Evaluation of OK-432 Injection Therapy as Possible Primary Treatment of Intraoral Ranula

Accepted Manuscript Evaluation of OK-432 injection therapy as a possible primary treatment for intraoral ranula Michihide Kono, DDS, PhD, Takafumi Satomi, DDS, PhD, Harutugi Abukawa, DDS, PhD, FIBCSOMS, On Hasegawa, DDS, Masato Watanabe, DDS, PhD, Daichi Chikazu, DDS, PhD PII:

S0278-2391(16)30743-1

DOI:

10.1016/j.joms.2016.08.013

Reference:

YJOMS 57400

To appear in:

Journal of Oral and Maxillofacial Surgery

Received Date: 7 June 2016 Revised Date:

15 August 2016

Accepted Date: 15 August 2016

Please cite this article as: Kono M, Satomi T, Abukawa H, Hasegawa O, Watanabe M, Chikazu D, Evaluation of OK-432 injection therapy as a possible primary treatment for intraoral ranula, Journal of Oral and Maxillofacial Surgery (2016), doi: 10.1016/j.joms.2016.08.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Evaluation of OK-432 injection therapy as a possible primary treatment for

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intraoral ranula

Michihide Kono, DDS1, PhD, Takafumi Satomi2, DDS, PhD, Harutugi Abukawa,

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DDS, PhD, FIBCSOMS3, On Hasegawa, DDS4, Masato Watanabe, DDS, PhD5,

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Daichi Chikazu, DDS, PhD6

Department of Oral and Maxillofacial Surgery, Tokyo Medical University, Tokyo,

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Japan

Instructor.

2

Associate Professor.

3

Lecturer.

4

Instructor.

5

Lecturer.

6

Professor and Chair.

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1

Correspondence to:

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Michihide Kono, DDS, PhD Department of Oral and Maxillofacial Surgery

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Tokyo Medical University

6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan

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Phone: +81-3-3342-6111

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Fax: +81-3-3342-1723

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E-mail: [email protected]

２

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Abstract A ranula is a pseudocyst caused by mucous extravasation from the sublingual

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gland. Recently, a sclerosing agent, OK-432 (Picibanil), has been reported to be highly effective for treating lymphangioma and cervical cystic lesions. This study aimed to assess the effectiveness of OK-432 injection therapy for intraoral

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ranula and to clarify whether it can be used as the primary treatment.

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Patients and methods

This study was a retrospective clinical study of patients with intraoral ranula who were treated with OK-432 injection therapy from 2005 to 2015. Ranula size was

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measured by computed tomography or magnetic resonance imaging. We prepared 1 Klinische Einheit (KE) unit of OK-432 powder dissolved in normal

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saline equal to the aspiration volume. The primary endpoint was the treatment results. The secondary endpoint was the relation between the treatment results

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and the lesion length and aspiration volume. Results

Twenty-three patients were treated for intraoral ranula by OK-432 injection therapy. The mean size of the lesions was 19.96 mm. The mean aspiration volume was 2.14 mL. The numbers of injections were 1 to 4 times (mean 1.70 times). Treatment results showed complete regression (CR) in 18 (78.2%),

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partial regression (PR) in 3 (13.0%), and no response (NR) in 2 (8%) patients after the last injection. The overall efficacy rate was 91.2% (21/23). There were

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no serious complications observed. The differences between the treatment results (CR vs PR/NR) and the lesion length and aspiration volume of the CR

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group showed 17.38 mm and 1.40 ml. The PR/NR group showed 29.20 mm and

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4.80 ml. The PR/NR group lesion was significantly larger than the CR group lesion. Conclusion

OK-432 injection therapy for intraoral ranula was found to be a safe and effective

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treatment compared with other surgical therapies. This therapy can potentially

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become a primary treatment for intraoral ranula.

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Introduction A ranula is a pseudocyst caused by mucous extravasation from the sublingual

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gland or other minor salivary glands in the floor of the mouth. Intraoral ranulas usually present in the floor of the mouth and gradually enlarge to a painless

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fluctuant swelling. Ranulas have routinely been treated by sublingual gland

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excision or marsupialization (1, 2).

Surgical excision of ranulas is difficult and this usually leads to recurrence as the ranula is easily ruptured during surgery because of its thin and friable cyst wall

(3)

. A recently introduced sclerosing agent, OK-432, has been

lesions

(4)

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reported to be highly effective for treating lymphangioma and cervical cystic . OK-432 was originally developed as an immunotherapy agent for

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cancer. Ogita et al. reported the effectiveness of the intracystic injection of (4)

. In fact, the intracystic

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OK-432 for the treatment of lymphangioma in 1987

injection of OK-432 has become a standard therapy for lymphangioma. From a number of previous reports in Japan and Korea, intracystic injection of OK-432 for other benign cystic lesions has recently been performed (3, 5-7).

