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OK-432 injection therapy for cystadenocarcinoma of the parotid gland: a case report.

Abstract

OK-432 is an immunomodulator that has been reported to be efficacious as an injection therapy for cervical lymphomas and ranulas. We performed OK-432 injection therapy to treat a cystadenocarcinoma of the parotid gland in a 72-year-old man. The 50 x 46-mm tumor was located in the deep lobe of the gland. The tumor had compressed the glossopharyngeal, vagus, and hypoglossal nerves, causing neurally mediated syncope, hoarseness, dysphagia, and dysarthria. A concentration of 5 KE/2 ml of OK-432 was injected. Within 2 months, the cyst had disappeared; no recurrence was apparent during 59 months of follow-up. To the best of our knowledge, no previous report has described injection of OK-432 for malignant cystic disease. We describethe injection method, injection dose, and postinjection course in the hope that this information will prove useful for future applications against malignant cystic disease.

Introduction

OK-432 is a lyophilized bacterial immunomodulator in which Streptococcus pyogenes (group A, type 3), a hemolytic streptococcal organism, is processed under fixed conditions in the presence of benzylpenicillin (penicillin G). OK-432 is measured in units of klinische Einheit (KE), each of which represents 0.1 mg of dried streptococci of standard quality according to various tests, including those for safety and antitumor activity. (1,2) This agent, which was developed in Japan, acts to (1) directly inhibit proliferation of tumor cells and (2) activate immune cells. OK-432 generates T-helper cell 1 cytokines such as interleukin (IL) -12 and interferon gamma, as well as IL-1, IL-2, and tumor necrosis factor alpha. (2-4) OK-432 also has been shown to enhance natural killer cell activity. (4,5)

OK-432 is reportedly effective against cystic diseases of the head and neck, but to the best of our knowledge, no previous reports have described the use of OK-432 injection to treat malignant cystic disease. In this article, we describe such a case in the hope that an understanding of the injection method, injection dose, and postinjection course will prove useful in future applications for malignant cystic disease.

This report was approved by the internal ethics committee at our institution, and the possibility of reporting the case and publishing the images was raised with the patient, who provided written consent.

Case report

Our patient was a 72-year-old man. Seven years earlier, he had undergone a deep lobectomy to remove a tumor of the deep lobe of the left parotid gland. At that time, the initial examination revealed no paralysis of the facial, glossopharyngeal, vagus, accessory, or hypoglossal nerves.

Magnetic resonance imaging (MRI) identified the presence of a cystic tumor with a maximum diameter of 38 mm. After deep lobectomy was performed to remove the cyst, histologic examination identified the tumor as an adenocarcinoma. Carcinoma cell populations with bleeding were attached to the lumen side of the cyst. No tumor cell invasion of the cyst wall was identified.

Postoperatively, 50 Gy of radiation was administered at 2 Gy/day to an area from the parotid gland to the neck. No remaining tumor was evident on MRI 4 months after surgery.

Four years and 3 months later, the patient developed hoarseness, followed 1 to 2 weeks later by the onset of dysarthria and dysphagia. We reexamined him on an outpatient basis 4.5 years after the lobectomy. Our examination identified tumefaction measuring 30 x 35 mm under the left ear. MRI demonstrated a 50 x 46-mm cystic lesion that had advanced from the left parotid gland to the parapharyngeal space (figure 1). The properties of this lesion were the same as those seen in the preoperative MRI 4.5 years earlier.

[FIGURE 1 OMITTED]

We diagnosed the lesion as a recurrent cystadenocarcinoma of the parotid gland. Examination also revealed paralysis of the left hypoglossal nerve and the left glossopharyngeal nerve. Left vocal fold paralysis was seen on fiberoptic laryngoscopy. Fine-needle aspiration cytology identified the recurrent tumor as a class V lesion.

During the subsequent weeks, the patient experienced a loss of consciousness several times, so a detailed examination was performed in the Department of Cardiovascular Medicine at our institution. The patient was diagnosed with neurally mediated syncope secondary to pressure on the vagus nerve exerted by the cyst. Several more episodes of a loss of consciousness occurred subsequently.

[FIGURE 2 OMITTED]

Surgical removal of the cyst was considered but was thought to be risky given the possibility of damage to the internal carotid artery or vagus nerve. Instead, OK-432 was injected with the aim of shrinking the cyst, thereby reducing nerve compression and eliminating the cause of the neurally mediated syncope. The patient provided written consent for the OK-432 treatment after the potential risks and benefits had been explained.

OK-432 injection was performed in an operating room under ultrasonographic guidance for the purpose of confirming the position of the needle within the cyst. A 22-gauge Cathelin needle was advanced 4 cm, and 20 ml of viscous brown fluid was aspirated from inside the cyst. Next, 5 KE/2 ml of OK-432 was injected into the cyst.

One day after the injection, the patient developed a fever of 38[degrees]C, and swelling appeared from the soft palate to the left pharyngeal wall on the side of the injection. Fiberoptic laryngoscopy revealed swelling in the pharynx. Swelling was also present from the epiglottis to the arytenoid area of the larynx. Edema was most severe on the third day after injection.

