Intralesional pingyangmycin injection sclerotherapy for oral ranulas

doi:10.4236/ojst.2013.37061

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Open Journal of Stomatology, 2013, 3, 359-364 OJST

http://dx.doi.org/10.4236/ojst.2013.37061 Published Online October 2013 (http://www.scirp.org/journal/ojst/)

Intralesional pingyangmycin injection sclerotherapy for

oral ranulas*

Zhifang Chen1#, Jiawei Zheng2#, Shanyong Zhang2#

1Department of Oral and Maxillofacial Surgery, Hefei Stomatological Hospital, Clinical School of Anhui Medical University, Hefei,

China

2Department of Oral and Maxillofacial Surgery, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University

School of Medicine, Shanghai, China

Email: #[email protected], #[email protected], #[email protected]

Received 12 March 2013; revised 12 April 2013; accepted 15 May 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Objective: To investigate the efficiency of pingyang-

mycin (PYM) intralesional injection for the treatment

of ranulas in clinical practice. Methods: PYM con-

centrations were 2.0 mg/ml (8 mg PYM powder + 1

ml normal saline + 2 ml 2% lidocaine + 1 ml dexa-

methasone). The mixed PYM solution was intrale-

sional injected into ranulas after drawing out isomet-

ric cyst fluid in 3 patients. Results: The ranulas of 3

patients showed total disappearance after the sclero-

therapy, and no recurrence was found after 6 months

to 3 years’ follow-up. Compared to surgical therapy,

the PYM sclerotherapy was advocated by clinicians

for its advantages of less injury, no scar, less suffering,

etc. Conclusions: PYM is an effective sclerosing agent

for ranulas. Intracystic injection of PYM may be an

optimal method for the treatment of ranulas.

Keywords: Ranula; Pingyangmycin; Sclerotherapy

1. INTRODUCTION

Ranulas are mucoceles that develop as a consequence of

mucous extravasation, which typically present in the

floor of mouth from the sublingual gland. Plunging

ranulas are mucous extravasation pseudocyst herniating

through the mylohyoid muscle. The treatments of ranulas

mainly include surgical excision of the ranulas and no-

surgical sclerotherapy. Surgical management of ranulas

is still the first-choice therapy. However, due to the sur-

gical complications, the latter has been advocated by

clinicians for its advantages of less injury, no scar, less

suffering, etc.

Pingyangmycin (PYM), the single component of bleo-

mycin A5, is an anticancer agent that is refined from

Streptomyces pingyangensis and shows a strong damage

function to vascular endothelial cells. PYM has been

used as a conventio nal sclerosing agent for hemang ioma,

vascular malformations and lymphatic malformations [1].

PYM also can be used to treat cysts as a sclerosing agent

[2]. Recently, it has been reported that PYM is also a

relatively effective sclerosing agent for ranulas [3]. Ac-

cording to a series of data obtained about the safety and

efficacy of direct puncture injection with PYM in treat-

ing superficial cysts, we have used this method to treat

ranula since the early days of October 2010. In our study,

we attempt to describe our experience and to ev aluate th e

efficacy of intralesional injection with PYM for the

treatment of ranulas.

2. MATERIALS AND METHODS

2.1. Patients and Evaluation

3 clinical cases related to 14 - 22 years old female pa-

tients (mean 18.3 years old) were included in our study.

All patients’ chief complaints were the swelling in the

floor of mouth, and suffered from 3 - 35 months. No

correlative treatment was performed before accepting

PYM sclerotherapy (Figure 1). They underwent sclero-

therapy with the direct intralesional injection of PYM

between 20th October 2010 and 5th March 2013. The

protocol was approved and written informed consent was

obtained from them before the procedures. All patients

were treated on an outpatient basis.

Initial evaluation of the patients was composed of

physical examination, recordings of case history, photo-

graph findings. All patients, treated with local submu-

cous intralesional injection of PYM, didn’t undergo acute

*Funding: Hefei City Science and Technology Bureau (No. 2010-070)

#Corresponding author.

OPEN ACCESS

Z. F. Chen et al. / Open Journal of Stomatology 3 (2013) 359-364

360

Figure 1. The patient had suffered from a ranula for 35

months, and taken no correlative treatment before ac-

cepting treatme nt.

pain and aggrav ated swelling any more.

