Journal of Pediatric Surgery (2011) 46, 912–922

www.elsevier.com/locate/jpedsurg

Sclerotherapy for lymphatic malformations in children:

a scoping review☆,☆☆
Paige Churchill a,b , Damanjot Otal a,c , Julia Pemberton a,c , Abdullah Ali a,b ,
Helene Flageole a,b,c , J. Mark Walton a,b,c,⁎
a
Department of Surgery, McMaster University, Hamilton, Ontario, Canada L8N 3Z5
b
McMaster Children's Hospital, Hamilton, Ontario, Canada L8N 3Z5
c
McMaster Pediatric Surgery Research Collaborative, Canada

Received 4 February 2011; accepted 11 February 2011

Key words:
Abstract
Sclerotherapy;
Purpose: This scoping review assesses the literature and summarizes the current evidence on
Lymphatic malformations;
sclerotherapy for the treatment of lymphatic malformations in pediatric patients.
Pediatric;
Methods: A comprehensive search of published and unpublished literature was conducted using
Scoping review
multiple databases. Title, abstract, and full-text screening was conducted by 2 independent clinicians.
All discrepancies were resolved during consensus meetings.
Results: A total of 182 articles were retrieved. Forty-four articles were removed as duplicates, and 11
articles were added after reviewing prominent studies. After full-text abstraction, 44 articles and 2
conference proceedings (N = 882 patients) were included in the final results. Twelve articles were
classified as level II and 34 articles as level IV evidence. Picibanil (OK-432) was the primary agent used
in most included studies. Postinjection symptoms with OK-432 were primarily fever, swelling, and
erythema at the site. Life-threatening complications were uncommon and involved postinjection
swelling of cervical lesions causing airway compromise.
Conclusions: The literature regarding sclerotherapy for lymphatic malformations is of a low level of
evidence and suffers from a lack of standardization. Randomized clinical trials focused on OK-432,
bleomycin, or alcoholic solution of zein; standardized dosing protocols; and consistent and reliable
outcome reporting will be necessary for further development of treatment guidelines.
© 2011 Elsevier Inc. All rights reserved.

Lymphatic malformations (LMs) are benign cystic masses
resulting from the abnormal development of lymphatic
☆
There were no issues of conflict of interest during the completion of
this project.
☆☆
This project received no funding.
⁎ Corresponding author. Department of Surgery, McMaster Children's
Hospital, MUMC 4E3, Hamilton, Ontario, Canada L8N 3Z5. Tel.: +1 905
521 2100x75244.
E-mail address: waltonj@mcmaster.ca (J.M. Walton).
channels. Lymphatic malformations occur primarily in the
head and neck, accounting for 75% of all cases [1,2] followed
by the axilla and mediastinum [3]. They are typically detected
at birth, where 50% of all cases are detected [1], and 90%
becoming clinically apparent by the age of 2 [1,3]. The
international incidence of lymphatic malformation (LM) is
about 1 in 6000 to 1 in 16 000 live births [1].
LMs are often asymptomatic, with cosmetic concern
being the primary indication for treatment. Historically, the