Beginning on postinjection day 2, hydrocortisone was administered for 5 days. The dosage was 300 mg/day on the first day, 200 mg/day on the second and third days, and 100 mg/day on the fourth and fifth days. Although edema of the pharynx and larynx and fever were observed, no mucositis or abscess was identified, so neither culture nor antibiotic therapy was deemed necessary. Mild respiratory distress occurred on the second day after injection, and stridor was also heard, but no severe respiratory discomfort was observed, and no endotracheal intubation or tracheotomy was required.

Five days after the injection, the fever diminished and the swelling in the soft palate, pharyngeal wall, and larynx decreased.

MRI performed just after the injection showed no change in the size of the cyst. However, a repeat MRI obtained 2 months later showed that the cyst had disappeared (figure 2).

After OK-432 therapy, the patient experienced no further episodes of losing consciousness. His symptoms of dysarthria and dysphagia began subsiding 3 months after injection, and improvements in soft palate and tongue movements were observed at the 4-month follow-up. At follow-up after 15 months, both the glossopharyngeal and hypoglossal nerve paralysis had resolved, and vocal fold motions on the left also had resumed.

At 59 months, the patient showed no signs of hoarseness and no findings indicative of tumor recurrence on MRI, and his quality of life was markedly improved.

Discussion

Method of injection. In ranulas, the cyst contents are very viscous, and an 18-gauge needle is needed for aspiration. (6) A 20-gauge needle is used for lymphangiomas because the fluid within is serous and can be aspirated with a thin needle. (7) We used a 22-gauge needle in the present case because we were concerned about disseminating cancer cells if we had punctured the cyst with a thicker needle.

Although a response was achieved in the present case with only a single administration, multiple injections of OK-432 have previously been used for treating stomach cancers, cervical lymphangiomas, ranulas, and cancers of the head and neck. (6,9) Ogita et al reported using OK-432 injections for cervical lymphangioma in 23 patients; all but 1 received multiple injections. (8) The largest number of injections in a single patient was 12. Fukase et al used 1 to 5 injections for treating ranulas in 32 patients. (6) Other authors have reported using 2 to 5 injections. (7,9)

In our case, the needle had to pass through skin, muscle, and the shallow lobe of the parotid gland before it could enter the cyst. Thus, the shallow lobe adjacent to the cyst might have been affected in some way by the OK-432 injection. We were also concerned about the risk of disseminating cancer cells through multiple punctures and aspiration procedures. Because there was no assurance that multiple injections would be possible or advisable, our approach from the beginning was to obtain therapeutic effects with a fairly large dose of OK-432 in a single injection.

Since no previous reports have described OK-432 injection for malignant cystic disease, we struggled with regard to choosing the concentration and amount of OK-432 to be injected. Various reports have described the concentration of injected OK-432 for ranulas with a relatively low concentration of 0.1 KE/ml. (6,10-12) Similarly, low concentrations of 0.1 to 0.2 KE/ml have been used for treating lymphangiomas. (7,9,13) In cases of carcinomatous pleuritis, large doses of OK-432 at concentrations of 10 KE/10 ml (14) and 5 KE/50 ml (15) have been reported; these large doses were injected so that OK-432 could be dispersed over an extensive area. In our case, we ultimately decided to use a large dose to achieve rapid alleviation of symptoms.

Effects of injection into the laryngopharynx. In our case, the patient developed a fever of 38[degrees]C on the day after the injection. On fiberscopic examination, edema-like swelling was seen from the soft palate to the left pharyngeal wall on the side of the injection. Swelling was also present from the epiglottis to the arytenoid area of the larynx. The edema was most severe on the third day after the injection. In addition, mild respiratory distress occurred on the second day after the injection, and stridor was also heard.

Tanaka and Sato reported 11 cases of carcinomatous pleuritis treated with intrapleural injections of 5 KE of OK-432 and 100 mg of minocycline. (15) Fever developed 6 hours after injection in the earliest instance, and continued until day 6 after injection in the latest instance. In all cases, the amount of pleural effusion drainage decreased after the emergence of fever. Tanaka and Sato also observed an increase in the neutrophil count that corresponded with the timing of the fever, and thus considered this increase as the cause of the fever. (15) Fever is thought to represent an important sign predicting the efficacy of OK-432 injection.

The cyst in our patient grew into the parapharyngeal space, where it compressed the carotid artery and jugular vein. Postinjection edema was attributed to the effect of OK-432 on the carotid artery and jugular vein via the cyst wall. Injection of the high concentration of 5 KE/2 ml might have caused circulatory impairment in the carotid artery and jugular vein.

