Treatment of Xanthelasma Palpebrarum With

Intralesional Pingyangmycin
Hui Wang, MD,* Yingshen Shi, MD,* Huapeng Guan, MD, PhD,† Caiyue Liu, DDS, MD,*
Wenjun Zhang, MD,* Yingfan Zhang, MD,* Antang Liu, MD,* Yuxin Qian, MD,*
Yaozhong Zhao, MD,* and Hua Jiang, MD*

BACKGROUND Xanthelasma palpebrarum (xanthelasma) is the most common type of cutaneous xanthoma,
and many patients tend to seek medical treatments for cosmetic reasons. Many methods treating xanthelasma
have been proposed, but none of these options can be regarded as a perfect solution.

OBJECTIVE To study and evaluate the intralesional injection treatment of xanthelasma with pingyangmycin,
which has been widely used as a broad-spectrum antitumor antibiotic.

MATERIALS AND METHODS 21 lesions in 12 patients were treated by intralesional pingyangmycin. Photo-
graphs were taken before and after each treatment session. Patients were followed up for 7 to 36 months.

RESULTS All patients except one received satisfactory results after up to 2 sessions. Only 1 patient had
a local recurrence 1 year after the treatment. No severe complications such as infection, atrophy, ulceration, or
scar were noticed.

CONCLUSION Intralesional pingyangmycin is a cheap, effective, and safe treatment for xanthelasma, which
has been well accepted by patients.

Supported by the Young start-up fund of Shanghai Changzheng Hospital (2013CZQN03). H. Wang, Y. Shi, H.
Guan, and C. Liu contributed equally to this work. The authors have indicated no significant interest with
commercial supporters.

X anthelasma palpebrarum (xanthelasma) is the

most common kind of cutaneous xanthoma,
which occurs on the eyelids and characterized by
yellow, soft, and painless plaques.1 An epidemiologic
study showed that the incidences of xanthelasma
among men and women were 0.3% to 1.54% and
0.82% to 3.4%, respectively,2 and it has shown
a tendency to increase during the recent years.
Histologically, xanthelasmata are composed of foam
cells laden with cholesterol deposits around dermal
capillaries and cutaneous appendages.3 The
histologic feature of xanthelasma is similar to
atherosclerotic plaques, and xanthelasma has been
recognized as an extrinsic manifestation of
dyslipidoses,4 which can be a possible indicator of
cardiovascular disease.5,6
Xanthelasma usually causes neither clinical symptoms
nor dysfunction; however, it occurs on the particular
sites that can seriously affect the appearance of the
patients and many patients tend to receive treatments
for cosmetic reasons. Xanthelasma can be classified
into 4 grades by clinical manifestation and invasion
range of the lesions: Grade I, the lesions involve only
the upper eyelids; Grade II, the lesions extend to the
medial canthal area; Grade III, the lesions involve the
medial side of the upper and lower eyelids; Grade IV,
the lesions diffusely involve the medial and lateral side
of the upper and lower eyelids7 (Figure 1).
Many methods have been proposed to treat xanthe-
lasma, including cryotherapy,8 trichloroacetic acid
peeling,9 electric cauterization,10 laser therapy (e.g.,

*Department of Plastic and Reconstructive Surgery, Changzheng Hospital, Second Military Medical University, Shanghai,
China; †Department of Orthopedics, PLA 456 Hospital, Jinan, China
© 2016 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.
· ·
ISSN: 1076-0512 Dermatol Surg 2016;42:368–376 DOI: 10.1097/DSS.0000000000000660

