 2-ap, 4-ap,

and 8-ap Z-plasty.

Regarding the tension needed to close the Z ap

and the area of distortion, the authors found that 8-ap

Z-plasty produced both the least tension and the least

area of distortion aer Z ap relocation, followed by

4-ap, 2-ap, and 1-ap Z-plasty.

From the data we found, the curve estimation models

were match with inverse equation; Y = b0 + (b1 / t),

(Y = result from equation, b0 = constant, b1 = constant,

t = number of Z plasty) (Fig 3A-C).

Finally, the mathematical models that were generated

to predict percent scar lengthening, tension to close Z

ap, and area of distortion outcomes aer Z-plasty are,

as follows:

Percent lengthening = 12.10 + (35.74 / t)

Tension to close Z ap = 0.05 + (5.36 / t)

Area of distortion = 26.54 + (184.65 / t)

Part 2

In this part, the authors set forth to evaluate the

eect of each modied Z-plasty technique. e studied

Fig 2. (A) Modication of the angles of each Z ap; 75 and 45 degrees,

(B) Modication of the angles of each Z ap; 90 and 30 degrees, (C)

Modication of the limb size of each Z ap; Z ap size 2.5 cm and

1.5 cm, (D) Unequal peripheral limb of Z ap size 2.5 cm, and 1.5

cm and central limb size 2.0 cm, (E) Addition of a gap between each

Z ap; Gap of 0.5 cm (25% of limb size), (F) Addition of a gap between

each Z ap; Gap of 1.0 cm (50% of limb size), (G) Addition of a gap

between each Z ap; Gap of 1.5 cm (75% of limb size), (H) Addition

of a gap between each Z ap; Gap of 2.0 cm (100% of limb size).

Fig 3. (A) Model summary of percent scar lengthening; percent scar lengthening: b0 (constant) = 12.10, b1 = 35.74, (B) Model summary

of tension to close Z ap; tension to close Z ap: b0 (constant) = 0.05, b1 = 5.36, (C) Model summary of area of distortion; area of distortion:

b0 (constant) = 26.54, b1 = 184.65.

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Type Original length Actual length Lengthening Percent Total tension Area of

(cm) (cm) (cm) lengthening to close (N) distortion

(%) (cm

)

1-ap Z-plasty 8.0 11.8 3.8 46.875 5.283 208.0

2-ap Z-plasty 8.0 10.5 2.5 31.25 5.913 122.375

      (2.957each)

4-ap Z-plasty 8.0 9.5 1.5 18.75 6.433 84.5

      (1.608each)

8-ap Z-plasty 8.0 9.4 1.4 17.5 3.255

      (0.407each) 37.5

TABLE 1. Measurement parameters compared among the 4 conventional Z-plasty designs.

modications included modifying the angle of each Z

ap (Fig 2A and 2B), modifying the limb size of Z ap

(Fig 2C and 2D), and adding a gap between each Z ap

(Fig 2E, 2F, 2G, and 2H). e results were then compared,

including with the conventional 4-ap Z-plasty design

(Fig 1C). e outcomes of each modication are shown

in Tables 2 to 9 (Supplement data), with comparative

data shown in Table 10.

In Table 2 and Table 3, modifying the angle of

each Z ap yield the results that less eective than the

conventional design in all 3 circumstances (Percent

lengthening, Tension to close Z ap, and Area of distortion).

In Table 4, modifying the limb size of Z flap from

2.5 cm to 1.5 cm yield the results that less eective than

the conventional design in all 3 circumstances. For

the modifying the limb size of Z ap to 2.0 cm for the

central limb size, and 2.5 cm and 1.5 cm for the sizes of

the peripheral limbs (Table 5) shown comparable result

to the conventional one in term of percent lengthening,

better in tension to close Z ap, but signicantly worse in

area of distortion. In Table 6 to Table 9, every design of

adding a gap between each Z ap can signicantly reduce

the tension to close Z ap better than the conventional

design. Especially for the design that adding a gap of

0.5 cm (25% of central limb length) that yield the best

result. And for percent lengthening, adding a gap between

each Z ap of 1.5 cm (75% of central limb length) shown

very interest outcome, because it yielded the better result

than the conventional design (21.60% vs 18.75%).