0022-3468/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.jpedsurg.2011.02.027
Sclerotherapy for LMs in children
first-line therapy for LM has been surgical excision [4].
Although this treatment is reasonably effective, high rates of
recurrence and the risk of complications have provided
plenty of incentive to develop a less-invasive management
approach [5,6]. After observing that infection led to
resolution of some LMs, a mechanism for inducing
inflammation was explored [7].
During the past 30 years, sclerotherapy has emerged as a
promising alternative to the surgical management for LMs
in children [8-10]. Several different sclerosing agents and
injection protocols have been documented in the literature,
each with varying amounts of success [1]. However, given
the heterogeneity of the treatment protocols used and
variable results obtained between studies, there appears to
be no clear consensus as to when sclerotherapy is
indicated, what agents offer the most benefit, and how
these agents should be administered for optimal results.
There is a particular paucity of information regarding the
use of this treatment option in intraabdominal lesions
because these masses are rare, and few prospective studies
have been conducted.
A scoping review provides a framework that makes it
possible to address broad topics and a methodology that
allows the inclusion of all study designs. The goal is not
necessarily to answer a specific research question on
treatment efficacy or to address the quality of literature, as
is the case with systematic reviews. Instead, a scoping review
aims to describe key concepts of a research area that have not
been comprehensively reviewed or studied previously with
consideration of all of the evidence that is available. Such
reviews are commonly used at the beginning of the research
cycle to examine the extent of research, determine if a
systematic review is feasible or relevant, disseminate
research findings, identify gaps in the existing literature,
and propose recommendations for future research [11].
The purpose of this scoping review is 2-fold. First, we will
assess the extent of the literature; and second, we will
summarize the current literature on sclerotherapy for the
treatment of LMs in pediatric patients. This will include
identifying the existing gaps in the literature through an
examination of research activity, determining the type of
research evidence present, describe the various chemical
agents tested thus far, the dosing of these agents, and
injection procedures. We will also descriptively compare the
effectiveness of these treatments with complications and side
effects where appropriate. By compiling the most current
data on this topic, we also aim to identify any areas requiring
further investigation and address any barriers preventing the
development of treatment guidelines.
1. Methods
A comprehensive search was conducted of MEDLINE,
EMBASE, CINAHL, CENTRAL, Cochrane Systematic
913
Review Database, and reference lists of prominent studies
from 1980 until 2009. A gray literature search was also
conducted of conference abstracts, theses, and dissertations
using the databases PapersFirst and ProceedingsFirst for the
same period. We also hand-searched the conference
proceedings from the International Head and Neck Confer-
ence special panel on pediatric tumors. All literature searches
used the SIGN search filters and/or MeSH headings where
applicable. An information specialist reviewed the search to
ensure accuracy and comprehensiveness.
All search results were included in the title and abstract
screening. The following inclusion criteria were applied: (1)
published between 1980 and 2009, (2) must include pediatric
patients, (3) primary diagnosis of included patients was LM,
and (4) sclerotherapy was used as a therapeutic agent. In
series that studied both pediatric (Peds) and adult patients,
adult patients were excluded where possible. All screenings
were conducted independently by 2 of the authors (PC, AA),
and all discrepancies were reviewed with a third party (JP)
and resolved through consensus.
The full text of each included article was obtained where
possible. Every attempt was made to find an appropriate data
abstractor fluent in the language of all non-English articles. If
no abstractor could be found, the article was excluded.
Again, 2 authors (PC, AA) independently abstracted the full-
text data, and consensus meetings were held. The data
abstraction form was piloted on the first 5 full-text articles. A
level of evidence (LOE) was applied to each article by a
clinical epidemiologist (JP) according to the Oxford
hierarchy of evidence tables [12]. Summary tables were
constructed for all included articles, and trends were
explored graphically. Attempts, where appropriate, were
made to compile and summarize the results. Clinical
implications and data interpretation were developed in
consultation with 2 pediatric general surgeons (HF, JMW).
During data extraction, we classified cysts into group-
ings of macrocystic, microcystic, and mixed morphology
that has proven useful in other sclerotherapy studies
[4,9,13]. We also further categorized reported patient
adverse events into either complications or side effects.
The reported event was considered a complication if it was
a clinically significant adverse event attributed to the
treatment and required additional significant treatment. An
event was classified as a side effect if the event was a
minor expected effect of the treatment (ie, fever), required
little or no additional intervention, and resolved quickly.
Because of the heterogeneity in outcome parameters
between studies, we classified the response to treatment
into 4 categories based on the percentage reduction in
lesion volume regardless of how cystic volume was
measured. The results from each article were organized
based on the following categories: excellent (N90%), good
(50%-89%), fair (20%-49%), or poor (b20%). This
modified categorization was based on a similar classifica-
tion system published in a recent systematic review in this
area [1].
914
2. Results
A total of 182 articles were retrieved. Forty-five articles
were removed as duplicates, and 11 articles were added after
reviewing the reference lists of prominent studies. After full-
text abstraction, 44 articles [3,8-10,13-52] and 2 conference
proceedings [53,54] (N = 882 patients) were included in the
final results. MEDLINE indexed 100.0% of all included
articles, whereas 86.4% of included articles were indexed in
EMBASE, and 11.4% were indexed in CINAHL. No theses
or dissertations were found, and only 2 conference abstracts
(gray literature) were included (Fig. 1).
Globally, the literature draws from 21 countries including
3 Canadian [13,19,49] and 5 American [8-10,22,23] studies.
Japan published the highest number of articles on this topic
(6 articles) [30,31,40,51,53,54]. Several articles were
excluded because of the lack of a fluent data abstractor
Fig. 1 Quorum flow chart.
P. Churchill et al.
[55-60]. These articles were written in Spanish, Italian,
Swedish, and German. One Hebrew article was identified
and screened with a fluent abstractor; however, it was
ineligible and therefore excluded [58]. In assessing the level
of research evidence, 12 articles were classified as level II
and 34 articles as level IV evidence. No level I articles were
found in the literature search. One multicentered, random-
ized, controlled trial using picibanil (OK-432) was identified
in our search [22]; however, it was assigned a level II rating
because of poor methodological quality [12].
Demographic data was collected from each article
(Table 1). The mean sample size was 19 (SD, 17.1), and
there was a slight preponderance of men (54%). The age
ranged from 0 to 46 years in the studies; but, wherever
possible, adult patients were excluded. Because of the low
level of evidence of the included studies as well as the lack of
consistency in reporting results, not all included patients
Sclerotherapy for LMs in children 915