368

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Figure 1. The clinical classification of xanthelasma. (A)
Grade I, the lesions involve only the upper eyelids; (B)
Grade II, the lesions extend to the medial canthal area; (C)
Grade III, the lesions involve the medial side of the upper
and lower eyelids; (D) Grade IV, the lesions diffusely
involve the medial and lateral side of the upper and lower
eyelids.
carbon dioxide,11 argon,12 Q-switched Nd:YAG,13 Er:
YAG,14 and pulsed dye lasers15), and surgical resec-
tion.7 However, each treatment has its own particular
limitations and complications, some of which may be
even worrying, such as recurrence, scarring, and pig-
ment alteration in local sites (hypopigmentation or
hyperpigmentation). Besides, a histologic study of
xanthelasma has demonstrated that the invasive depth
of xanthelasma histiocytes (foam cells) was generally
much deeper and reached musculus orbicularis oculi in
a larger percentage of patients than the authors
expected.3 Based on this observation, complete
removal of the invaded tissues in treatment of xan-
thelasma may not be easily achieved by this method;
therefore, high recurrence rate in these xanthelasma
patients may occur.
Pingyangmycin, also known as bleomycin A5, is one of
the 13 components of bleomycin. First reported to be
produced by Streptomyces pingyangensisn in China, it
is widely used as a broad-spectrum antitumor antibiotic
in the treatment of vascular malformations,16 lym-
phatic malformations,17 various malignant/benign
neoplasms,18,19 verruca,20 etc. The use of pingyang-
mycin has been shown to be effective and safe in clinical
studies, especially in treatment of vascular malforma-
tions. In this study, the authors propose and explore
© 2016 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
WANG ET AL
a new method to treat xanthelasma by intralesional
injection of pingyangmycin and satisfying outcomes
were observed through a long-term follow-up. Besides,
the authors have chosen 4 representative cases to show
the effectiveness of pingyangmycin on different types of
xanthelasma as well as its main complications.
Methods
Patients
This study was conducted according to the Declara-
tion of Helsinki principles, approved by the Ethical
Committee of Shanghai Changzheng Hospital of
Second Military Medical University, and written
informed consent was obtained from all patients.
Between November 2011 and July 2014, 12 patients
with 21 xanthelasma lesions were enrolled in this
study, including 9 women and 3 men, of 30 to 59 years
(mean age 47.7 6 8.22) of age. Serum lipid levels were
evaluated in 8 patients of whom 3 patients were
diagnosed with dyslipidemia. All of the 12 cases
were followed up for 7 to 36 months (mean 14.7 6
10.1 months) for any side effects or recurrence. Pho-
tographs were taken before and after each treatment
session and evaluated by an independent expert. The
results were scored from 0 to 3 based on the clearing of
the xanthelasma lesions: 0, poor outcome (<25%
clearing); 1, moderate outcome (25%–50% clearing);
2, good outcome (50%–75% clearing); 3, excellent
outcome (>75% clearing).
Intralesional Injection With Pingyangmycin
Patients were injected with a solution of pingyang-
mycin (8 mg; Tianjin Taihe Pharmaceutical Co., Ltd.,
Tianjin, China) in 0.9% NaCl solution (4 mL). Before
injection, the area of xanthelasma lesion was carefully
disinfected by 75% alcohol swab to protect the eyes
from alcohol. A 1 mL syringe with 26 G needle con-
taining the pingyangmycin solution was pricked at
a 30° angle into the xanthelasma lesion. The pin-
gyangmycin solution was then slowly injected (after
withdrawing without backflow blood) until the skin
color turned pale and covered the edge of xanthelasma
lesion by 1 mm (Figure 2). Throughout the process of
injection, the inclined plane of the needle tip was kept
42:3:MARCH 2016 369
 NEW TREATMENT OF XANTHELASMA PALPEBRARUM

received 2 sessions of treatment and other 9 patients

received the treatment only once. The treatment out-
comes were scored as 0 in 0 patient (0%); 1 in 1 patient
(8.3%); 2 in 2 patients (16.7%); 3 in 9 patients (75%)
(Figure 3). Detailed information of all patients and
their clinical outcomes are listed in Table 1.

In view of the side effects of pingyangmycin injection,

notable swelling accompanied by mild pruritus was
observed in 4 patients hours after injection. However,
these temporary symptoms subsided spontaneously in
3 to 5 days in all 4 patients. Besides these, persistent
hyperpigmentation was noticed in 1 patient and no
other severe side effects, such as infection, atrophy,
ulceration, scarring, or hypopigmentation, occurred
during the follow-up. Only 1 patient with bilateral
lesions had experienced a unilateral recurrence (left
side) about 1 year after the treatment.

Additionally, biopsy specimens were obtained on 1

patient pretreatment and posttreatment. Pretreatment
Figure 2. Intralesional injection with pingyangmycin. (A) histologic findings showed lots of foamy histiocytes
Pinhead was pricked into the xanthelasma lesion with deposited diffusely and densely in the entire dermis. In
a 30° angle; (B) Injected slowly until skin color turned to
yellowish-white and got over the xanthelasma lesion
contrast, the posttreatment histologic findings showed
by 1 mm. that the foamy histiocytes were deposited focally in the
dermis and decreased significantly both in number and
upward to ensure delivery of drug infiltrate only in the volume (Figure 4).
superficial (and not deep) level of the skin. After the
completion of injection procedure, patients were asked Case Reports
to press on the injection sites with a swab for 3 minutes
at least. For the large lesions or the lesions that pro- Case 1
truded markedly from the skin, a layered injection was
required to guarantee the effectiveness of treatment. A 45-year old man with xanthelasma on bilateral
Repeated treatment was performed when needed, with upper eyelids was treated for 2 sessions with a 1-month
a 4-week interval between each treatment session. interval. No swelling at the injection site was seen after
each treatment, and, after the second session, the
When performing intradermal injections, the pene-
tration depth of the pinhead should be carefully
monitored. For the deeper invaded lesions, an injec-
tion in musculus orbicularis oculi is required with
avoidance of intravascular injection; therefore, a pull-
back before injection was necessarily done.