2.2. Procedure

For the safety sake, the patient received relevant exami-

nations before accepting sclerotherapy, including blood

routine, hepatic and renal function, and chest radiography.

No contraindicating was found in the ex amination results.

The PYM solution in these cases was prepared before the

procedure. The mixed liquor with 2.0 mg/ml concen-

trations was configured as follows: 8 mg of PYM powder

(Laibotong Pharmaceutical Co. LTD, Harbin, China) was

dissolved in the mixed liquor which was composed of

1ml normal saline, 2 ml 2% lidocaine and 1ml dexa-

methasone [2]. The dosage of PYM varied from 0.05 to

0.2 mg/kg of body weight according previous literatures

experience [1].

Half an hour before the procedure, local anesthetic

was performed after sterilization of the oral region. A

1.5-inch (3.8-cm) 25-gauge fine-needle was used for the

puncture. 1ml 2% lidocaine was directly injected into the

critical normal site of the lesion. The normal location for

submucous was determined by the needle route.

After the point of the needle found intralesionally,

Partial cyst fluid was drawn out before sclerosing agent

had been injected (Figure 2, 3). The liquid volume aspi-

rated was about half of the cyst. Otherwise, it is difficulty

to puncture again. The sclerosing agent was injected

slowly to ensure that PYM was confined solely to the

lesions. Finally the injection was stopped when the lesion

was filled sufficiently (Figure 4, 5). The volume of scle-

rosing agent injected was estimated by the initial volume

of cyst fluid drew out. Care was taken not to go too far

medially and to avoid puncturing out of the cystic wall.

The puncture site was gently compressed for 5 - 10 min-

utes with a bandage. Patients were observed during the

procedure the time lasted least 4 hours for the detection

Figure 2. After the point of the needle found intra-

lesionally, Partial cyst fluid was drawn out before scle-

rosing agent had been injected.

Figure 3. The cyst fluid drawn out show saffron yellow,

glutinous liquid after 4 years.

of early complication after the procedure (Figure 6).

Systemic corticosteroids (dexamethasone, 10 mg/d for 3

days) were administered to manage postoperative oral

swelling. Nonstero idal antiinfla mmatory agents were used

for the pain relief when necessary.

2.3. Definitions and Follow-Up

The effectiveness of sclerotherapy was assessed on the

basis of the follow-up clinical findings and the photo-

graph findings of follow-up (Figure 7). The treatment of

the patient, who has not presented oral regional recur-

rence after the procedure followed-up more than 6

months, is considered to be effective.

3. RESULTS

3.1. Efficacy Outcomes

Technically, the intralesional PYM injection of sclero-

therapy was successful after more than 6 months fol-

lowed-up. The volume of PYM solution injected was 2.0

- 3.0 ml (mean, dose of PYM 4.9 mg), PYM was well

Z. F. Chen et al. / Open Journal of Stomatology 3 (2013) 359-364 361

Figure 4. Pingyangmycin was well impregnated in the

lesions, The volume of PYM injected was 3.0 ml (total

dose of PYM 6.0 mg)

Figure 5. To prevent the cyst liquid mixed residual

Pingyangmyein outflow from ruptured cyst, puncture

local was pressured for 10 minutes after Pingyang-

myein injection

impregnated in the lesions (Figures 4 and 5). Outflow of

cyst liquid with residual PYM from ruptured cyst was

spitted out. The patient expressed some clinical symptoms

such as: local light swelling within 1 week after the pro-

cedure, light pain after the cyst rupturing and pain dis-

appearance within 4 - 8 days (mean, 5.3 days). At the

same time, the articulation and swallowing function in-

disposed because of the swelling cyst displaced and in-

terfered the tongue. The procedure was beneficial for the

patient with diffuse lesions (Figure 7). The results were

reported in the Table 1.

3.2. Safety Outcomes

Local swelling and pain in the floor of mouth disappeared

after the administration of anti-inflammatory agents and

oral care. Others complications, such as acute oral in-

flammation, infection, hemorrhage, mucous necrosis,

oral scar, symptomatic embolism of sclerosing agent into

submaxillary gland duct, blood routine, hepatic and renal

Figure 6. Patients have been observed during the

procedure and been for at least 4 hours after the pro-

cedure for detection of early complications. Local swell-

ing and pain in the floor of mouth were light. Others

complications, such as acute oral inflammation, hemor-

rhage, and symptomatic embolism of sclerosing agent

into submaxillary gland duct were not observed.