e results revealed that the addition of a gap of

1.5 cm (or 75% of central limb length) was the best design

for lengthening the Z scar, followed by the conventional

design and then the design that alternates the limb size of

the Z ap from 2.5 cm to 1.5 cm. Regarding the lowering

of tension, addition of a gap of 0.5 cm (or 25% of central

limb length) yielded the best result, followed by addition

of a gap of 1.5 cm (or 75% of central limb length). For

area of distortion, the conventional technique yielded

the best outcomes (Table 10).

DISCUSSION

In part 1, the authors generated the following

mathematical formulas to predict surgical outcomes

aer Z-plasty:

Percent scar lengthening = 12.10 + (35.74 / t)

Tension to close Z ap = 0.05 + (5.36 / t)

Area of distortion = 26.54 + (184.65 / t)

Compare to the previous studies

1, 11

, our new version

of mathematical models are easier to use, to remember

and can estimate the nal outcomes of multiple Z plasty

not only the percentage of scar lengthening but also the

ap tension and area of distortion.

In part 2 of this study, the authors found that addition

of a gap of 1.5 cm (or 75% of the central limb length) was

the best design to optimally lengthen the Z scar (2.85%

better than the conventional design (21.6% vs 18.75%)).

is new knowledge will signicantly help us to combat

with the contracted scar. e design that added a gap of

0.5 cm (or 25% of the central limb length) yielded the

best outcome relative to lowering the tension needed

to close the Z ap. e conventional Z-plasty design

was found to deliver the best outcome relative to area

of distortion.

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TABLE 2. Outcomes of modifying the angle of each Z ap from 75 degrees to 45 degrees.

Parameter Actual length Lengthening Percent Result

(cm) (cm) lengthening (%)

Actual length  8.0  

 A’B’(AB=8.0) 9.2 1.2 15.00

 A’G’(AG=2.0) 2.2 0.2 10.00

 G’J’(GJ=2.0) 2.2 0.2 10.00

 J’M’(JM=2.0) 2.3 0.3 15.00

 M’B’(MB=2.0) 2.5 0.5 25.00

Actual length

 C’D”(CD=3.80) 1.9 -1.9 -50.00

 E’F’(EF=2.83) 2.2 -0.63 -22.26

 H’I’(HI=3.80) 2.1 -1.7 -44.74

 K’L’(KL=2.83) 2.1 -0.73 -25.80

Tension to close (N)    10.086

 FirstZ-plasty    2.850

 SecondZ-plasty    1.578

 ThirdZ-plasty    3.499

 FourthZ-plasty    2.159

Area of distortion (cm

)    96.0

TABLE 3. Outcomes of modifying the angle of each Z ap from 90 degrees to 30 degrees.

Parameter Actual length Lengthening Percent Result

(cm) (cm) lengthening (%)

Actual length  8.0  

 A’B’(AB=8.0) 9.2 1.2 15.00

 A’G’(AG=2.0) 2.4 0.4 20.00

 G’J’(GJ=2.0) 2.1 0.1 5.00

 J’M’(JM=2.0) 2.5 0.5 25.00

 M’B’(MB=2.0) 2.2 0.2 10.00

Actual length

 C’D”(CD=4.0) 2.3 -1.7 -42.50

 E’F’(EF=2.0) 1.8 -0.2 -10.00

 H’I’(HI=4.0) 2.4 -1.6 -40.00

 K’L’(KL=2.0) 1.7 -0.3 -15.00

Tension to close (N)    15.726

 FirstZ-plasty    5.643

 SecondZ-plasty    2.960

 ThirdZ-plasty    5.288

 FourthZ-plasty    1.835

Area of distortion (cm

)    99.375

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TABLE 4. Outcomes of modifying the limb size of the Z ap from 2.5 cm to 1.5 cm.