Results

Of the 12 patients treated with 21 xanthelasma lesions

by the method mentioned above, 3 patients had Figure 3. Clinical results and follow-ups.

370 DERMATOLOGIC SURGERY

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 TABLE 1. Summary of Clinical Manifestation and Results of the Patients

Postinjection
Age, Number/Location Preinjection Serum Lipid Dosage Per Follow-up, Reaction and
Patient years Sex of Lesions Treatments Levels Sessions Session, mL months Result Side effects
1 45 M 2/Bilateral upper TG[, HDL-CY 2 0.34/0.26 36 3
eyelids
2 36 F 2/Bilateral upper Normal 1 0.28 36 3 Swelling
eyelids
3 30 F 1/Left upper eyelid LDL-C[ 1 0.20 13 3 Swelling;
Hyperpigmentation
4 49 F 2/Bilateral upper Normal 1 0.16 12 1
eyelids
5 54 F 1/Left upper eyelid — 1 0.10 12 3
6 47 M 4/Bilateral upper Surgical — 2 0.48/0.42 12 2
and lower eyelids resection
7 46 F 1/Left upper eyelid — 1 0.14 11 3 Swelling
8 40 F 1/Right upper eyelid — 1 0.10 11 3
9 59 M 1/Left upper eyelid Normal 1 0.10 9 3
10 54 F 2/Bilateral upper TC[, TG[, Lp-a[ 1 0.30 9 3 Swelling
eyelids
11 52 F 2/Bilateral upper Normal 2 0.30/0.26 8 3
eyelids
12 50 F 2/Bilateral upper Laser therapy Normal 1 0.28 7 2
eyelids

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride.
42:3:MARCH 2016

WANG ET AL
371

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 NEW TREATMENT OF XANTHELASMA PALPEBRARUM
Figure 4. Histologic results of the xanthelasma lesion
pretreatment and posttreatment. Hematoxylin and eosin
stain. (A) Pretreatment histologic findings, the foamy his-
tiocytes deposited diffusely and densely in the entire der-
mis. (B) Posttreatment histologic findings after 1 session,
the foamy histiocytes decreased significantly in number
and volume and deposited focally in the dermis.
lesions were cleared markedly. The result was scored
as 3 (patient no. 1, Figure 5). This patient was followed
up for 36 months (the longest follow-up period in this
study) with no noticeable sign of recurrence or any
other side effects.
Case 2
A 59-year-old man with a markedly protruded xan-
thelasma lesion from the skin was treated. A layered
injection was given to ensure that the drug was fully
infiltrated into the lesion and no swelling or other
discomfort occurred after the pingyangmycin treat-
ment. The outcome of the pingyangmycin injection
after one treatment was excellent and scored as 3
(patient no. 9, Figure 6). Throughout the 9-month
372 DERMATOLOGIC SURGERY
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Figure 5. Case 1. (A) Patient with xanthelasma on bilateral
upper eyelids; (B) the lesion was cleared entirely after 2
sessions.
follow-up period, no sign of recurrence or any other
side effect symptoms were noticed.
Case 3
A 47-year-old man diagnosed with Grade IV xanthe-
lasma was enrolled in the study. Before the treatment
with pingyangmycin, he had undergone a surgical
resection on bilateral upper eyelids and experienced
a recurrence. After 2 treatment sessions with pin-
gyangmycin, the large area of lesions on bilateral
lower eyelids was markedly dissolved whereas lesions
on the upper eyelids did not give such satisfactory
results and the overall results was scored as 2 (patient
no. 6, Figure 7).
Case 4
A 30-year-old woman with xanthelasma on the left
upper eyelid was treated with pingyangmycin injec-
tion. After the treatment, marked swelling was seen on
the injection site that subsided spontaneously in 5
days. The result showed an excellent clearing of the
lesion and was scored as 3; however, a hyperpigmen-
tation on the local site of injection was noticed. The
hypopigmentation had not dissolved completely until

