doi: 10.1111/1346-8138.

14740 Journal of Dermatology 2018; : 1–4

ORIGINAL ARTICLE
Effectiveness of topical propranolol 4% gel in the treatment
of pyogenic granuloma in children
Jacob MASHIAH,1,2,3 Smail HADJ-RABIA,4,5,6 Dan SLODOWNIK,2,3 Avikam HAREL,1
1,2,3
Eli SPRECHER, Ana KUTZ1
1
Pediatric Dermatology Unit, Dana Children’s Hospital, 2Department of Dermatology, Tel Aviv Sourasky Medical Center, 3Sackler
Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, 4Department of Dermatology, Reference Center for Genodermatoses and Rare
Skin Diseases (MAGEC), H^opital Universitaire Necker-Enfants Malades, AP-HP, 5Institut Imagine, INSERM U1163, 6Universite
Paris Descartes-Sorbonne Paris Cite, Paris, France

ABSTRACT
Pyogenic granuloma is a benign acquired vascular tumor that affects the skin and mucous membranes, occurring
more often in children and young adults. Treatment is often required due to the associated risk of ulceration and
bleeding. There are several publications reporting the use of beta-blockers for the treatment of pyogenic granu-
loma. The aim of the present study was to evaluate the clinical effectiveness and safety profile of topical propra-
nolol 4% gel for the treatment of pyogenic granuloma. A retrospective study of all cases of pyogenic granuloma
treated with topical propranolol 4% gel between 2014 and 2015 was performed. Epidemiological, clinical and
treatment data, including effectiveness score and safety, were reviewed. Of a total of 18 patients with pyogenic
granuloma, 11 (61.1%) showed complete resolution of the lesion while two (11.1%) had an almost complete
response. In three cases (16.6%), the treatment was discontinued due to bleeding, and the lesions were removed
by curettage. Local irritation and lack of compliance led to treatment discontinuation in two cases. Altogether, 13
out of 18 patients (72%) had complete or almost complete response to treatment. There was a correlation
between treatment duration and response to treatment. One patient only reported local side-effects including irri-
tation, redness and scaling of the treated area leading to discontinuation of the treatment and curettage of the
pyogenic granuloma. No systemic adverse effects were reported. This is an uncontrolled retrospective study. Pro-
pranolol 4% gel may be considered as a safe and efficient topical therapy for pyogenic granuloma.

Key words: capillary, granuloma, hemangioma, propranolol, pyogenic.

INTRODUCTION Although PG is considered a benign vascular tumor, treat-

ment is often required due to the associated risk of ulceration
Pyogenic granuloma (PG), or lobular capillary hemangioma, is and bleeding. Various treatment modalities are available includ-
a benign acquired vascular tumor which affects the skin and ing intralesional injections of bleomycin, corticosteroids or etha-
mucous membranes, occurring more often in children and nol, topical treatment with silver nitrate, phenol and imiquimod
young adults.1 The pathogenesis of this common condition 5%, laser treatment, curettage, electrocautery, radiosurgery,
remains unknown, but overexpression of growth factors such cryosurgery and surgical excision.5 However, recurrence is
as vascular endothelial growth factor (VEGF),2 vascular adhe- common.6
sion molecules such as intercellular adhesion molecule (ICAM)- Beta-blockers such as timolol (topical) and propranolol (topi-
2 and vascular cell adhesion molecule (VCAM)-1,3 suggest that cal or systemic) are non-selective b-adrenergic receptor antago-
it may result from inappropriate activation of pro-angiogenic nists, widely used in the treatment of infantile hemangiomas.6,7
circuits. Moreover, mutations in the proto-oncogene BRAF Several studies have evaluated their therapeutic effectiveness in
have been identified in PG lesions associated with port-wine the context of PG.6,8–14
stains.4 Several drugs, including oral retinoids, oral contracep- Here, we aimed to evaluate the clinical effectiveness and
tives, epidermal growth factor receptor inhibitors, BRAF inhibi- safety profile of a higher concentration of propranolol for the
tors, mitogen-activated protein kinase inhibitors and rituximab, topical treatment of PG in a large series of cases treated at a
are associated with PG occurrence and viral infections have single tertiary center.
also been implicated in the pathogenesis of PG.5

Correspondence: Jacob Mashiah, M.D., Department of Dermatology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv-Yafo
64239, Israel. Email: ymashiah1@gmail.com
Received 24 September 2018; accepted 13 November 2018.

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J. Mashiah et al.

