lymphangiomas ( lms ) are congenital malformations of the lymphatic system consisting of lymphatic channels and cystic spaces of varying size . they often occur in the head and neck region ( 75% of all cases ) and represent about 5% of all benign neoplasm in infants and children . their incidence in the literature is quite variable raging from 4/10,000 to 1/16,000 births and no significant gender or racial difference in lms incidence has been reported . up to 90% of lms the ordinary clinical presentations of lms are slowly growing , painless , soft , and compressible masses , which are usually asymptomatic . they often cause cosmetic deformities in the maxillofacial area , while lesions of the upper aero - digestive tract ( mouth floor , hypo - pharynx , and larynx ) may have functional consequences , such as airway obstruction or dysphagia . neck lesions may cause torcicollis , whereas peri - orbital lms may produce globe displacement and decrease visual acuity . basing on cysts size , lms are divided into macrocystic ( lesions with cysts larger than 2 cm ) , microcystic ( cysts smaller than 2 cm ) , and mixed lesions . in particular , ultrasound ( us ) and magnetic resonance imaging ( mri ) are essential for lms identification and differential diagnosis from other vascular malformations ( vms ) , branchial and thyroglossal cysts or thyroid mass . observation is usually not recommended especially in case of enlarging lms , since spontaneous regression occurs in only 6 - 15% of lms . even though the surgical removal is generally considered the first choice treatment of lms , the need of extensive approaches to attain the complete removal of the lesion may cause anesthetic and functional consequences . in order to avoid such consequences , nonsurgical approaches have been proposed , such as picibanil ( ok-432 ) , a lyophilized biological preparation containing cells of streptococcus pyogenes su - strain treated with benzylpenicillin . even though some japanese authors reported the efficacy of ok-432 to produce a sclerosis of cystic spaces in lms , the cumulative literature on this topic remains limited , particularly in pediatric patients outside japan . we present our experience in children and infants affected by macrocystic lms treated with local injections of ok-432 at the department of pediatric maxillofacial surgery , children 's hospital of brescia ( italy ) . local response and possible side effects of our treatment have been recorded . between september 2005 and october 2010 , 15 consecutive caucasian children ( 7 m , 8 f ; mean age : 28.9 months ; age range : 6 - 60 months ) with head and neck macrocystic lms . were treated with ok-432 at the department of pediatric maxillofacial surgery , children 's hospital of brescia ( italy ) . all the patients underwent physical examination , laboratory analysis ( complete blood cell count , electrolyte analysis , serum creatinine , and urinalysis ) , medical photography , and imaging ( us and mri ) . lms location was as follows : lateral - cervical region ( 4/15 cases ) , sovraclavear region ( 2/15 ) , submandibular region ( 3/15 ) , and maxillofacial region ( 6/15 ) . among them , 3/15 patients had been previously submitted to lm surgical excision with local recurrence within 6 months [ table 1 ] . consecutive lm patients treated with picibanil ( ok-432 ) after an accurate informed consent ( including treatment modalities and possible side effects ) , in which patients parents were offered to submit their kids to ok-432 lm injection as a  not currently approved ( for the italian law )  alternative to traditional surgical excision , the parents accepted to submit their children to picibanil treatment . after an accurate examination of the medical literature , the ethics committee of our hospital approved the use of ok-432 intralesional injection in children affected by lms , even though such use is not among the currently approved indications for picibanil . all 15 children were submitted to intralesional injection of ok-432 ( chugai pharmaceutical co , tokyo , japan ) in the operating room in general anesthesia . under us guidance , a 25-g needle was introduced into lm cystic spaces , the cystic fluid was aspirated , and the ok-432 solution was instilled . in each session , 0.2 mg of picibanil was injected . based on the literature , in case of lm incomplete shrinkage , second and third ok-432 injections were performed 6 months after the previous session . antibiotic prophylaxis ( amoxicillin + clavulanic acid 50 mg / kg twice a day per os for 6 days ) was administered . all side - effects and complications , such as fever , swelling , pain , redness , indurations , or respiratory difficulties , were recorded [ table 1 ] . clinical , photographic , and imaging assessment was performed 3 , 12 , and 24 weeks after each session to determine lm shrinkage . as suggested by rautio et al . ( > 50% of the initial volume ) ,  moderate  ( < 50% of the initial volume ) , or three weeks after the first injection of 0.2 mg picibanil , we observed a complete clinical disappearance of lm in 5 ( 33.33% ) cases [ figures 1 - 3 ] , a marked reduction in 2 ( 13.33% ) patients , a moderate response in 2 ( 13.33% ) , and no response in 6 ( 40% ) children . among the 10 patients submitted to a second ok-432 injection 6 months after the first session , 3 children presented lm complete disappearance , 1 a marked reduction , 3 a moderate shrinkage , and 3 no response . among the 7 patients submitted to a third picibanil injection 6 months after the second session , 5 patients presented a marked reduction and 2 patients showed a moderate response [ table 1 ] . among the 8 kids who had a complete clinical response , 1 ( 12.5% ) regardless of the medical evaluation , all children 's parents reported a satisfactory