Table 1 Study characteristics of included tables

Author Year Country Therapy Study type LOE Minimum Maximum Peds/ n % Language Follow-
age (y) age (y) adults/ male up (mo)
both
Jain et al 2002 India 1% Prospective 2 7 27 Both 3 0 English Not
polidocanol
cohort stated
Won et al 2004 Korea Acetic acid
Retrospective 4 1 29 Both 12 50 English 3-47
cohort
Dubois et al 1997 Canada ASZ Prospective 2 0 13 Peds 14 50 English 24
cohort
Puig et al 2003 Austria ASZ Prospective 2 0.5 17 Peds 15 60 English 3
cohort
Roelly et al 1991 France ASZ Retrospective 4 Not Not Not 22 41 French 22
cohort reported reported reported
Herbreteau et al 1992 France ASZ Retrospective 4 Not Not Both 70 61 English Not
cohort reported reported stated
Roelly et al 1992 France ASZ Retrospective 4 Not Not Not 24 38 French Not
cohort reported reported reported stated
Baud et al 2000 ASZ Retrospective 4 0.1 22 Both 9 78 French 6
cohort
Emran et al 2006 Canada ASZ Retrospective 4 Not Not Peds 63 0 English 42
cohort reported reported
Baskin et al 2005 Turkey Bleomycin Prospective 2 0 6 Peds 9 44 English 6
cohort
Orford et al 1995 Australia Bleomycin Case series 4 0.1 1 Peds 16 0 English 6
Sung et al 1995 South Bleomycin Retrospective 4 0 12 Peds 10 60 English 3-36
Korea cohort
Zulfiqar et al 1999 Malaysia Bleomycin Retrospective 4 0.5 1.7 Peds 11 0 English 3-24
cohort
Al-Salem 2004 Saudi Bleomycin Retrospective 4 0 12 Peds 22 45 English Not
Arabia cohort stated
Mathur et al 2005 India Bleomycin Retrospective 4 0.6 10 Peds 7 71 English 6-24
cohort
Molitch et al 1995 US Doxycycline Case report 4 3 46 Both 5 40 English 5-24
Burrows et al 2008 US Doxycycline Retrospective 4 0.2 31 Both 41 41 English 11
cohort
Castanon et al 1999 Spain Fibrin Retrospective 4 0.1 16 Peds 19 68 English 40
sealant cohort
Emery et al 1984 UK Hypertonic Retrospective 4 0 Not Not 37 49 English 86
saline, cohort reported reported
boiling
water
Ogita et al 1987 Japan OK-432 Prospective 2 0.3 14 Peds 9 44 English 6-14.4
cohort
Greinwald et al 1999 US OK-432 Prospective 2 0.1 7.4 Peds 13 69% English Not
cohort stated
Giguere et al 2002 US OK-432 RCT 2 0.5 18 Peds 30 60% English 26
Claesson & 2002 Sweden OK-432 Prospective 2 0.2 17 Peds 31 29% English 2-72
Kuylenstierna cohort
Rautio et al 2003 Finland OK-432 Prospective 2 0.8 42 Both 14 57% English 12-8
cohort
Baskota et al 2007 Nepal OK-432 Prospective 2 1.4 25 Both 10 70% English 14
cohort
Eivazi et al 2009 Germany OK-432 Review 2 0 13 Peds 9 67% English Not
stated
Ogita et al 1991 Japan OK-432 Retrospective 4 0.1 15 Peds 21 57% English 4-35
cohort
(continued on next page)
916 P. Churchill et al.