Figure 6. Case 2. (A) Patient with a xanthelasma lesion
markedly protruded from the skin; (B) the lesion was
cleared entirely after 1 layered injection.
the end of this study (9 months after the treatment)
(patient no. 3, Figure 8).
Discussion
The treatment of xanthelasma remains a challenge in
clinical practice. Although many methods have been
proposed to deal with xanthelasma, each of them has
its particular limitations and side effects. Surgical
resection is one of the traditional therapies and is
considered to be an effective way to remove the lesion
completely. However, a histologic study demon-
strated that the foamy histiocytes either touched or
infiltrated the stratum musculare in over 40% of the
examined xanthelasma lesions.3 Therefore, a complete
resection of all infiltrated tissues including musculus
orbicularis oculi is needed. Besides, it is also necessary
to repair the resected skin defect by a skin graft or
a flap when dealing with a large lesion. The physical
approaches, such as cryotherapy, trichloroacetic acid
peeling, and electric cauterization, only affect the
surface or the superficial layer of the skin, and the
damage to the skin is quite notable, thereby increasing
the chances of leaving scars with hypopigmentation or
hyperpigmentation. Laser therapy is also considered
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WANG ET AL
Figure 7. Case 3. Patient with Grade IV xanthelasma (A),
the large area lesions on the lower eyelids were markedly
dissolved while lesions on the upper eyelids did not get
such satisfactory results (B).
as a physical approach, using the thermal effect pro-
duced due to the absorption of specific laser by body
tissues. However, the absorption and strength of
penetration by lasers of different wavelengths would
vary in different target tissues; therefore, it becomes
difficult to control the duration/depth of treatment and
the outcome of the treatment is very inconsistent in
clinical reports.
In this study, of all the 12 patients who were treated by
intralesional pingyangmycin, 9 were scored as 3,
confirming the effectiveness of pingyangmycin treat-
ment. Notably, of the 2 patients who were scored as 2,
1 patient (No. 12) had undergone a laser therapy
before this treatment and the lesions did not respond to
the laser treatment markedly; however, after 1 pin-
gyangmycin treatment session, the patient was com-
pletely satisfied with the outcome and hence decided
not to receive a second session treatment. The other
patient scored as 2 was diagnosed with Grade IV
xanthelasma, the lesions on bilateral lower eyelids
were markedly dissolved while a very unsatisfactory
result on the upper eyelids was the consequence of
surgical treatment before receiving the pingyangmycin
42:3:MARCH 2016 373
 NEW TREATMENT OF XANTHELASMA PALPEBRARUM
Figure 8. Case 4. (A) Patient with xanthelasma on the left
upper eyelid, with temporary postinjection swelling (B)
and persistent hypopigmentation (C).
injection treatment. The cicatricial tissue after surgical
treatment might affect the absorption of the pin-
gyangmycin solution. Only 1 patient scored as 1
(lesion clearing less than 50%) decided to receive laser
therapy after pingyangmycin treatment.
In the authors’ opinion, the advantages of using pin-
gyangmycin injection for the treatment of xanthe-
lasma are as follows: (1) the therapeutic effect can be
accurately achieved within the lesions, causing mild
damage to the periphery tissues and skins. This is
a tremendous advantage over other physical
approaches or laser therapy, in which the therapeutic
effects occur only on the surface or superficial layer of
the skin. (2) Layered or fractional injection can be
practiced to the large or convex lesions to achieve
better results (Figures 6 and 7). (3) The side effects of
this treatment are mild because temporary swelling
accompanied by mild pruritus was primarily seen
(noticed in 4 patients, 25%) (Figure 8B), and that
subsided spontaneously in 3 to 5 days. Persistent
374 DERMATOLOGIC SURGERY
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hypopigmentation occurred on 1 patient (1/12, 8.3%
in patients and 1/21, 4.8% in lesions) (Figure 8C),
whereas no other severe side effects, such as infection,
scarring, hypopigmentation, fever, allergic reactions,
or pulmonary fibrosis, were observed. (4) The recur-
rence rate after this treatment is considered to be
acceptable (1/12, 8.3% in patients and 1/21, 4.8% in
lesions). (5) This treatment had little effect on the daily
life activities of the patients. After the treatment,
patients were only advised to protect the injection site
from the water for at least 12 hours and no other
managements were needed. (6) The ease and simplicity
of operation is another added advantage of this
treatment over other therapies. The pingyangmycin
injection is easy to handle, and it only takes about
5 minutes to perform one treatment. (7) Cost of overall
treatment is much less as compared with laser therapy
or surgical resection, and the cheaper cost of pin-
gyangmycin than bleomycin makes it advantageous
over bleomycin. In summary, the treatment of xan-
thelasma by intralesional injection of pingyangmycin
is minimally invasive, cost-effective, and safe, thus
making this treatment well accepted by the patients.
Previous published reports by others have shown that
pingyangmycin achieves its therapeutic effect by pro-
moting the oxidation of Fe2+ to Fe3+ and producing
OH2, which can combine and uncoil the DNA,
thereby inhibiting the proliferation of cells.21 In addi-
tion, pingyangmycin can also induce cell apoptosis.22
In this study, the histologic findings showed that
foamy histiocytes decreased significantly both in
number and volume after intralesional injection of
pingyangmycin. Therefore, the authors presume that
pingyangmycin may have similar effects on xanthe-
lasma histiocytes because it exerts on vascular endo-
thelial cells or tumor cells when used in treatment of
vascular malformations or tumors. However, the
exact mechanism of pingyangmycin in treating xan-
thelasma has not been explored yet.
The metabolism of pingyangmycin in vivo mostly
depends on an enzyme bleomycin hydrolase, which
exists in bone marrow, liver, spleen, and intestine at
a relative high density and however has nearly no
activity in skin and lung.23 That explains why pin-
gyangmycin shows a therapeutic effect in those specific

