This study was supported by grants from the Ministry of Education, Science, Sports, and Culture, Japan. The authors have no other funding, financial relationships, or conflicts of interest to disclose.
Although surgery is the treatment of choice for thyroglossal duct cysts, it can give rise to complications, including nerve injury, cyst recurrence, wound infection, and cosmetic problems. Use of a nonsurgical procedure could prevent these complications. Although simple aspiration of otolaryngological cystic diseases is a noninvasive treatment, cyst recurrence is commonly observed despite repeated aspiration. Ogita et al. reported in 1987 that OK-432 therapy was effective for lymphangioma.1 OK-432 was originally developed as an immunotherapeutic agent for cancer, but it is widely accepted that it is very effective in reducing ascites and pleural effusion in patients with carcinomatous peritonitis and pleuritis.1–4 When it is injected into the peritoneal or pleural cavity, reduction of ascites and pleural effusion occurs and adhesion of the cavity develops.5 OK-432 therapy is also effective for lymphangioma, branchial cleft cysts, salivary mucocele, auricular hematoma, thyroid cysts, cervical lymphocele, and plunging ranula,1–3, 6–14 but studies of the effectiveness of OK-432 in treating thyroglossal duct cysts have been rare.7, 8 The purpose of this study was to investigate the effectiveness of OK-432 therapy in patients with thyroglossal duct cysts.
MATERIALS AND METHODS
Seventeen patients with thyroglossal duct cysts underwent OK-432 therapy. One representative case is presented here. All patients except for a few that were at potential risk of airway obstruction were treated on an outpatient basis without hospitalization.
We aspirated as much of the fluid content of each cystic lesion as possible. To aspirate the contents sufficiently, compression of the cyst was sometimes needed. The aspirated fluid contents were admitted to pathological examination. After determining the capacity of the lesion, we prepared a sufficient quantity of OK-432 (picibanil; Chugai Pharmaceutical Co., Tokyo, Japan) diluted with saline solution (0.1–0.5 Klinische Einheit (KE)/mL; 0.01 to 0.05 mg/mL). With the same needle that was used for aspiration, we injected OK-432 solution (at a volume equal to about half that of the fluid removed) into the cyst by changing the syringe. There was no resistance in cases of successful injection into the cystic lesion.
All patients were regularly observed for a mean of 14.8 months (range, 4–46 months) after the last injection. To treat potential fever, analgesics were prophylactically given to all patients. Analgesic suppositories were also used as needed. The skin at the injection site became red and indurated the day after injection. On day 2 we punctured the skin over the otolaryngological cysts and aspirated the fluid. We examined all patients on days 2, 7, 14, and 28 after OK-432 injection and judged the response at 6 to 8 weeks. If the response was insufficient, we repeated the same therapy with a 100% increase in the volume of OK-432. Cure, marked reduction, and partial reduction of neck cysts were respectively defined as complete absence, a decrease of more than half, and a decrease of less than half, compared with the pretreatment size, as determined clinically or by computed tomography.
OK-432 therapy was performed in a total of 17 patients with thyroglossal duct cysts. The mean age was 36.4 years (range, 24–69 years). Maximum diameters of the cysts ranged from 2.1 to 6.8 cm (mean, 2.7 cm). The number of treatments ranged from one to five (mean, 2.2), and the mean follow-up period was 14.8 months (range, 7–46 months). The dose of OK-432 given at each treatment ranged from 1 to 3 KE (mean, 1.2 KE), and the total dose given ranged from 1 to 8 KE (mean, 2.5 KE), respectively. The outcome of OK-432 therapy in thyroglossal duct cysts seemed not to depend on the cyst size, cyst location, or the patient's age. Thirty-six treatments were performed on 17 lesions, but six of the 17 patients required only one treatment. Fourteen (82%) cases of thyroglossal duct cyst were cured (follow-up for more than 4 months after the last injection with no recurrence) after one to five injections of OK-432 solution. After receiving a maximum of three injections of OK-432, one (6%) patient had marked reduction and one patient had a partial reduction in cyst size. One patient showed no response to OK-432 therapy after three OK-432 injections. A typical case of thyroglossal duct cysts is shown in Figure 1. Subtotal shrinkage after five OK-432 injections was observed in this patient.