Table 1 (continued)
Author Year Country Therapy Study type LOE Minimum Maximum Peds/ n % Language Follow-
age (y) age (y) adults/ male up (mo)
both
Ogita et al 1994 Japan OK-432 Retrospective 4 Not Not Not 64 0% English 6-86.4
cohort reported reported reported
Smith et al 1996 US OK-432 Retrospective 4 0.1 7.7 Peds 6 67% English 5-25
cohort
Ogita et al 1996 Japan OK-432 Retrospective 4 1.1 38 Both 6 67% English Not
cohort stated
Brewis et al 2000 UK OK-432 Retrospective 4 1 14 Peds 11 82% English Not
cohort stated
Charabi et al 2000 Denmark OK-432 Retrospective 4 0 28 Both 44 55% English Not
cohort stated
Sung et al 2001 South OK-432 Retrospective 4 0.2 46 Both 19 68% English 4-64
Korea cohort
Laranne et al 2002 Finland OK-432 Retrospective 4 0.7 13 Peds 11 64% English 7-30
cohort
Uchida et al 2002 Japan OK-432 Case Report 4 0.1 Not Peds 1 100% English 12
applicable
Blaszczynski 2004 Poland OK-432 Case series 4 Not Not Peds 2 100% Polish 1
et al reported reported
Sichel et al 2004 Israel OK-432 Case series 4 0 6 Peds 7 100% English 8-58
Guvenc et al 2005 Turkey OK-432 Case report 4 0.1 Not Peds 1 0% English 39
applicable
Peters et al 2006 Canada OK-432 Retrospective 4 0.4 15 Peds 12 42% English 23.4
cohort
Yoo et al 2009 Korea OK-432 Case series 4 0.2 34 Both 55 49% English 63
Schmidt et al 1996 Austria OK-432 Retrospective 4 0.1 11 Peds 11 55% English 2-84
cohort
Luzzatto et al 2000 Italy OK-432 Retrospective 4 0 15 Peds 15 20% English 84
cohort
Sanlialp et al 2003 Turkey OK-432 and Prospective 2 0 12 Peds 15 33% English 6-36
bleomycin cohort
Kim et al 2004 South OK-432 and Retrospective 4 0 32 Both 27 63% English 1-71
Korea bleomycin cohort
Okazaki et al 2007 Japan OK-432 and Retrospective 4 Not Not Not 28 257% English Not
bleomycin cohort reported reported reported stated
Shankar et al 2001 UK Tetracycline Case report 4 4 Not Peds 1 0% English 12
and applicable
lignocaine
LOE indicates level of evidence; Peds, pediatrics.

