Eur Arch Otorhinolaryngol (2002) 259 : 274–278 Jussi Laranne · Leo Keski-Nisula · Riitta Rautio ·
Markus Rautiainen · Mari Airaksinen

OK-432 (Picibanil) therapy for lymphangiomas in children Received: 20 July 2001 / Accepted: 26 October 2001 Abstract Lymphangiomas are benign, soft tumors that
sent as soft, non-tender masses. Lymphangiomas may most often affect the head and neck area, usually causing cause marked disfigurement, recurrent infections, respira- marked cosmetic and functional problems. Treatment op- tory obstruction, malocclusion, dysphagia, dysphonia and tions include surgery and a large number of different scle- dysarthria as a result of the infiltration and compression of rotherapy agents. Surgical treatment is challenging be- neighboring structures. On the basis of their histological cause of the need for complete excision. The risk of dam- appearance, lymphangiomas are classified as capillary, age to surrounding structures or poor cosmetic results is cavernous or cystic and contain dilated lymphatic spaces high. Various sclerotherapy agents have been shown to in sizes ranging from small channels to large cysts. Often have minimal effects on lymphangiomas. Their use has the lesions are a combination of these subtypes and may been associated with severe systemic, local and cosmetic also contain hemangiomatous components [l]. Otolaryn- side effects. OK-432 (Picibanil) is a new and promising gologic manifestations are common since the head and form of sclerotherapy. An intracystic injection of OK-432 neck region is the most often affected area [6]. Further- produces a local inflammatory reaction, which leads to more, lesions involving the lip, hypopharynx, larynx, resolution of the lesion. We have treated 11 pediatric lym- tongue and floor of the mouth have high rates of recurrent phangioma patients with OK-432 with excellent results: or persistent disease [11]. Spontaneous regression is un- complete regression in six, marked regression in four and no response in one case. Local swelling should be antici- Complete and meticulous surgical excision is the text- pated, especially when treating lesions near the upper air- book recommendation for the primary approach to lym- way. We found OK-432 injections to be safe and effective phangiomas. However, complete excision is often impos- as a first line of treatment for lymphangiomas.
sible due to the risk of damage to vitally or functionallyimportant surrounding structures. In addition, the cos-metic outcome after such radical surgery may be unac- ceptable, especially in children, because it is an essen-tially benign lesion.
To avoid complications of surgical therapy, several Lymphangiomas are relatively rare congenital malforma- treatment options, including laser therapy [5], interferon- tions of the lymphatic system. They make up approxi- alpha [12] and various intralesional sclerosing agents, i.e., mately 6% of all benign lesions in children [11], occur steroids, hypertonic saline, ethanol, and bleomycin, have typically in patients younger than 2 years of age and pre- been used to treat lymphangiomas, usually with little suc-cess. Intralesional injections of sclerosing agents are asso-ciated with a risk of extensive scar formation, resulting in cosmetically unacceptable results and making eventual Department of Otolaryngology, Head and Neck Surgery, later surgical procedures more difficult. In addition, other local and systemic side effects, such as pulmonary fibro- P.O. Box 2000, 33521 Tampere, Finlande-mail: [email protected] sis with bleomycin, make most sclerosants unsatisfactoryforms of treatment.
OK-432 (Picibanil, Chugai Pharmaceutical Co, Tokyo) Department of Radiology, Tampere University Hospital, P.O. Box 2000, 33521 Tampere, Finland is a lyophilized biological preparation containing the cellsof Streptococcus pyogenes (group A, type 3, strain Su) treated with benzylpenicillin. It has been used in Japan Department of Pharmacy, Tampere University Hospital, P.O. Box 2000, 33521 Tampere, Finland primarily as immunotherapy for malignant tumors. The Table 1 Results of OK-432 therapy
first report of its use for the treatment of lymphangiomas microcystic component in four cases. There were seven boys and was published in 1987 [9]. Since then, more reports with four girls with a mean age of 5.5 years (9 months–13 years) at thetime of the first injection. Four patients had been operated on, and good results and without any serious side effects have one had received interpheron-alpha without success prior to the been published [1, 3, 6, 8, 12, 13, 14]. We report our re- sults using OK-432 in the treatment of lymphangiomas in All treatments were performed under general anesthesia, and the number of treatments per patient ranged from one to seven(Table 1). Lymphangiomas were punctured under ultrasound guid-ance, and a small amount of contrast was injected into the cysts todefine the position of the needle and dimensions of the lesion. In- tracystic fluid was aspirated, and an equal volume of 0.01 mg/mlOK-432 solution was injected into the lesions. In one patient Eleven children with lymphangioma were treated with OK-432 at with a large cystic lesion in the hypopharynx (case 6), a pretreat- Tampere University Hospital between 1998 and 2000. The diagno- ment tracheotomy was performed as a safety measure. Following the sis was made after clinical and radiological examinations. All lym- treatment, the patients were monitored in the hospital for 24– phangiomas were considered to be macrocystic, but with a mixed Fig. 1 MRI-images of patient no. 3. *Lymphangioma in the right axilla: a before treatment, b complete regression after one OK-432 in-
Fig. 2 MRI-images of patient no. 2. *Lymphangioma behind the
right sternocleidomastoid muscle: a before treatment, b complete
lems it may cause. Especially in the head and neck region, acute complications such as airway obstruction and prob-lems with swallowing and speech production may arise.
