Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature.Sclerosing Agents So, sclerosing agents, what are they? They are substances that cause a marked tissue irritation and/or thrombosis with subsequent local inflammation and tissue necrosis. This inflammation and tissue necrosis results in fibrosis and tissue contraction. These come in multiple forms including powders, solutions, fatty acid derivatives which are also called detergents, acids and bases. Here’s a list of available sclerosants that I found in my literature search, although I am sure they are more: they range from simple things like boiling water and hypertonic saline and hypertonic glucose to detergents, which are molecules which have a hydrophobic end and a hydrophilic end. In addition, talc, which is a mixture of silicate and magnesium oxide has been used, as well as acetic acid and a variety of other agents. However, the most popular sclerosants used today are alcohol, bleomycin, OK-432, which is also known as Picibanil, Ethibloc, as well as 3% sodium tetradecyl sulfate. Sclerosing agents are found in a wide variety of applications and medicines and their earliest use dates back to over 100 years with the treatment of varicose veins. They have also been used in the treatment of GI bleeding, and multiple types of cysts, including parathyroid cysts and thyroid cysts. Their use is well-known in malignant pleural effusions and malignant pericardial effusions; prolotherapy, which is therapy treating tendons; and also in the treatment of solid tumors such as bladder, kidney and head and neck cancer. In children, however, the use of sclerosing agents is limited mainly to symptomatic vascular malformations. These include venous malformations and lymphatic malformations, arteriovenous malformations and AV fistulas. I have also found isolated reports of their use with hemangiomas, a case report of a fungi granuloma treated with a sclerosing agent, and even a case report for tracheomalacia and one case report for treatment of intrauterine fetal lymphatic malformation. A vascular malformation is symptomatic when it causes severe cosmetic deformity, pain or functional impairment such as problems swallowing or breathing or chewing problems; if the lesion bleeds or causes a nerve palsy; and if it’s located in an extremity and causes claudication. In severe cases it can cause heart failure. Treatment of symptomatic vascular malformations really depends on the location of the lesion and the size. For example, airway lesions are commonly treated using some sort of laser ablation treatment. However if the lesion is accessible surgically, then surgical excision is the gold standard of treatment. However, there are several obstacles when considering surgery. First of all, complete excision is not always possible. Vascular malformations can grow very large. They can intimately involve vital structures in the head and neck such as cranial nerves and great vessels. They can also involve the maxillofacial skeleton and therefore require bone removal at surgery. Their dissection is often complicated by extensive bleeding. If the whole lesion is not removed, recurrence is known to be very common. Large lesions typically require staged procedures and staged surgeries are associated with an increased complication rate, increased morbidity and increased mortality. These issues have led people to seek alternative treatments for these malformations: cautery, cryotherapy, radiation and sclerosing agents. Often more than one modality is needed, in this case, embolization or percutaneous sclerosis followed with surgical excision. It is a multi-disciplinary approach involving pediatric surgeons, plastic surgeons, otolaryngologists, and interventional radiologists, especially those who are experienced with selective and super-selective embolization techniques. Today, I’m going to be covering four sclerosing agents, the tried and true alcohol, bleomycin and the new agents, OK-432 and Ethibloc. Why use alcohol? Alcohol has been used for over 100 years in treating varicose veins. It has known, controlled side effects. It’s quickly diluted, inexpensive and everybody can get it. It’s also the most potent sclerosant available. It’s typically used as either a 95% or a 100% solution and it’s mode of action is by injuring the vascular endothelium and denaturing blood protein, which results in an intense thrombosis. Alcohol is typically used in the venous type of malformation. It has also been reported to successfully treat extremity and renal arteriovenous malformations and this has led to investigations of its use in the treatment of AVMs, AV fistulas and lymphatic malformations in the head and neck region as well. Ethibloc is another agent and this was licensed in West Germany in 1979 and Ethibloc currently is not approved by the Federal Drug Administration of the United States. Ethibloc was initially used to treat pancreatic disease and also for embolization of kidney tumors. It’s basically viscous alcohol and you can find it under viscous alcohol in the PubMed search. It’s a mixture of corn protein, sodium trizoic, olium papaveris and propylene glycol and it’s 20 times more viscous than conventional aqueous solutions. It comes supplied in 7.5cc vials and its