TABLE 5. Outcomes of modifying the limb size of Z ap to 2.0 cm for the central limb size, and 2.5 cm and 1.5

cm for the sizes of the peripheral limbs.

Parameter Actual length Lengthening Percent Result

(cm) (cm) lengthening (%)

Actual length 8.0  

 A’B’(AB=8.0) 9.4 1.4 17.50

 A’G’(AG=2.5) 3.0 0.5 20.00

 G’J’(GJ=1.5) 1.7 0.2 13.33

 J’M’(JM=2.5) 2.9 0.4 16.00

 M’B’(MB=1.5) 1.8 0.3 20.00

Actual length

 C’D”(CD=4.4) 2.6 -1.8 -40.91

 E’F’(EF=2.6) 1.8 -0.8 -30.77

 H’I’(HI=4.4) 2.6 -1.8 -40.91

 K’L’(KL=2.6) 1.8 -0.8 -30.77

Tension to close (N)    8.425

 FirstZ-plasty    1.481

 SecondZ-plasty    1.877

 ThirdZ-plasty    3.022

 FourthZ-plasty    2.045

Area of distortion (cm

)    95.25

Parameter Actual length Lengthening Percent Result

(cm) (cm) lengthening (%)

Actual length 8.0  

 A’B’(AB=8.0) 9.5 1.5 18.75

 A’G’(AG=2.0) 2.3 0.3 15.00

 G’J’(GJ=2.0) 2.3 0.3 15.00

 J’M’(JM=2.0) 2.5 0.5 25.00

 M’B’(MB=2.0) 2.4 0.4 20.00

Actual length

 C’D”(CD=3.5) 2.4 -1.1 -31.43

 E’F’(EF=3.5) 2.5 -1.0 -28.57

 H’I’(HI=3.5) 2.6 -0.9 -25.71

 K’L’(KL=3.5) 2.5 -1.0 -28.57

Tension to close (N)    5.620

 FirstZ-plasty    2.212

 SecondZ-plasty    0.703

 ThirdZ-plasty    1.937

 FourthZ-plasty    0.768

Area of distortion (cm

)    120.25

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TABLE 6. Outcomes of adding a gap between each Z ap of 0.5 cm (25% of central limb length).

TABLE 7. Outcomes of adding a gap between each Z ap of 1.0 cm (50% of central limb length).

Parameter Actual length Lengthening Percent Result

(cm) (cm) lengthening (%)

Actual length  9.5  

 A’B’(AB=9.5) 10.9 1.4 14.74

 A’G’(AG=2.25) 2.6 0.35 15.56

 G’J’(GJ=2.5) 2.8 0.3 12.00

 J’M’(JM=2.5) 2.8 0.3 12.00

 M’B’(MB=2.25) 2.7 0.45 20.00

Actual length

 C’D”(CD=3.46) 2.3 -1.16 -33.53

 E’F’(EF=3.46) 2.4 -1.06 -30.64

 H’I’(HI=3.46) 2.4 -1.06 -30.64

 K’L’(KL=3.46) 2.4 -1.06 -30.64

Tension to close (N)    1.154

 FirstZ-plasty    0.214

 SecondZ-plasty    0.204

 ThirdZ-plasty    0.191

 FourthZ-plasty    0.545

Parameter Actual length Lengthening Percent Result

(cm) (cm) lengthening (%)

Actual length  11  

 A’B’(AB=11.0) 12.5 1.5 13.64

 A’G’(AG=2.5) 3.1 0.6 24.00

 G’J’(GJ=3.0) 3.2 0.2 6.67

 J’M’(JM=3.0) 3.2 0.2 6.67

 M’B’(MB=2.5) 3.0 0.5 20.00

Actual length

 C’D”(CD=3.46) 2.2 -1.26 -36.42

 E’F’(EF=3.46) 2.3 -1.16 -33.53

 H’I’(HI=3.46) 2.3 -1.16 -33.53

 K’L’(KL=3.46) 2.2 -1.26 -36.42

Tension to close (N)    3.171

 FirstZ-plasty    0.372

 SecondZ-plasty    0.639

 ThirdZ-plasty    1.318

 FourthZ-plasty    0.842

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TABLE 8. Outcomes of adding a gap between each Z ap of 1.5 cm (75% of central limb length).