could be represented in all tables. All excluded studies are
noted in each table.
The outcomes from each article are summarized in
Table 2 according to our classification system. The most
commonly studied sclerotherapy agent was OK-432 (n =
23), followed by bleomycin (n = 6), alcoholic solution of
zein (ASZ, or ethibloc) (n = 7), and doxycycline (n = 3).
Hypertonic saline, 1% polidocanol, acetic acid, and fibrin
sealant were used in 1 study each. Three studies used a
combination of OK-432 and bleomycin. An overall excel-
lent response rate was seen in 48% of all patients treated
with percutaneous sclerotherapy (n = 571) (Table 3).
Further exploratory analysis demonstrated that, of those
patients treated with OK-432 (n = 318), 56% had excellent
results; and of those treated with bleomycin (n = 66) and
ASZ (n = 93), 45% and 44%, respectively, had excellent
results (Table 3).
In studies where type of lesion (macrocystic, micro-
cystic, or mixed) was reported, crude data analysis showed
varying degrees of treatment success. In patients with
macrocystic lesions (n = 209), 66% had excellent results
with sclerotherapy, whereas only 23% of the patients with
microcystic lesions (n = 52) had excellent results (Table 4).
The success rate, defined as resolution greater than 50%,
with OK-432, bleomycin, and ASZ on macrocystic lesions
was similar at 87%, 83%, and 86%, respectively. For
microcystic lesions, ASZ had a 77% success rate, whereas
OK-432 had a success rate of 39%. Bleomycin was not
used frequently to treat microcystic lesions. Alcoholic
solution of zein also showed a 100% success rate on mixed
 Sclerotherapy for LMs in children
Table 2 Outcomes of included studies
Therapy Dose Location Primary/ Type Outcome
secondary Excellent Good Fair Poor
treatment (≥90%) (50%-89%) (20%-49%) (b20%)
1% polidocanol [26] 1 mL; maximum, 6 mL Limb, head/neck Not stated Not stated 3 0 0 0
Acetic acid [41] 40%-50% concentrated, 2-70 mL Limb, head/neck, Secondary Macrocystic/ 5 1 0 1
other microcystic and other
ASZ [33] 1 mL/kg Limb, head/neck, Not stated Not stated All patients had partial or total reduction
other
ASZ [17] 10% of estimated volume, 2 mL; lipiodol, 7.5 mL; Limb, head/neck, Primary Macrocystic 7 2 0 0
Ethibol, 4 mL absolute alcohol abdomen, other
ASZ [19] 10% of aspirated fluid (not N15% of lesion volume) Other Not stated Macrocystic and 5 5 0 0
other
ASZ [13] 10% of aspirated volume Limb, head/neck Primary Macrocystic/ 29 26 0 12
microcystic and other
ASZ [25] up to 7 mL (1/4 to 1/10 cyst volume) Limb, head/neck, Both Not stated Excellent (total regression) and good
abdomen, other (satisfactory result), 60%. Failure (no
response, 23%; n = 16); second surgery (sx),
17% (n = 12). Reasons for second sx
include 4 facial reconstruction, 2 insufficient
regression, 4 persistent inflammatory nodes,
and 2 aseptic necrosis
ASZ [35] a Not stated Head/neck, other Secondary Not stated Ethibloc, 8. 3 alone: 1 partial regression, 1 no
regression, and 1 follow-up (F/U) too short.
3 postoperative: 1 partial regression,
1 short F/U, and 1 recurrence. 2 preoperative:
2 partial regressions
ASZ [36] a Not stated Head/neck Not stated Not stated 8 cases—all had important inflammatory
reaction, 3 cases—good regression, 2 cases
—surgery after Ethibloc, 3 cases—done after
surgical failure with good results
Bleomycin [14] 0.6 mg/kg Limb, head/neck, Secondary Not stated 3 0 0 0
abdomen, other
Bleomycin [15] 1-3 mg/kg, maximum ≤15 mg Other Primary Not stated 6 0 3 0
Bleomycin [29] 1 mg/kg; maximum, 6 mg/kg Head/neck Primary Not stated 2 1 1 3
Bleomycin [32] 9 mg/mL Limb, head/neck, Not stated Other 7 7 0 2
other
Bleomycin [43] 0.5 mg/kg Head/neck Not stated Not stated 4 5 0 2
Bleomycin [46] 1 mg/mL to maximum 6 mg Head/neck Both Macrocystic/ 4 3 2 1
microcystic and other
Doxycycline [8] 100 mg powder in 5 mL water-soluble contrast; Limb, head/neck, Secondary Macrocystic/ 5 4 3 3
maximum, 20 mg/kg abdomen microcystic and other

917
(continued on next page)
 918
Table 2 (continued)
Therapy Dose Location Primary/ Type Outcome
secondary Excellent Good Fair Poor
treatment (≥90%) (50%-89%) (20%-49%) (b20%)
Doxycycline [10] 5-20 mg/mL; maximum, 100 mL Limb, head/neck, Not stated Not stated 5 0 0 0
other
Fibrin sealant [45] 10%-15% of aspirated volume Head/neck Secondary Other Postpuncture volume (0 cm), 17; 14 simple;
3 multicystic, (15 × 7 mm) 1, original
(60 × 37mm), cystic; (90 × 45mm) 1,
original (90 × 45mm) simple
Hypertonic saline (HTS), Not stated Head/neck Not stated Not stated 7 patients had HTS or boiling water:
boiling water [21] 1 case successful; 2 patients had aspiration
only: success
OK-432 [16] 0.1 mg per 10 mL Head/neck Not stated Not stated 9 0 0 0
OK-432 [18] 0.1/0.5 mg Head/neck Secondary Macrocystic significantly smaller after 1 mo
OK-432 [20] Maximum, 0.1 mg Head/neck Not stated Macrocystic and 7 2 0 0
other
OK-432 [22] 0.1 mg per 10 mL; maximum, 20 mL Head/neck Not stated Macrocystic/ 18 1 2 8
microcystic and other
OK-432 [23] 0.1 mg/10 mL; maximum, 20 mL Head/neck Not stated Macrocystic/ 4 1 4 4
microcystic and other
OK-432 [24] 10 mL of 0.01 mg/mL Abdomen Primary Not stated 0 1 0 0
OK-432 [27] 0.01 mg/mL Head/neck, other Secondary Macrocystic and 6 4 0 1
other
OK-432 [30] 0.1 mg/10 mL Limb, head/neck, Not stated Not stated 8 1 0 0
abdomen
OK-432 [34] 0.01 mg/mL Head/neck, other Primary Macrocystic and 6 5 2 1
other
OK-432 [39] 0.01 mg/mL; maximum, 0.2 mg Head/neck Not stated Macrocystic 3 1 1 2
OK-432 [9] 0.01 mg/mL Head/neck Not stated Macrocystic/ 2 0 0 4
microcystic and other
OK-432 [40] 0.01 mg/mL, 20 mL injected Abdomen, other Not stated Not stated 0 1 0 0
OK-432 [42] 0.01 mg/mL; maximum, 30 mL Head/neck Primary Not stated Initial response (1 mo). Complete—no
lesion, clinically or range. Near complete—
grossly no lesion but minimal or examination
or image. Marked—decrease in size N50%.
Partial—decrease in size b50%. No response
—no change in size. Success rate, 83.5