Figure 7. Local bump was disappeared after Pingyang-

myein injection 2 weeks.

function, and pulmonary fibrosis, and so on, were not

observed during the follow-up periods.

4. DISCUSSION

Ranulas is a kind of pseudocyst that has been developing

as a result of mucous extravasation from the sublingual

gland which can be originated from obstruction of ex-

cretory ducts or extravasation and subsequent accumula-

tion of saliva caus ed by trauma [4]. It is classified into 3

clinical types according to the sites of primary swelling:

oral ranula, plunging ranula, and mixed ranula. Oral

ranula often presents as fluctuation, soft mass with light

blue colour which locates between the mucosa and mus-

cles in the floor of mouth and may displace the tongue

and interfere with oral fun ction when the cyst extends.

A variety of therapeutic modalities hav e been reported

to manage ranulas in the past literatures, mainly includ-

ing surgical resection of the lesion and/or sublingual

Z. F. Chen et al. / Open Journal of Stomatology 3 (2013) 359-364

362

OPEN ACCESS

Table 1. The results of PYM sclerotherapy.

Patient No. Age (y)/Sex Location Aspiration (cc)Injection (cc)Duration of Follow- up ( mo) Result

1 22/F Left sublingual 3.0 3.0 35 total disappearance

2 19/F Right sublingual 2.4 2.4 13 total disappearance

3 14/F Left sublingual 2.0 2.0 6 total disappearance

gland, marsupialization and sclerotherapy using sodium

morrhuate [5-7], OK-432 [8,9], ethanol [10], trichlo-

roacetic acid [11], etc. Surgical resection of the lesion

and/or sublingual gland is the mainstay treatment of

ranulas. However, the effect is still controversial, due to

the various kinds of complications such as recurrence,

tongue hypesthesia, bleeding/hematoma, postoperative

infection, Wharton’s duct injury, etc. In addition, surgi-

cal therapy might be difficult for infant an d child patien ts

with ranulas under local anesthesia. Marsupialization is

not approved of adoption because of its high recurrence

rate. To avoid the complications associated with the sur-

gical procedures, nonsurgical sclerotherapy, reported to

have the advantages of minimal scaring, little morbidity,

and few complications, has been better to treat oral and

plunging ranulas, compared with surgical procedures.

According to the literatures, there are several kinds of

sclerosing agents that are used clinically. For example,

OK-432, a lyophilized mixture of low-virulence group A

Streptococcus pyogens with penicillin G potassium, has

been applied to the treatment of patients with lymphatic

malformations due to its cytotoxic action against endo-

thelial cells and the fibrotic changes related to cytokine

action in the lymphatic malformations [12]. Ogita et al.

first reported intracystic injection of OK-432 for cystic

hygroma in 1987 [12]. Henceforth, the effectivences and

safety of intralesional injection of OK-432 for lymphan-

gioma has been reported repeatedly [13,14]. Recently, it

was reported that OK-432 could also be used in ranulas

by increasing absorption and decreasing saliva produc-

tion, resulting in the collapse and adhesion of the pseu-

docyst [11-15]. However, patients often suffered from a

lot of troubles because of its high incidence of recurrence

and repeated intralesional injection. Rhoa et al. reported

OK-432 sclerotherapy of plunging ranula in 21 patients,

only 7 patients (33.3%) showed total shrinke and resolu-

tion, and the overall recurrence rate after each injection

was 47% (16 of 34 injections in 21 patients) [8].

Pingyangmycin (PYM) has been successfully used in

intralesional injection treatment of cystic hydromas and

haemangiomas, based specifically on a high sclerosing

effect on vascular endothelium [2]. It is a kind of bleo-

mycin A5 isolated from many components of bleomycin

made in China which can affect G2 and S phases of fast

dividing cells and causes breakage of single-stranded

DNA via preventing DNA repair by inhibiting DNA li-

gase. Intralesional injection of PYM brings the drug into

direct contact with the endoth elial linin g and destroys th e

endothelial cells, resulting in sclerosteno sis of the lumen,

and has been proved to be an effective, inexpensive, and

safe method for venous malformations of oral and max-

illofacial region [16,17]. Yang et al. [3] hypothesize that

PYM may cause damage of the cystic wall of the ranulas,

resulting in local fibrosis which subsequently eliminate

the cyst of ranulas and yield excellent treatment effects.