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This study aimed to assess the effectiveness of intracystic injection of

the primary treatment for intraoral ranulas.

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Materials and Methods

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OK-432 for intraoral ranula and to clarify whether such therapy can be used as

This investigation was a retrospective clinical study of patients with intraoral ranulas who were treated with OK-432 injection therapy from 2005 to 2015. All the patients provided written informed consent. This study was approved by the

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institutional review board of our university (IRB #2088). The predictor variables were the admitted patient’s age, sex, mass of cystic disease, numbers of

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treatment, outcome recurrence, and complications. The ranula size was

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measured on computed tomography or magnetic resonance imaging (MRI). The primary endpoint was treatment results. The secondary endpoint was the numbers of treatment and treatment side effects.

OK-432 injection therapy (Fig. 1a-e)

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OK-432 (Picibanil; Chugai Pharmaceutical Co., Tokyo, Japan) is a lyophilized mixture of a low virulence strain (Su) of Streptococcus pyogenes incubated with

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benzylpenicillin. We used OK-432 with a modified method described by Fukase et al (3) as follows:

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gauge needle away from the lesion. (Fig. 1a-c)

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1. Needle aspiration was performed from a normal submucosa using an 18

2. Aspiration volume < 10 mL; we prepared 0.1 mg of OK-432 powder which was dissolved with normal saline of the same amount as the aspiration volume. When the aspiration volume was more than 10 mL, we prepared 0.1 mg of

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OK-432 powder which was dissolved with 10 mL of normal saline. (Fig 1d) 3. The aspiration syringe was changed to another syringe containing OK-432

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solution while holding in place the 18 gauge needle that was injected into the

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cyst cavity. During this time, care must be taken so that the needle tip is not located outside the cyst cavity to avoid outflow of the injected OK-432 solution. Usually, if the needle tip is placed in the cyst cavity, the drug can be easily injected. (Fig. 1e,f) 4. There is usually no need for antibiotics after treatment. Only NSAIDs are to be used when fever develops. Before treatment, it is necessary to confirm any

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history of penicillin allergy because the components of OK-432 contain benzyl penicillin.

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Resolution was determined by clinical examination (i.e., visual inspection and palpation). When the results of the clinical examination were

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unclear, we performed MRI. The criteria for repeat injections were as follows: 1)

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the regression rate of the lesion was less than 70%, and 2) the symptoms of discomfort, dysphagia, and dyslalia failed to improve. The maximum injection times were five times. If the lesion size remained unchanged after 2 injections, we stopped the injection. The time interval for repeat injection was 2 weeks.

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However, if the lesion became small, we observed the lesion until 4 weeks. Treatment results were classified as follows: 1) complete regression

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(CR) when no visible mass was observed, 2) partial regression (PR) when any

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visible residual mass was observed in the primary site, 3) no response (NR) if there was no reduction or minimal shrinkage of the cyst, and 4) recurrence if there was regrowth of the cystic mass after CR. The efficacy rate included CR and PR. Statistical analysis was performed using SPSS 21.0 software (SPSS Inc., Chicago, IL). Correlations among the numbers of treatment and the lesion

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maximum length and aspiration volume were determined using the Student t-test and Mann-Whitney U test. Correlations among the treatment side effects and the

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numbers of treatment and treatment results were obtained using the chi-square correlation test. The statistical significance level was defined as a p-value of less

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than 0.05 (two-tailed).

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Results

The results are shown in Table 1 and Figure 2 a-d. Twenty-three patients (18 women and 5 men) were treated for intraoral ranula by OK-432 injection therapy.

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The patients’ ages ranged from 9 to 66 years (mean, 29-30 years). The lesion sizes ranged from 7 to 40 mm (mean ± standard error [SE], 19.96 ± 2.11

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mm). The aspiration volume ranged from 0.2 to 9 mL (mean ± SE, 2.14 ±

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0.47 mL). The OK-432 injection volume ranged from 0.2 to 9 mL (mean ± SE, 2.14 ±0.47 mL). The numbers of injections were 1 to 4 times (mean ± SE, 1.70 ± 0.18 times). After the initial injection, CR was noted in 11 patients (47.8%). However, after several injections (mean, 1.70 injections), CR was observed in 18 (78.2%) and PR in 3 (13.0%) patients after the last injection. The overall efficacy rate was 21/23 (91.3%). There was no response in 2 patients

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(8.6%) in whom there was recurrence after 1 month from the last injection. Side effects of the intracystic injection of OK-432 appeared in 9 patients (42%)

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who complained of fever (38%) and in 8 patients (38%) who developed oral floor swelling. In many cases, fever was observed in about 2-3 days, but the pain

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disappeared in a few days. All patients were prescribed an NSAID for a few days

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and it was possible to treat them as outpatients. Serious complications such as duct injury, tongue hypesthesia, and drug allergy did not occur. The follow-up period was 3-24 months (mean, 5.4 months).