METHODS such as erythema, itching, ulceration, bleeding and/or infection,

the patients were instructed to immediately discontinue the
Patient selection treatment and return for evaluation. Curettage was performed
In a retrospective chart review, children with a clinical diagno-
in case of bleeding or worsening. Follow up and evaluation vis-
sis of PG treated exclusively with topical 4% propranolol gel at
its including clinical photographs were performed every
the pediatric dermatology unit, Tel-Aviv Sourasky Medical Cen-
2 months until cessation of the treatment. Two blinded derma-
ter, between January 2014 and December 2015, were enrolled.
tologists evaluated the effectiveness of the treatment.
The study protocol was reviewed and approved by our institu-
tional review board. Medical records of patients who met the Statistical analysis
inclusion criteria were reviewed for demographic and clinical Descriptive statistics were used to summarize demographic data
characteristics (Fig. 1). (age and sex) and clinical characteristics (age at treatment, type,
size and color of the lesions and duration of treatment).
Gel production The continuous variables did not follow a normal distribution
The medication was supplied by a compounding pharmacist. and therefore were reported by the median and interquartile
Optimization of drug delivery through the skin barrier has range. Categorical variables were reported by their relative fre-
been previously reported.15 In short, propranolol HCl is dis- quencies. Univariate analysis was used to examine a possible
solved in a solvent, and inserted into phosphatidylcholine- relationship between demographic and clinical selected vari-
based liposome of a pluronic lecithin organogel (PLO) using ables and response to treatment (resolved vs not resolved). A
massive shear forces. PLO is a gel base used to enhance Wilcoxon two-sample test was used to examine a possible
penetration into the skin of various medications. The safety relationship between continued variables and response. Fish-
and efficacy of this vehicle have previously been evaluated in er’s exact test was used to examine a possible relationship
clinical trials.16 between categorical variables and response. Statistical analy-
sis was performed with SAS for Windows version 9.4 (SAS
Treatment protocol Institute, Cary, NC, USA).
Parents were instructed to apply topical propranolol 4% gel
over the PG lesional area twice daily without occlusion. The
RESULTS
quantity of the gel used for every application over an average
lesion of 0.5 cm2 was 15 mg, containing 0.6 mg propranolol. In The study included 18 patients (eight girls and 10 boys), with
the event of any systemic, generalized or local side-effects an average age of 4.7 years (range, 4 months to 12 years). The

(a) (b)

(c) (d)

Figure 1. Effectiveness of propranolol 4% gel for the treatment of pyogenic granuloma. (a,b) Pyogenic granuloma on the left cheek
of a 7-year-old male, (a) before and (b) after treatment with propranolol 4% gel. (c,d) Pyogenic granuloma on the left labia majora of
a 1.5-year-old female, (c) before and (d) after treatment with propranolol 4% gel.

2 © 2018 Japanese Dermatological Association

 Topical propranolol 4% gel for PG

average longest diameter of the lesions was 5.5 mm (range, spontaneous regression is very rare, treatment is often
4–7 mm). Eight (44%) lesions were located on the cheeks, four required.
(22%) on the neck, two (11%) on the extremities, and one each Several publications have reported the use of topical beta-
on the scalp, forehead, labia major and chest. In nine cases blockers such as timolol and propranolol for the treatment of
(50%) bleeding was recorded prior to treatment. The mean PG.6,8–14 In a recently published study, out of 22 cases treated
duration of treatment was 6.5 weeks (range, 2 weeks to with topical propranolol 1% twice daily under occlusion, 59%
10 months). completely regressed following 9.5 weeks on average.12 Our
Out of 18 lesions, 11 (61.1%) completely resolved by the study demonstrated complete or almost complete regression
end of the treatment; two tumors (11.1%) almost resolved, with in 72% of cases following an average treatment duration of
a residual small macule; in three cases, the treatment was dis- 6.5 weeks without occlusion. The shorter treatment time in our
continued due to bleeding, and the lesions were removed by study, despite administration without occlusion, is likely to be
curettage. due to the higher concentration of propranolol in the gel, thus
Local irritation to the propranolol gel was documented in eliminating the need for occlusion. However, the treatment
one case (5%) and lack of compliance in another case (5%) duration is probably related as well to the size and localization
leading to discontinuation of treatment and curettage as well. of the lesions, as seen in the case of a relatively big lesion with
Altogether, 13 patients (72%) had complete or almost com- a diameter of 7 mm on the labia. The size of the lesion and the
plete response to treatment. A Wilcoxon two-sample test indi- localization that prevents proper application of the medication
cated that treatment time was greater for resolved lesions than necessitated longer treatment time, shown by the Wilcoxon
for not resolved (P = 0.05). For all other examined factors, two-sample test, indicating that treatment time was greater for
there was no statistical significant difference between resolved resolved lesions than for not resolved (P = 0.05). We used the
and not resolved lesions. same concentration for the treatment of infantile hemangiomas
No recurrence was recorded during a 6-month post treat- and found it to be entirely safe and can be applied to any area
ment follow-up period. Only one patient reported local adverse of the body.7
effects including irritation, redness and scaling of the treated In the past several years topical and systemic beta-blockers
area, leading to discontinuation of the treatment and curettage have been effectively used for the treatment of infantile heman-
of the PG. No systemic adverse reactions were reported giomas. Angiogenesis is crucial for PG formation and overex-
(Table 1). pression of ICAM-1 and VCAM-1 has been shown in gingival
PG.3 ICAM-1 and VCAM-1 are inhibited by b1-receptor antago-
nists (metoprolol, nebivolol, celiprolol) and by b1/b2 receptor
DISCUSSION
antagonists (carvedilol).17,18 Therefore, inhibition of critical
The current study revealed that topical propranolol 4% gel is a modulators of angiogenesis may underlie the therapeutic effect
safe and effective treatment modality for PG in children which of beta-blockers, such as the b1/b2 receptor antagonist pro-
can be considered as a first-line treatment and prevents the pranolol, on PG.19
need for surgical intervention. Topical beta-blockers are considered extremely safe with a
Because bleeding (even after a minor trauma) is common in single report of sleep disturbances and a few reports of skin
PG, and may be profuse and difficult to control, and because irritation.20,21 Our study demonstrated a good safety profile of