P. Churchill et al.
OK-432 [53] 0.02-0.2 mg Limb, head/neck, Primary Not stated 6 0 0 0
abdomen
OK-432 [54] 0.1 mg/10 mL; maximum, 20 mL Not stated Primary Macrocystic and 28 10 12 14
other
OK-432 [44] 0.01 mg/mL; maximum, 20 mL Head/neck, other Secondary Not stated 2 2 5 2
OK-432 [46] 0.1 mg/10 mL Head/neck Secondary Macrocystic/ 12 2 1 0
Sclerotherapy for LMs in children 919

lesions (Table 5), although the sample size was small (n =

7) and only represented a single study. Most cases of LM
1

0
2

2
0

1
4

0
occurred in the head and neck region, whereas other
locations included the abdomen, mediastinum, and axilla.
Picibanil and bleomycin showed similar success rates
(resolution N50%) in the head and neck regions at 79%

18
0

0
2

0
6

0
and 72%, respectively (Table 6). Alcoholic solution of zein
seemed to have good affect for head and neck LMs, but
only 5 cases were documented (Table 6).
There were several side effects from all sclerotherapeu-
32
5

0
8

4
4

0
tic agents used. For those treated with OK-432, common
side effects included fever (68.0%), local inflammation
(46.0%), pain (31.0%), and swelling (10.0%). Fever was
25

17
the most common side effect noted for patients treated with
4

2
9

7
0

1 bleomycin (30.0%). Frequent side effects with the use of

microcystic and other

microcystic and other

microcystic and other

microcystic and other

microcystic and other

microcystic and other

ASZ included fever (36.0%) and leakage (31.0%) from the

puncture site. Four patients treated with OK-432 experi-
Macrocystic/

Macrocystic/

Macrocystic/

Macrocystic/

Macrocystic/
Macrocystic

enced a major complication, including 1 case of intracystic

Not stated

Not stated

Not stated

Not stated Not stated

hemmorhage and 3 cases of airway obstruction. Two

patients experienced localized infection. There were 2
incidents of cellulitis and 1 death because of worsening
pneumonia in a patient treated with bleomycin. The use of
Primary

Primary
Primary

Primary

Primary
Primary

Primary

ASZ resulted in 4 cases of localized infection, 4 patients

Both

Both

with skin ulcerations, 4 subcutaneous granulomas, and

3 fistulas/sinuses.
Limb, head/neck,

Limb, head/neck,
Head/neck, other

Head/neck, other

Head/neck, other

Head/neck, other
Limb, head/neck

abdomen, other

3. Discussion
Head/neck

Head/neck

500 mg/10 mL H2O and 3 mL/kg of 1% solution Abdomen

This scoping review provides a broad look at where the

other

existing literature is being published, the existing level of

evidence, synthesized clinical results, where possible, and an
evaluation of the existing gaps in research. All of the relevant
1 mg/mL; maximum, 20 mL and 0.01 mg/mL;

evidence focused upon the treatment of LMs with scler-

otherapy in children seem to be adequately represented in the
0.1 mg/10 mL saline; maximum, 0.2 mg

MEDLINE database with very little existing gray literature.

0.1 mg/10 mL and 6 mg bleomycin

The overall level of evidence was fair to poor; however, it

0.25 mg/kg and 0.1 mg in 10 mL
0.01 mg/mL; maximum, 0.2 mg

was promising to find a multicenter, randomized, controlled

trial in the literature on this topic.
There were many challenges associated with the assim-
Not all study patients could be classified in this table.

ilation of the results of this study. Variable cutoffs in percent

reduction parameters and qualitative outcome descriptions
0.1 mg in contrast

maximum, 20 mL

made data pooling and outcome classification difficult.