aesthetic results and an improvement of their kid 's quality of life after the treatment . a 24-month - old female with macrocystic lymphangioma of the tongue the patient 1 year after the injection of picibanil clinical resolution of swelling due to tongue lymphangioma in two cases ( children with tongue lm ) , the patients were transferred from the operating room to the pediatric intensive care unit for the first 12 hours for a better postoperative management of the upper airway [ figure 2 ] . as to postinjection complications , all children had fever ( 38.5 - 39c ) , treated with paracetamol ( 10 - 15 mg / kg , 3 - 4 times / day ) and resolved after 1 - 3 days . five children presented signs of inflammation ( pain , redness , and induration ) in the site of injection , which were treated with nonsteroidal antiinflammatory drug ( ibuprofen 15 mg / kg 3 times / day ) and resolved after 3 - 5 days . one patient presented anemia ( hb = 6 g / dl ) 7 days after the injection ; he was treated with concentrated red blood cells transfusion and did not show any further blood alteration . in six cases we noticed a transitory increase of platelets concentration , with spontaneous resolution within 1 month [ table 1 ] . the main goal in the management of head and neck lms is the restoration or preservation of functional and aesthetic integrity . surgery is traditionally considered the first choice treatment of lms , however , such approach can have anesthetic and functional consequences . furthermore , the impossibility to perform extensive resections in the head and neck region , may prevent radical tumor excision , with consequent high rates of recurrence , complications , and persistent symptomatic disease . in the attempt to avoid such complications , in 1987 ogita et al . described the use of ok-432 ( picibanil ) as a sclerosing agent in the management of lms . despite the positive results reported in the literature , the use of ok-432 in children with lms is still controversial . our experience confirms the efficacy and safety of ok-432 intralesional injection in the treatment of macrocystic lms in children . after 1 - 3 injections 8/15 patients showed clinical complete disappearance of the lesion , with a recurrence rate ( 12.5% ) comparable to that reported in the literature ( 11% ) . a marked to moderate response was noticed in the other 7 kids and all children presented an improvement in their quality of life . the efficacy of ok-432 lms intralesional injection seems to be related to its capacity to induce a local inflammatory reaction with activation of macrophages and production of cytokines ( i.e. , tumor necrosis factor , tnf ) , which increase the permeability of endothelial cells and promote lymph excretion . these events cause a decrease in the size of lymphatic vascular lumen and cause cyst sclerosis . since this reaction seems too limited to the lm lumen , no perilesional fibrosis is produced , which will not increase the difficulty of surgical excision in case of ok-432 unsuccessful . another advantage of picibanil is represented by the possibility to perform multiple subsequent injections with additional shrinkage responses . in the medical literature , a dose not exceeding 0.2 mg of ok-432 per single injection is recommended . however , as a general rule , the dosage should equal the amount of aspirated fluid from lms , so the dose may be adjusted depending on the patient 's age and clinical conditions . since size reduction of lms may take weeks to months , we suggest waiting 6 months before assessing lesion shrinkage and performing a subsequent injection . even though several ok-432 injection side effects have been reported ( erythema , discomfort at the injection site , swelling and pyrexia , and anaphylaxis in patients with allergy to penicillin ) in the literature , in our experience , picibanil side effects were limited : the only relevant side effect was represented by a single case of anemia resolved with concentrated red blood cells transfusion . our results suggest that ok-432 intralesional injections can be considered a feasible alternative to surgical treatment in children with lms . the absence of cervical / facial incisions results in a better overall functional outcome and prevention of cervical scars with improved aesthetic results in comparison to traditional surgical approach . even though multiple injections of ok-432 require successive episodes of sedation , 6 - 7 picibanil shrinking effect on lms and low complication rate suggest introducing lms treatment among the indications of ok-432 also outside japan .
background : picibanil ( ok-432 ) is a lyophilized mixture of group a streptococcus pyogenes with antineoplastic activity . 
 because of its capacity to produce a selective fibrosis of lymphangiomas ( lms ) , it has been approved by japanese administration in 1995 for the treatment of lms.materials and methods : we treated 15 children ( age range : 6 - 60 months ) affected by head and neck macrocystic lms with intracystic injections ( single dose of 0.2 ml ) of picibanil ( 1 - 3 injections).results : complete disappearance of the lesion was noticed in eight ( 53.33% ) cases , a marked ( > 50% ) reduction of lms was found five ( 33.33% ) cases , while a moderate ( < 50% ) response was recorded in two ( 13.33% ) cases . 
 picibanil side effects included fever , local inflammation , and transitory increase of blood platelets concentration ; a single case of anemia was resolved with concentrated red blood cells transfusion.conclusions:intracystic injection of picibanil is an effective and safe treatment for macrocystic lms in pediatric patients and may represent the treatment of choice in such cases , especially where surgical excision is associated with the risk of functional / cosmetic side effects .