The differences among the numbers of treatment (one time injection vs

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more than two times injection) and lesion maximum length and aspiration volume are shown in Table 2. In the one time injection group, the mean lesion

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length was 18.18 ± 7.38 mm and the mean aspiration volume was 1.80 ±

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1.62 mL. In the more than two times injection group, the mean lesion length was 21.0 ± 10.97 mm and the mean aspiration volume was 2.45 ± 0.70 mL. The differences were not significantly different. The differences between the treatment results (CR vs PR/NR) and the lesion length and aspiration volume are shown in Table 3. The CR group showed a mean lesion length of 17.38 ± 7.10 mm and a mean aspiration volume of

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1.40 ± 0.81 mL. The PR/NR group showed a mean lesion length of 29.20 ± 11.10 mm and a mean aspiration volume of 4.80 ± 1.31 mL. The PR/NR group

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showed significantly larger values than the CR group. Analyses of the relationships between therapy side effects and numbers of treatment and

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treatment results showed no significant relations (Table 4).

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Discussion

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A ranula is thought to be a pseudocyst caused by mucous extravasation from the sublingual gland with a thin and friable cyst wall. This makes ranula excision (7)

. The present study showed that

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alone difficult as it leads to recurrence

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OK-432 injection therapy for intraoral ranula had an efficacy rate of approximately 90%. Moreover, this treatment method is easy to perform and major complications such as duct injury or tongue hypesthesia have not yet been observed. This drug is very safe because its side effects are not serious such as

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fever and swelling. We believe that this treatment method has the potential to become the primary treatment for intraoral ranula as it is less invasive than

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surgical methods such as marsupialization and complete sublingual gland

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excision. Many other treatments have been reported such as aspiration, marsupialization,

ranula

excision,

submandibular

gland

excision,

and

submandibular gland and ranula excision. There are also a few reports on micro-marsupialization and the use of the YAG-laser method

(8, 9)

. Typically, the

primary treatment of ranula is marsupialization and the definitive treatment is sublingual gland and ranula excision. Ranula excision alone is difficult as it leads

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to recurrence from the easy rupture of the cyst because of its thin and friable cyst wall. However, definitive excision is reported to have a higher complication (1)

have

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rate than other treatment methods for intraoral ranula. Patel et al

reported on the complication rates of sublingual gland and ranula excision as tongue

hypesthesia,

4.8%;

Wharton

injury,

0.7%;

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bleeding/hematoma, 4.8%; infection, 2.7%.

duct

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follows:

The previous recurrence rates for various treatment methods were reported by Patel et al

(1)

and Sigismund et al

(10)

(Table 5). Sigismund et al

showed data on recurrence rates as follows: marsupialization, 13.6%; complete

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sublingual gland excision, 3.6%; ranula excision alone, 36.4%. Patel et al showed data on recurrence rates as follows: marsupialization, 19.8%; ranula

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excision, 20%; aspiration, 81.8%; OK-432, 57.5%; sublingual gland + ranula

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excision, 0%. The data of Sigismund et al and Patel et al showed a low recurrence rate for sublingual gland and ranula excision compared with the high recurrence rate for OK-432 injection therapy which is different from our present data. We validated the efficacy of OK-432 injection therapy similarly to the reports of Fukase et al

(3)

, Lee et al

(7)

, and Roh et al

(11)

(Table 6). The total

number of cases was 75. The median number of injection times was 1.99 times

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(1-5). The complete response rate was 80% (60/75). The no response and recurrence rate was 9% (7/75). We believe that the difference in the estimate of

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Patel et al regarding the OK-432 injection therapy result can be explained by only the one time injection. Our data of one time injection showed a complete

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response rate of 57% (11/23) which is similar to the report of Patel et al.