Image-guided pretreatment and posttreatment lesional
0.1-0.2 mg
Not stated

volumes were not reported for many patients, and cystic

0.1 mg

volume reduction (outcome success) varied from computed

tomography or magnetic resonance imaging to visual
assessment. In the treatment protocol and dosing used,
OK-432 and bleomycin [3]
OK-432 and bleomycin

OK-432 and bleomycin

there was a lack of uniformity between studies for most

agents. The only exception was OK-432, which followed the
lignocaine [38]

Ogita et al [30,51] protocol in all included studies. A further

Tetracycline and
OK-1432 [37]

challenge was differentiating between patients who received

OK-432 [50]

OK-432 [49]

OK-432 [52]
OK-432 [51]

OK-432 [28]

1 dose of the sclerosing agent vs successive treatments with

sclerotherapy. The number of successive treatment was not
[31]

[47]

discussed in detail in most studies but, when mentioned,

consisted of an average of 2 to 3 treatments given in 4- to 8-
920 P. Churchill et al.

Table 3 Treatment success in patients with different agents (n = 571 patients)

% resolution OK-432 Bleomycin ASZ Doxycycline OK-432 and Other b Overall
(n = 318) (n = 66) (n = 93) a (n = 20) bleomycin (n = 63) (n = 11) (n = 571)
n (%) n (%) n (%) n (%) n (%) n (%) n (%)
Excellent (≥90%) 178 (56) 30 (45) 41 (44) 10 (50) 8 (13) 9 (82) 276 (48)
Good (50%-89%) 53 (17) 18 (27) 36 (39) 4 (20) 36 (57) 1 (9) 148 (26)
Fair (20%-49%) 35 (11) 9 (14) 3 (3) 3 (15) 18 (29) 0 (0) 68 (12)
Poor (b20%) 52 (16) 9 (14) 13 (14) 3 (15) 1 (1) 1 (9) 79 (14)
Six studies were excluded because the results could not be classified according to the established categories of success [18,21,25,33,42,45]. Two studies
were only partially classified according to the success categories [35,36].
a
Because of the exclusion of 8 studies, 124 patients treated with ASZ are not represented in this table.
b
Other includes 1% polidocanol, tetracycline and lignocaine, and acetic acid.

week intervals. The number of doses that a patient received
before the outcome assessment was further confounded with
a lack of clarity surrounding patients who underwent surgery
as a primary treatment option vs those patients where surgery
was either not attempted or only attempted after a failed
course of sclerotherapy.
Given the objective of this review, it is not possible to
ascertain whether 1 agent is more effective than the other.
The side effect profiles for OK-432 and ASZ were similar,
although leakage from the injection site seemed to be a
frequent occurrence after ASZ, which in 1 paper was felt to
be a predictor of a good result [19]. Pain was a significant
side effect of doxycycline, with 100.0% (n = 41) patients
reporting this side effect. Bleomycin poses a theoretical risk
of pulmonary fibrosis [61,62], although no cases were
identified in this literature review. Picibanil also caused a
significant local and systemic inflammatory response (pain,
redness, swelling, fever). For cervicofacial lesions near the
airway, there may be a risk of airway compromise because
of swelling and inflammation. Emergency tracheostomy
was necessary in 2 patients suffering this complication
[22,27]. One of these tracheostomies was performed
prophylactically before the second injection of OK-432
[27]. One death occurred in a patient who was treated with
bleomycin because of an incidental pneumonia [46]. This
Table 4 Number of successfully treated patients based on
type (n = 334)
Resolution Macrocystic Microcystic Mixed
(n = 209) (n = 52) (n = 73)
n (%) n (%) n (%)
Excellent (≥90%) 139 (66) 12 (23) 26 (36)
Good (50%-89%) 43 (21) 12 (23) 27 (37)
Fair (20%-49%) 7 (3) 5 (10) 11 (15)
Poor (b20%) 20 (10) 23 (44) 9 (12)
Twenty-two studies were not included because the type was not stated
[3,4,10,15,16,21,24-26,29,30,33,35-38,40,42-44,52,53]. Two studies
were excluded because the results could not be placed into our
established categories of success [18,45]. Three studies were excluded
because the results were not reported by type [8,31,51].
was not felt to be because of pulmonary complications
directly attributable to the sclerosing agent. Other serious
complications included a case of Horner syndrome when
doxycycline was used [8] and a patient in whom left-sided
proptosis developed secondary to a spontaneous intracystic
hemorrhage 4 weeks after OK-432 injection of a LM
adjacent to the left eye, which was treated with orbital
decompression [22].
The current literature suggests that most patients with
simple LMs who undergo sclerotherapy with OK-432,
bleomycin, or ASZ will achieve a good to excellent clinical
response. However, the lack of rigorous randomized
clinical studies comparing the various sclerotherapy agents
prevents us from drawing any clear conclusions as to which
patients would benefit most from which agent. Trends in the
data suggest that microcystic lesions are poor candidates
for sclerotherapy, but a lack of level I evidence and
heterogeneity in outcome reporting between studies
hinder our ability to draw definitive conclusions on these
patient subpopulations.
There are several limitations of this study that must be
noted. The synthesized data presented in this review has
limited clinical impact because many of the included studies
were not amendable to classification. This scoping review
did not include a quality assessment of the included
literature. To make clear recommendations for treatment, a
systematic review (which includes quality assessment) is
necessary. A further recommendation for a future systematic
review would be to ensure that data abstractors are fluent
in multiple languages because this review suffers from a lack
of inclusion of non-English studies that could potentially
impact the conclusions.
The availability of sclerosing agents does pose some
challenges. Bleomycin is widely available, but OK-432 is
not Food and Drug Administration–approved or Health
Canada–approved and needs special dispensation. Alcoholic
solution of zein (Ethibloc-Ethicon) is no longer available in
Canada but has been used in France. The availability of
sclerosing agents would also be an essential consideration
for any future clinical trials.
The published literature regarding sclerotherapy for LMs
is of a low level of evidence and suffers from a lack of
Sclerotherapy for LMs in children 921