There were no serious complications, although patients experienced fever (37.5°C to 38.5°C) for a few days after injection. It was usually controlled by antipyretics. No infection or abscesses developed after OK-432 injection. None of the patients had evidence of scarring of the skin at the injection site. All patients received therapy on an outpatient basis without hospitalization, with the exception of a few that were at risk of airway obstruction.
Surgery is considered to be the treatment of choice for various otolaryngological cystic diseases, but surgical complications, including nerve injury, cyst recurrence, and cosmetic problems can occur. It has been reported that OK-432 therapy may become a first-line treatment for lymphangioma.1–3 OK-432 is a lyophilized streptococcal preparation made from the Su strain of group A Streptococcus pyogenes incubated with penicillin.4 It was originally developed as an immunotherapeutic agent for cancer.1–5 We reported previously that OK-432 therapy is effective in the treatment of ranula, auricular hematoma, and salivary mucocele,9, 12–14 and Roh et al. have demonstrated that OK-432 therapy is effective in the treatment of branchial cleft cysts.10 OK-432 seems to be safer and more effective than other sclerosing agents, such as boiling water, hypertonic saline, ethanol, tetracycline, cyclophosphamide, sodium morrhuate, and bleomycin.7 Although the complication rates of treatment with these sclerosing agents are minimal, limited success and unpredictable local scarring, as well as systemic side effects caused by spread of the agents beyond the endothelial lining of the lesion, have been observed. Bleomycin, in particular, can have serious side effects, including fibrosis of the lung, independent of the total dosage.7 The complication rate of OK-432 is minimal, and use of this agent does not require local anesthesia or patient hospitalization and leaves no scar on the skin at the injection site. From the point of cost effectiveness, OK-432 therapy is inexpensive and requires no special equipment or medication. All patients received the therapy on an outpatient basis without hospitalization, except in a few patients who had a potential risk of airway obstruction with a cyst deep to the hyoid as shown in Figure 1. Benefits of OK-432 therapy over surgical excision are summarized as follows: 1) the time taken for the procedure is brief, and it seems particularly suitable for children and other patients who cannot tolerate long procedures; 2) no local anesthesia is required during treatment; 3) the treatment is painless, so children and nervous patients can be treated readily; and 4) secondary infection and hemorrhage are rare. OK-432 therapy is economically and cosmetically more advantageous than surgery and could be considered as a possible alternative therapy.7, 12–14 With regard to long-term follow-up results, Yoo et al. reported that in 55 lymphangioma patients who underwent OK-432 therapy, initial and the long-term response rates were equally good; initial response rates were 83.5%, and long-term follow-up (30–144 months) response rates were 76.3%.15 The fluid content of each cystic lesion was aspirated as much as possible and admitted to pathological examination in case of the coexistence of carcinoma. However, the coexistence of carcinoma in the thyroglossal duct is extremely rare, with most being papillary carcinomas, but the possibility should be kept in mind.16
The mechanism underlying the effectiveness of OK-432 therapy is very strong production of interleukin (IL)-6, IL-8, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and vascular endothelial growth factor, as found in fluids aspirated after OK-432 therapy. When OK-432 is administered locally, inflammatory cells such as neutrophils and monocytes infiltrate the cyst, and various cytokines, including IL-6, IL-8, IFN-γ, and TNF-α are secreted.7, 12–14 These cytokines induce strong local inflammatory reactions in the cyst wall, resulting in fluid drainage, shrinkage, and fibrotic adhesion of the cyst.7, 12–14
Our study is the first to show the efficacy of OK-432 therapy in thyroglossal duct cysts. OK-432 therapy does not require patient hospitalization, except in patients at risk of airway obstruction, and it does not scar the skin at the injection site. OK-432 therapy has economic and cosmetic advantages over surgery and can be used several times, if needed, as a primary treatment for thyroglossal duct cysts. Surgery is recommended only for limited cases in which there is a poor or no response to OK-432 therapy.
Our results suggest that the treatment of thyroglossal duct cysts by OK-432 is a simple, easy, safe, and effective therapy that results in complete or a significant decrease in the volume of thyroglossal duct cysts. This therapy is a potentially curative procedure that may be used as a first-choice treatment for thyroglossal duct cysts before considering a surgical procedure.
This manuscript is dedicated to Professor Masaru Aoyagi, Chairman, Department of Otolaryngology, Yamagata University School of Medicine, Yamagata, Japan, who recently retired.