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However, our data showed that OK-432 injection therapy requires more than one time injection to achieve a complete cure. Thus, we believe that OK-432 injection therapy should be performed more than once to obtain optimal results. OK-432 is a lyophilized mixture of low-virulence group A Streptococcus

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pyogenes with penicillin G potassium. Intracystic injection therapy with OK-432 in lymphangioma was first reported in 1987

(4)

. The effectiveness and safety of are well known. Moreover,

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intracystic injection of OK-432 for lymphangioma

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the intracystic injection of OK-432 for lymphangioma has recently been the first-choice treatment in Japan. Ohta et al reported the mechanism and effectiveness of OK-432

injection therapy

(5)

. They measured the levels of various cytokines in each

aspirated fluid before and after the OK-432 injection therapy and showed significantly higher expressions of IL-6, IL-8, IFN-

, TNF-

, and VEGF than

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before the OK-432 injection therapy. These cytokines induce strong local inflammatory reactions in the cyst wall, resulting in fluid drainage, shrinkage, and

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fibrotic adhesion of the cyst.

OK-432 injection therapy is a very simple and easy method. It is,

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however, important to avoid OK-432 outflow from the puncture hole. We

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punctured the mucous membrane of the oral floor at a distance from the cyst wall to avoid OK-432 outflow from the puncture hole. However, this treatment method is unable to achieve a complete cure in all patients. From our data, the PR/NR group showed significantly larger values than the CR group. This

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indicates that OK-432 had a high therapeutic effect in smaller lesions. Recently, micro-marsupialization has been reported to have a high response rate for

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intraoral ranula treatment (9). In the near future, we plan to conduct a randomized

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control trial to assess the efficacies of different intraoral ranula treatment methods.

In conclusion, we evaluated the efficacy of OK-432 injection therapy for

intraoral ranula. We found that this treatment method was easy to perform and was less invasive than the other treatment methods. Moreover, OK-432 injection therapy showed a high efficacy rate. Thus, we believe that OK-432 injection

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therapy has the potential to become the first-choice treatment for intraoral ranulas. Moreover, the treatment combination of OK-432 injection therapy and

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surgery may be less invasive and highly curative for intraoral ranulas.

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Acknowledgement The authors thank Dr. Edward Barroga, Associate Professor and Senior

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Medical Editor from the Department of International Medical Communications of

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Tokyo Medical University for the editorial review of the manuscript.

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References

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1. Patel MR, Deal AM, Shockley WW. Oral and plunging ranulas: What is the most effective treatment? The Laryngoscope. 2009;119(8):1501-9. 2. Morita Y, Sato K, Kawana M, Takahasi S, Ikarashi F. Treatment of ranula--excision of the sublingual gland versus marsupialization. Auris, nasus,

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larynx. 2003;30(3):311-4. 3. Fukase S, Ohta N, Inamura K, Aoyagi M. Treatment of ranula wth intracystic injection of the streptococcal preparation OK-432. The Annals of Otology, Rhinology, and Laryngology. 2003;112(3):214-20.

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4. Ogita S, Tsuto T, Tokiwa K, Takahashi T. Intracystic injection of OK-432: a new sclerosing therapy for cystic hygroma in children. The British Journal of Surgery. 1987;74(8):690-1. 5. Ohta N, Fukase S, Watanabe T, Ito T, Aoyagi M. Effects and mechanism of OK-432 therapy in various neck cystic lesions. Acta Oto-laryngologica. 2010;130(11):1287-92. 6. Ohta N, Fukase S, Suzuki Y, Kurakami K, Aoyagi M, Kakehata S.

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OK-432 treatment of ranula extending to the parapharyngeal space. Acta Oto-laryngologica. 2014;134(2):206-10. 7. Lee HM, Lim HW, Kang HJ, Chae SW, Hwang SJ, Jung KY, et al. Treatment of ranula in pediatric patients with intralesional injection of OK-432.

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The Laryngoscope. 2006;116(6):966-9. 8. Zola M, Rosenberg D, Anakwa K. Treatment of a ranula using an Er,Cr:YSGG laser. Journal of Oral and Maxillofacial Surgery. 2006;64(5):823-7. 9. Woo SH, Chi JH, Kim BH, Kwon SK. Treatment of intraoral ranulas with micromarsupialization: clinical outcomes and safety from a phase II clinical trial. Head & Neck. 2015;37(2):197-201. 10. Sigismund PE, Bozzato A, Schumann M, Koch M, Iro H, Zenk J. Management of ranula: 9 years' clinical experience in pediatric and adult patients. Journal of Oral and Maxillofacial Surgery. 2013;71(3):538-44. 11. Roh JL. Primary treatment of ranula with intracystic injection of OK-432. The Laryngoscope. 2006;116(2):169-72.