Postinjection course. Follow-up MRI revealed that the cyst had disappeared within 2 months of the injection. Ikarashi et al reported that a 1-KE injection of OK-432 in a patient with cervical cystic lymphangioma had little effect, but 4 months after the patient received a second injection of 3 KE, computed tomography showed a complete disappearance of the lymphangioma.16 Watari et al injected 0.1 KE for a ranula and reported no shrinkage 1 month later; a second injection at the same dose resulted in shrinkage 2 to 4 weeks later. (10)

In our patient, the effects of OK-432 were seen within 2 months after a single injection. The volume of cystic fluid in our patient was about 100 ml, so the disappearance of such a large cyst with a single injection was surprising.

Our findings suggest a potential for expanding the indications for OK-432 injection.

References

(1.) Uchida A, Hoshino T. Clinical studies on cell-mediated immunity in patients with malignant disease. I. Effect of immunotherapy with OK-432 on lymphocyte subpopulation and phytomitogen responsiveness in vitro. Cancer 1980;45(3):476-83.

(2.) Fujimoto T, Duda RB, Szilvasi A, et al. Streptococcal preparation OK-432 is a potent inducer of IL-12 and a T helper cell 1 dominant state. J Immunol 1997;158(12):5619-26.

(3.) Fujii M, Abo T, Kumagai K. Cytokines produced by blood mononuclear cells stimulated with the streptococcal preparation OK-432: Effect on production by supplementing the medium with xenogeneic serum. Cancer Immunol Immunother 1988;27(2):97-102.

(4.) Kim SY, Park HC, Yoon C, et al. OK-432 and 5-fluorouracil, doxorubicin, and mitomycin C (FAM-P) versus FAM chemotherapy in patients with curatively resected gastric carcinoma: A randomized phase III trial. Cancer 1998;83(10):2054-9.

(5.) Chirigos MA, Saito T, Talmadge JE, et al. Cell regulatory and immunorestorative activity of Picibanil (OK432). Cancer Detect Prev Suppl 1987;1:317-28.

(6.) Fukase S, Ohta N, Inamura K, Aoyagi M. Treatment of ranula with intracystic injection of the streptococcal preparation OK-432. Ann Otol Rhinol Laryngol 2003;112(3):214-20.

(7.) Giguere CM, Bauman NM, Sato Y, et al. Treatment of lymphangiomas with OK-432 (Picibanil) sclerotherapy: A prospective multi-institutional trial. Arch Otolaryngol Head Neck Surg 2002;128(10):l 137-44.

(8.) Ogita S, Tsuto T, Deguchi E, et al. OK-432 therapy for unresectable lymphangiomas in children. J Pediatr Surg 1991;26(3):263-8; discussion 268-70.

(9.) Smith RJ, Burke DK, Sato Y, et al. OK-432 therapy for lymphangiomas. Arch Otolaryngol Head Neck Surg 1996;122(11):1195-9.

(10.) Watari H, Yamada H, Fujino T, et al. A case of intrauterine medical treatment for cystic hygroma. Eur J Obstet Gynecol Reprod Biol 1996;70(2):201-3.

(11.) Watanabe K, Tomiyama S, Jinnouchi K, et al. Local injection of OK-432 in the treatment of ranula: A case report. Ear Nose Throat J 2002;81(2):97-8.

(12.) Rebuffini E, Zuccarino L, Grecchi E, et al. Picibanil (OK-432) in the treatment of head and neck lymphangiomas in children. Dent Res J (Isfahan) 2012;9(Suppl 2):S192-6.

(13.) Claesson G, Gordon L, Kuylenstierna R. A revolutionary Japanese method for treatment of lymphangioma [inSwedish], Lakartidningen 1998;95(18):2074-7.

(14.) Yamaguchi Y, Satoh Y, Miyahara E, et al. Locoregional immunotherapy of malignant ascites by intraperitoneal administration of OK-432 plus IL-2 in gastric cancer patients. Anticancer Res 1995;15(5B):2201-6.

(15.) Tanaka A, Sato T. Adhesion therapy for malignant pleural effusion (intrapleural administration of OK-432 with minocycline) [in Japanese]. Nihon Kokyuki Gakkai Zasshi 1999;37(7):531-7.

(16.) Ikarashi T, Inamura K, Kimura Y. Cystic lymphangioma and plunging ranula treated by OK-432 therapy: A report of two cases. Acta Otolaryngol Suppl 1994;511:196-9.

Kiyoshi Makiyama, PhD, MD; Ryoji Hirai, PhD, MD; Fusako Iikuni, MD; Atsuo Ikeda, MD; Hirotaka Tomomatsu, MD

From the Department of Otorhinolaryngology, Nihon University Hospital, Tokyo.

Corresponding author: Kiyoshi Makiyama, PhD, MD, Department of Otorhinolaryngology, Nihon University Hospital, 1-6 Kandasurugadai, Chiyoda, Tokyo 101-8309, Japan. Email: mak@med.email.ne.jp
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Title Annotation:ORIGINAL ARTICLE
Author:Makiyama, Kiyoshi; Hirai, Ryoji; Iikuni, Fusako; Ikeda, Atsuo; Tomomatsu, Hirotaka
Publication:Ear, Nose and Throat Journal
Article Type:Report
Date:Apr 1, 2016
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