Table 5 Successfully treated patients (resolution N50%)/total number of patients treated for each agent by type (n = 334)
Type OK-432 (n = 210) Bleomycin (n = 36) ASZ (n = 86) Acetic acid (n = 7)
Success treated Success (%) Success treated Success (%) Success treated Success (%) Success treated Success (%)
Macrocystic 110/126 87 0/12 83 57/66 86 5/5 100
Microcystic 14/36 39 0/2 0 10/13 77 0/1 0
Mixed 28/43 65 17/22 77 7/7 100 1/1 100
Twenty-two studies were not included because the type was not stated [3,4,10,15,16,21,24-26,29,30,33,35-38,40,42-44,52,53. Two studies were excluded
because the results could not be placed into our established categories of success [18,45]. Three studies were excluded because the results were not reported
by type [8,31,51].

Table 6 Successfully treated patients (N50% resolution)/total number of patients treated for each agent by location (N = 323)
Location OK-432 (n = 229) Bleomycin (n = 66) ASZ (n = 12) Acetic acid (n = 7) Other (n = 9)
Success Success Success Success Success Success Success Success Success Success
treated (%) treated (%) treated (%) treated (%) treated (%)
Head/neck 156/197 79 44/61 72 5/5 100 2/2 100 3/3 100
Abdomen 3/3 100 0/0 0 0 0 0 0 2/2 100
Other a 28/29 96 4/5 80 7/7 100 4/5 80 4/4 100
Six studies were excluded because the results could not be classified according to the established categories of success [18,21,25,33,42,45]. Two studies
were only partially classified according to the success categories [35,36]. Five studies did not report outcome by location [8,13,19,49,54]. Two studies were
excluded because both bleomycin and OK-432 were used, and the results were not distinguished between the 2 [3,31].
a
Other includes breast, mediastinum, scrotum, axilla, thorax, back, trunk, chest, and retroperitoneum.

standardization. Randomized clinical trials focused on the
most heavily used agents identified in this review (OK-432,
bleomycin, ASZ), standardized dosing protocols, and
consistent and reliable outcome reporting (ie, using radio-
logic assessment of lesion volume preinjection and postin-
jection) will be necessary for the future development of
treatment guidelines. This would be particularly helpful in
challenging areas such as microcystic LMs and those located
within the abdomen. Clear classification adherence for cyst
type (ie, macrocystic, microcystic, and mixed) would also
decrease the heterogeneity of the literature, which would be
beneficial for future systematic reviews.
Acknowledgments
This study would not have been possible without the help
of Dr Tal Shichor and Ms Violet Szlachetka. We are grateful
for their assistance in abstracting data from our Hebrew and
Polish articles.
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