Table 1. Clinical characteristics of the cohort of patients with pyogenic granuloma treated with propranolol 4% gel

Sex Age (years) Distribution Size (mm) Bleeding Treatment time (weeks) Response
1 M 7 Cheek 5 Yes 24 Resolved
2 F 2.8 Cheek 4 No 4 Resolved
3 F 3 Cheek 4 No 2 Resolved
4 F 1.6 Cheek 6 Yes 4 Resolved
5 M 0.8 Cheek 4 Yes 2 Resolved
6 F 5 Neck 6 No 10 Resolved
7 M 7 Neck 6 No 4 Resolved
8 M 6 Neck 6 No 3 Resolved
9 F 1.6 Arm 5 Yes 2 Resolved
10 M 7 Arm 7 No 3.5 Resolved
11 F 1.5 Labia 7 Yes 40 Resolved
12 M 0.4 Cheek 5 No 4 Almost resolved
13 M 7.8 Forehead 6 Yes 2 Almost resolved
14 M 11 Chest 4 Yes 1 Propranolol ? irritation ? curettage
15 M 5.4 Scalp 6 Yes 6 50% diminished trauma ? excision
16 F 12 Neck 5 No 4 Bleeding ? curettage
17 F 1 Cheek 7 Yes 2 Bleeding ? curettage
18 M 4 Cheek 6 No 1 Curettage

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J. Mashiah et al.

propranolol gel 4%, with no report of systemic side-effects, 8 Gupta D, Singh N, Thappa DM. Is timolol an effective treatment for
and only skin irritation in one case. Clearly, application over pyogenic granuloma? Int J Dermatol 2016; 55: 592–595.
9 Khorsand K, Maier M, Brandling-Bennett HA. Pyogenic granuloma
mucous membranes, ulcerated surfaces or large body surface
in a 5-month-old treated with topical timolol. Pediatr Dermatol 2015;
areas merits special attention. 32: 150–151.
Considering the relatively small cohort of the present study, 10 Knopfel N, Escudero-Gongora MDM, Bauza A, Martin-Santiago A.
larger randomized controlled studies are needed to determine Timolol for the treatment of pyogenic granuloma (PG) in children. J
Am Acad Dermatol 2016; 75: e105–e106.
the best regimen and fully delineate the safety and efficacy of
11 Malik M, Murphy R. A pyogenic granuloma treated with topical timo-
topical propranolol for PG. Nevertheless, the present data indi- lol. Br J Dermatol 2014; 171: 1537–1538.
cate that topical administration of propranolol 4% gel for PG in 12 Neri I, Baraldi C, Balestri R, Piraccini BM, Patrizi A. Topical 1% pro-
children could be considered as a safe alternative to surgical pranolol ointment with occlusion in treatment of pyogenic granulo-
removal. mas: an open-label study in 22 children. Pediatr Dermatol 2018; 35:
117–120.
13 Oke I, Alkharashi M, Petersen RA, Ashenberg A, Shah AS. Treat-
CONFLICT OF INTEREST: None declared. ment of ocular pyogenic granuloma with topical timolol. JAMA Oph-
thalmol 2017; 135: 383–385.
14 Piraccini BM, Alessandrini A, Dika E, Starace M, Patrizi A, Neri I.
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