tissues but may induce interstitial pneumonitis or
pulmonary fibrosis in an experimental high dose with
intratracheal24 or intraperitoneal25 application. A risk
of pulmonary fibrosis was shown once the dosage of
bleomycin used was over 160 mg systemically,26 and,
in general, bleomycin may cause interstitial pneumo-
nitis in up to 46% of the patients and 3% of those
patients would develop fatal pulmonary fibrosis.27
However, severe systemic side effects caused by thera-
peutic doses of pingyangmycin were rare, especially
when used for intralesional injection (no relevant
reports have been published so far). The authors sug-
gest that pingyangmycin has this advantage of lower
toxicity because of the unicity of the component;
however, further research is required to investigate and
confirm the toxic effects. Besides, the exact mechanism
that bleomycin and pingyangmycin induce, pulmonary
fibrosis is yet undiscovered. Intravascular risks should
also be considered, although the dosage of pingyang-
mycin used in treatment of xanthelasma is usually
under 1 mg in 1 session (much lower than the systemic
application), which is considered to be safe. A recent
study, however, has suggested that intralesional pin-
gyangmycin may increase risks of soft-tissue atrophy or
ulceration after long-term observation in the treatment
of infantile hemangiomas.28 Use of intralesional pin-
gyangmycin to treat xanthelasma must be closely
monitored, although the authors did not observe such
side effects in this study for low dose.
Moreover, in this study of intralesional injection
treatment, pingyangmycin was applied with physio-
logic saline only, which ensured that the therapeutic
effect was achieved by pingyangmycin. A published
report showed that lidocaine has a synergistic effect
with pingyangmycin for the treatment of venous mal-
formation.21 Further studies are necessary to determine
if lidocaine and pingyangmycin have similar synergistic
effect for the treatment of xanthelasma. Xu and col-
leagues29 suggested that the concentration of pin-
gyangmycin was significant in treating macrocystic
lymphatic malformations by intralesional injection;
larger lesions required higher concentration of pin-
gyangmycin. With regard to the treatment of xanthe-
lasma, no research concerning the optimal therapeutic
concentration of pingyangmycin has been carried out
yet. The authors also suggest that dexamethasone could
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WANG ET AL
be added to the pingyangmycin solution to lower the
incidence of postinjection swelling. All these above
mentioned directions would need to be discussed in
further studies with a larger sample size.
Conclusion
In conclusion, intralesional injection of pingyangmy-
cin is a safe, effective, and technically simple option to
treat various types of xanthelasma. Additionally, this
treatment is well accepted by patients for its advan-
tages of being minimally invasive, affordable, and
cost-effective, as well as good recovery with no side
effects. In this preliminary report, the authors believe
that the pingyangmycin injection treatment for xan-
thelasma deserves further applications and studies.
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Address correspondence and reprint requests to: Hua
Jiang, MD, Department of Plastic and Reconstructive
Surgery, Changzheng Hospital, Second Military Medical
University, 415 Fengyang Road, Huangpu District,
Shanghai 200003, China, or e-mail: dosjh@126.com