Complete regression was observed in six patients, marked Lesions in this region also cause a notable cosmetic prob- regression in four and no response in one patient (Table 1).
In patients with complete regression, no recurrence has In a recent review of pediatric lymphangiomas, Orvi- been observed during the follow-up period (Fig. 1, Fig. 2, das and Kasperbauer [11] recommend that meticulous sur- gical excision should be the primary approach to treat All patients with complete regression had not been op- these lesions. On the other hand, they report a quite re- erated on or otherwise treated prior to sclerotherapy with markable 20% incidence of permanent cranial nerve in- jury in their own study involving 49 patients. Further- Swelling, slight tenderness and fever continuing for more, there was a positive correlation between the num- 2–4 days after the injection were noted in each case. In ber of surgical procedures and the surgical complications.
case no. 6 (Fig. 4), marked soft tissue swelling developed This underlines the importance of complete removal of following the first treatment, and the decision to perform the lesion during the primary operation.
a pretreatment tracheotomy served the patient well. Dur- Particularly in the head and neck region, this is often ing the following treatments, tracheotomy was not extremely difficult, and the operation has to be staged, needed. In other patients, serious side effects were not en- leading to an increased risk of surgical complications.
countered, and the local inflammation did not cause scar Thus, when dealing with complicated lymphangiomatous formation or damage to the overlying skin.
lesions in the head and neck area, one might primarilyconsider non-surgical treatment options.
The spontaneous infection of lymphangioma can lead to total regression of the lesion. This finding has led to the Even though lymphangioma is a benign lesion, some kind idea of using intracystic sclerosing agents. The mecha- of treatment is necessary because of the potential prob- nism behind a sclerosant involves the destruction of the Fig. 3 CT-images of patient no. 6. *A large lymphangioma in the
neck compressing the larynx and hypopharynx: a before treatment,
b marked regression after three OK-432 injections
epithelial lining of the cysts, with the following decrease lesions respond better than cavernous or microcystic ones in fluid production and collapse of the lesion. So far, the because of greater communication between the intrale- best results have been obtained with bleomycin. Orford et sional spaces, which allows for better diffusion of the al. [10] report good or excellent results in 88% of their sclerosing agent throughout the lesion.
cases. However, with bleomycin there is a small risk of Our results seem to be in line with the previously pub- pulmonary fibrosis developing as a complication, and lished studies. Complete regression was observed in six therefore, its use has virtually been abandoned. The use of patients, marked regression in four and no response in alcohol (Ethibloc) has led to mediocre results with subse- one. In our study, it appears that previous, unsuccessful quent scar problems [4]. Recently, good results have been surgical treatment hampers the sclerosing effect of OK- obtained by intracystic injections of a fibrin sealant (Tis- 432. Only marked regression or no response was observed sucol) in simple, monocystic lymphangiomas [2].
in this group. Postoperative intralesional scar formation OK-432 is produced by incubating a culture of a low obviously hinders the sclerosing agent’s diffusion through virulence, SU strain of type III, group A Streptococcus the lymphangioma, thus giving only partially satisfactory pyogenes of human origin with penicillin G potassium results. For this reason, we feel that OK-432 should be followed by the lyophilization of the incubation mixture.