The cystic wall of oral ranula is similar to the endothe-

lial lining in that it is also very th in. The effectiveness of

PYM for treating the cystic hydromas and haemangio-

mas might also be effective for treating ranulas. Zhao et

al. [18] attempted PYM scleroyherapy in 785 cases of

sublingual cyst, 756 patients were cured completely, oth-

ers had significant improvement, and concluded that it is

a safe and effective therapy for sublingual cyst, and can

be used as a treatment of choice in some selected cases.

The similarity conclusion was obtained by other Chin ese

resarchers. PYM expressed more significant effective

compared with OK-432. Similarly, in our study, the cyst

showed total disappearance after PYM sclerotherapy

about 2 weeks (Figure 7) in 3 patients with ranulas. The

reason for the different cure time in our study may be

related to a different concentration of PYM in cyst, as the

different volume injected of PYM solution and the dif-

ferent residual cystic fluid.

Zhou et al. [19] believe, to achieve the desired effect,

that concentration is more important than dose per treat-

ment. However, most authors didn’t report the concen-

tration they used and the dose varied greatly [17,18]. The

most serious potential complication of using PYM is

pulmonary fibrosis in cancer therapy. The risk of this

toxicity is felt mini mal when, as suggested by Sung et al.

[20] that the dose per treatment be kept under 1 mg/kg

per session and no more frequently than an interval of a

week, with the total dose limited to 5 mg/kg. We believe

that the use of minimum per kg dose as described in the

literature is not mandatory for the sclerosing effect of

PYM to occur, and that the maximum dose and concen-

tration are important for efficiency and safety.

Higher PYM concentrations 2.0 mg/ml (8 mg PYM

powder + 1ml normal saline + 2 ml 2% lidocaine + 1 ml

dexamethasone) was adopted in our study. Although

most of ranulas described as “mucous extravasation cysts

[21]” without epithelial lining, should have a higher rate

of response to intralesional PYM injectio n in theory, Par-

tial residuary and secretory cyst fluid should dilute the

Z. F. Chen et al. / Open Journal of Stomatology 3 (2013) 359-364 363

concentrations of PYM. We achieved the desired clinic

effect in fact. The addition and peroral of dexamethasone

is to prevent fever, pain and swelling post injection. We

believe that this modality is more rational and further

clinical trials are required for validation.

The advantage of PYM intralesional injection for oral

ranulas less trauma, low recurrence rate, and it is simple

and practicable. While surgery of ranula is not just only

selectable treatment which is a more complicated proce-

dure with the sequela of leaving some residual lesion and

the chance of recurrence. Other complications of surgery

include temporary or permanent paraesthesia in the dis-

tribution of the lingual nerve, transient or permanent

marginal mandibular nerve palsy, wound infection, and

stitch granuloma. Wh at’s more, PYM is a potential better

sclerosing agent than others reported, such as OK-432,

Iodine tinctune, Trichloroacetic acid (TDA), sodium

morrhuate, etc. The mechanism of PYM sclerotherapy is

that PYM can affect cell division directly via preventing

DNA, which leads to apoptosis. We speculated that the

cystic wall cell might be necrotic and ruptured after the

injection of PYM solution. All 3 patients were cured af-

ter only one injection and showed no recurrence fol-

lowed-up for 6 - 35 months. Finally, the advantage of

PYM sclerotherapy is that the complications are mini-

mal, as seen in the Zhao’s paper [18]. In our study, minor

discomforts, such as light swelling at the injection site,

light pain in rupture site, were seen within the first week

after the injection and diappeared after 2 weeks. There

were no more complications found in our study probably

because the number of the collected patients was insuffi-

cient.

6. CONCLUSION

Our results suggest that PYM scleroyherap y of ranulas is

a safe and significantly effective therapy, which may be

used as a primary or first-choice treatment of ranulas.

Further studies may be desired to focus on the ranula

animal models to investigate the effects and side effects

of this method as well as its exact mechanisms. Our

prospect is to find a safe and convenient concentration

that is less suffering to patients with ranulas in the fu-

ture.

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