TABLE 9. Outcomes of adding a gap between each Z ap of 2.0 cm (100% of central limb length).

Parameter Actual length Lengthening Percent Result

(cm) (cm) lengthening (%)

Actual length  12.5  

 A’B’(AB=12.5) 15.2 2.7 21.60

 A’G’(AG=2.75) 3.6 0.85 30.91

 G’J’(GJ=3.5) 4 0.5 14.29

 J’M’(JM=3.5) 4 0.5 14.29

 M’B’(MB=2.75) 3.6 0.85 30.91

Actual length

 C’D”(CD=3.46) 2.2 -1.26 -36.42

 E’F’(EF=3.46) 2.2 -1.26 -36.42

 H’I’(HI=3.46) 2.3 -1.16 -33.53

 K’L’(KL=3.46) 2.2 -1.26 -36.42

Tension to close (N)    1.867

 FirstZ-plasty    0.665

 SecondZ-plasty    0.47

 ThirdZ-plasty    0.381

 FourthZ-plasty    0.351

Parameter Actual length Lengthening Percent Result

(cm) (cm) lengthening (%)

Actual length  14.0  

 A’B’(AB=14.0) 15.3 1.3 9.29

 A’G’(AG=3.0) 3.6 0.6 20.00

 G’J’(GJ=4.0) 4.1 0.1 2.50

 J’M’(JM=4.0) 4.1 0.1 2.50

 M’B’(MB=3.0) 3.5 0.5 16.67

Actual length

C’D”(CD=3.46) 2.2 -1.26 -36.42

E’F’(EF=3.46) 2.2 -1.26 -36.42

H’I’(HI=3.46) 2.2 -1.26 -36.42

K’L’(KL=3.46) 2.2 -1.26 -36.42

Tension to close (N) total 2.954

FirstZ-plasty    0.713

SecondZ-plasty    0.680

ThirdZ-plasty    0.887

FourthZ-plasty    0.674

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Limitations

Even though this experimental study was performed

using a pig skin model, the authors propose that these

ndings may be extrapolatable to single and multiple

Z-plasty procedures performed in human patients.

CONCLUSION

Using a pig skin model, mathematical formulas

were generated to predict Z ap percent lengthening,

Z ap tension to close, and area of distortion. Addition

of a gap 75% of the central limb length was the most

ecacious Z-plasty conguration for increasing Z ap

length and also better than many designs to reduce Z

ap tension to close.

ACKNOWLEDGMENTS

e authors gratefully acknowledge Miss Julaporn

Pooliamof the Division of Clinical Epidemiology,

Department of Research and Development, Faculty

of Medicine Siriraj Hospital, Mahidol University for

assistance with statistical analysis.

Conict of interest declaration: Both authors declare

no personal or professional conicts of interest, and no

nancial support from the companies that produce and/

or distribute the drugs, devices, or materials described

in this report.

TABLE 10. Measured parameters compared among the studied modied Z-plasty designs.

Type Original length Actual length Lengthening Percent Total tension Area of

(cm) (cm) (cm) lengthening to close (N) distortion

(%) (cm

)

Conventional design 8.0 9.5 1.5 18.75 6.433 84.50

Angle 75 : 45 8.0 9.2 1.2 15.00 10.086 96.00

Angle 90 : 30 8.0 9.2 1.2 15.00 15.726 99.375

Size 2.5 switching 1.5 8.0 9.4 1.4 17.50 8.425 95.25

Limb size 2.5 &1.5 8.0 9.5 1.5 18.75 5.620 120.25

Add gap of 0.5 cm 9.5 10.9 1.4 14.74 1.154

Add gap of 1.0 cm 11.0 12.5 1.5 13.64 3.171

Add gap of 1.5 cm 12.5 15.2 2.7 21.60 1.867

Add gap of 2.0 cm 14.0 15.3 1.3 9.29 2.954

Funding disclosure: is was an unfunded study.

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