used as the primary form of treatment for lymphangio- This results in the complete disappearance of the strep- mas, and surgery should be considered only if sclerother- tolysin S-producing ability [7]. In lymphangioma, an in- tracystic injection of OK-432 produces an inflammatory Here, we report the first serious side effect with OK- reaction leading to the destruction of the epithelial lining 432. In case no. 6, soft tissue swelling after the first treat- and the subsequent sclerosis and cicatricial contraction of ment was quite marked and resulted in hypopharyngeal the lesion. The only common side effects reported in pre- edema with swallowing problems and a relative airway vious studies have been fever and a local inflammatory re- obstruction. This resolved in 5 days, and the tracheotomy tube eventually was removed without further problems.
In seven different studies [1, 3, 6, 8, 12, 13, 14], a total Since the local inflammatory reaction with swelling is a of 64 children with lymphangiomas have been treated normal response to the treatment, one should keep in with OK-432, and the combined results show total shrink- mind and be prepared for possible airway obstruction age in 31, marked shrinkage in 10, slight shrinkage in 12 when treating paratracheal or hypopharyngeal lesions and no response in 11 patients. It appears that macrocystic Fig. 4 Patient no. 6: a follow-
ing the first OK-432 injection
a marked soft tissue swelling
in the neck and laryngopharyn-
geal region developed; b com-
plete regression after four OK-
432 injections
Our results and those of the previously published stud- 6. Greinwald JH, Burke DK, Sato Y, Poust RI, Kimura K, Bau- ies show that OK-432 is safe and effective in the treat- man NM, Smith RJH (1999) Treatment of lymphangiomas inchildren: an update of Picibanil (OK-432) sclerotherapy. Oto- ment of lymphangiomas. It can be considered as the first line of treatment, especially in cases where surgical treat- 7. Ishida N, Hoshimoto T (1985) A streptococcal preparation as a ment is associated with the possibility of serious func- potent biological response modifier OK-432, 2nd edn. Amster- 8. Luzatto C, Midrio P, Tchaprassian Z, Guglielmi M (2000) Sclerosing treatment of lymphangiomas with OK-432. ArchDis Child 82: 316–318 9. Ogita S, Tsuto T, Tokiwa K, Takahashi T (1987) Intracystic in- jection of OK-432: a new sclerosing therapy for cystic hy- 1. Brewis C, Pracy JP, Albert DM (2000) Treatment of lymphan- groma in children. Br J Surg 74: 690–691 giomas of the head and neck in children by intralesional injec- 10. Orford J, Barker A, Thonell S, King P, Murphy J (1995) tion of OK-432 (Picibanil). Clin Otolaryngol 25: 130–134 Bleomycin therapy for cystic hygroma. J Ped Surg 30: 1282– 2. Castanon M, Margarit J, Carrasco R, Vancells M, Albert A, Morales L (1999) Long-term follow-up of 19 cystic lymphan- 11. Orvidas U, Kasperbauer JL (2000) Pediatric lymphangiomas of giomas treated with fibrin sealant. J Pediatr Surg 34: 1276– the head and neck. Ann Otol Rhinol Laryngol 109: 411–421 12. Reinhardt MA, Nelson SC, Sencer SF, Bostrom BC, Ku- 3. Claesson G, Gordon L, Kuylenstierna R (1998) Japansk metod racheck SC, Nesb ME (1997) Treatment of childhood lym- revolutionerar behandlingen av lymphangiom. Läkartidningen phangiomas with interferon-alpha. J Pediatr Hematol Oncol 19: 4. Dubois J (1997) Lymphangiomas in children: percutaneous 13. Schmidt B, Schimpl G, Höllwarth ME (1996) OK-432 therapy sclerotherapy with an alcoholic solution of zein. Radiology of lymphangiomas in children. Eur J Pediatr 155: 649–652 14. Smith RJH, Burke DK, Sato Y, Poust RI, Kimura K, Bauman 5. Eyrich GK, Bruder E, Hilfiker P, Quick HH, Patak MA, Grat NM (1996) OK-432 therapy for lymphangiomas. Arch Oto- KW, Sailer HF (2000) Temperature mapping of magnetic reso- nance-guided laser interstitial thermal therapy (LITT) in lym-phangiomas of the head and neck. Lasers Surg Med 26: 467–476

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Andrea’s help sheet on preparing solutions

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