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Figure legends

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Figure 1 a-f. Needle aspiration was performed from the normal submucosa using an 18 gauge needle away from the lesion (Fig. 1a-c). We prepared 0.1 mg of OK-432 powder which was dissolved with normal saline at the same

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aspiration volume (Fig. 1d). The aspiration syringe was replaced with an

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aspiration syringe that was filled with OK-432 solution while holding the 18 gauge needle that was injected into the cyst cavity. At this time, care must be taken so that the needle tip is not found outside of cyst cavity to avoid outflow of

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the injected OK-432 solution. Usually, if the needle tip is placed in the cyst cavity,

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the drug can be easily injected (Fig. 1e-f)

Figure 2 a-d. a and c indicate before treatment, whereas b and d indicate after

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treatment, which shows a complete response. MRI involved T2W1 imaging.

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Tables Table 1. Sex

Age

no.

Maximum

Aspiration

OK-432

Number of

length

volume

injection

injections

volume (years)

(mm)

(ml)

(ml)

27

40

5.0

5.0

2

2

F

66

18

2.0

2.0

1

M

48

16

25

1.0

1.0

2

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4

51

3.0

3.0

results

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F

F

Follow-up

Complications

period

(months)

1

3

Treatment

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Case

1

NR

8

CR

4

None Oral floor swelling Oral floor

NR

5 swelling Fever, Oral

CR

4 floor swelling

F

11

28

1.5

1.5

1

CR

3

Fever

6

M

9

15

1.0

1.0

1

CR

3

Fever

7

F

26

10

1.0

1.0

1

CR

3

Fever

8

F

26

30

6.0

6.0

1

PR

3

None

9

F

27

9.0

3

PR

24

11

F F

30

25

20

10

36

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12

F

40

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10

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5

9.0

2.0

Fever, Oral floor swelling Oral floor 2.0

1

CR

5 swelling Fever, Oral

2.0

2.0

4

CR

8 floor swelling

7

0.2

0.2

2

CR

4

None

13

F

22

19

1.0

1.0

2

CR

5

None

14

F

20

30

2.0

2.0

2

CR

4

Fever

15

F

27

8

0.2

0.2

1

CR

3

None

16

F

25

20

2.0

2.0

3

CR

6

None

17

M

9

10

0.5

0.5

2

CR

6

Fever, Oral floor swelling Fever, Oral

18

F

19

20

3.0

3.0

2

PR

5 floor swelling

19

F

22

13

0.2

0.2

1

CR

3

None

20

M

35

15

1.2

1.2

2

CR

5

None

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21

M

63

15

1.0

1.0

1

CR

3

22

F

23

25

2.5

2.5

2

CR

7

None Fever, Oral floor swelling Fever, Oral

23

F

32

20

2.0

2.0

1

CR

3

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floor swelling

NR, No response CR, Complete regression

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PR, Partial regression

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Table 2.

Differences in the numbers of treatment and maximum lesion length

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and aspiration volume

Number of injection times more than two times (SD)

p-value

18.18 (7.38) 1.80 (1.62)

21.00 (10.97) 2.45 (0.70)

0.58 0.46

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Lesion length Aspiration volume

one time (SD)

Student t-test

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Table 3. Differences between treatment results and lesion length and aspiration

Treatment results CR (SD) PR/NR (SD) Lesion length Aspiration volume

17.38 (7.10) 1.40 (0.83)

29.2 (11.09) 4.80 (1.35)

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volume

p-value 0.02 0.01

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Mann-Whitney U test

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Table 4. Analysis of relationship between therapy side effects and numbers of treatment and treatment results

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4 6

Treatment result CR PR/NR

10 3

8 2

0.50

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Number of treatment one time more than two times

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Therapy side effects appearance none p-value

0.85

CR, complete regression PR, partial regression

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NR, no response

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Chi-square test

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Table 5. Recurrence rate of each treatment method Sigismund et al. (10)

total cases

recurrence

%

complication

22

3

13.6

2

28

1

3.6

3

11

4

36.4

2

Complete sublingual gland excision

Aspiration

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OK-432

recurrence

%

complication

86

17

19.8

0

146

0

0

7

5

1

20

0

11

9

81.8

0

40

23

57.5

0

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Ranula excision

total cases

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Marsupialization

Patel et al. (1)

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Table 6. Summary of OK-432 injection therapy results median number of cases of intraoral type

injection

CR (%)

NR (%)

21

1,47

Lee et al. (7)

12

2,5 (2-4)

Roh et al. (11)

19

2.3 (1-5)

Our cases

23

1.7 (1-4)

Total

75

1.99

19 (90)

2 (9)

9 (75)

1 (8)

14 (74)

3 (15)

18 (78)

2 (8)

60 (80)

7 (9)

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Fukase et al. (3)

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(times)

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