mechanism of action is also intravascular fibrosis and necrosis. The active ingredients are the alcohol and the corn protein. It has a slow rate of solidification, requiring 10 to 15 minutes to solidify. This allows migration and diffusion of the product, which will become important later on in the talk. After injection, it is noted to be degraded within 11 days into various amino acids and glutamic acids. In 1979, Ethibloc was first used in the treatment of a venous malformation by Riche in Paris and he reported these results in a paper in 1983. He gives his experience with 16 patients. This is a review of venous malformations. They’re always present at birth. They do not proliferate but they do undergo hypertrophy as the patient ages. They come in two varieties – localized and diffuse. They can present as a small simple ectasia or they can involve extensive areas. These are low-flow lesions and they typically communicate with the normal venous system through a few narrow tributaries. Diagnosis of venous malformations includes history, which will reveal episodes of sudden pain, tenderness and ecchymosis. This is related to the fact that they are local lesions which can spontaneously thrombose. On examination you will note that these lesions will expand with the Valsalva maneuver, when the patient bends over or with exercise. These masses are easily compressible. On radiograph you may see a phlebolith. Workup of venous malformations includes MRI with contrast and, importantly, angiography. Sometimes regular angiography isn’t sufficient to detect the venous malformation because they are low-flow lesions. This is where the catheter is placed into the external carotid artery and there is no blush here in the face region where the malformation is located. However, with super-selective angiography, putting the catheter into the internal maxillary artery, the venous malformation becomes readily apparent. They have this characteristic grape-like clustering seen on fluoroscopy and you need angiography to also define the malformation’s venous runoff pattern. It’s also good to rule out the presence of other vascular malformations because these can occur as mixed entities. But the gold standard for workup is a direct puncture or phlebography, where you actually percutaneously puncture the venous malformation and inject contrast. To sclerose a venous malformations, the actual lesion is injected via an intraluminal catheter or percutaneously. Transarterial embolization is not sufficient because this embolic material only occludes the arterioles and capillaries and the lesion can get filled with collateral circulation. These sclerosing procedures are done under general anesthesia because when the agent is injected into the lesion it is very painful. You want to canalize it with an angiocatheter and then once you think you’re in the right position, inject a small amount of contrast to determine if you are in the right place. At this point you want to compress the outflow vein and then compress the actual lesion to see if you have any extravasation of the contrast to make sure the sclerosing agent is not going to leak out of the venous malformation. Ethibloc and alcohol are dosed as follows: alcohol dosed at one ml per kg maximum and you want to inject until you fill the lesion. A direct proportional relationship between the amount of alcohol injected and the amount of alcohol that is found in the systemic circulation after therapy has been demonstrated. Ethibloc is injected anywhere from 1cc to 15cc and again, you want to inject until you fill the lesion - but it i important not to overfill the lesion since overfilling can cause the sclerosant to leak either out of the venous circulation or extravasate outside the tissue. Inject until the area becomes thrombosed and until the red blood no longer returns with aspiration of the vein. Small malformations are usually done in one setting but, for a couple of reasons, large malformations need to be staged. First of all, long procedures, especially if being done by an interventional radiologist, can become very fatiguing and mistakes can happen. Secondly, the amount of contrast agent used in each setting should be limited to protect the kidneys. Post-injection the lesions will immediately become thrombosed and hard and will stay inflamed anywhere from three to seven days. Patients usually experience fever for two to three days after injection. Various levels of discomfort after the procedure are experienced, and this is treated symptomatically. How well does it work? Most of the literature is small case series and there are no prospective trials looking at this agent in the treatment of venous malformations. I was able to find five papers, which covered 82 patients. Eighty-three percent of these patients had either an excellent or a good response, a good response being defined as the lesion having greater than a 50% reduction in size. Seventeen percent of patients had minimal or no response. Ethibloc suffers the same problems. Although it’s an even newer agent than alcohol, I was able to find four papers with 73 patients. Again, it had a similar efficacy of 82% experiencing either an excellent or good response and 18% with minimal or no response. In approximately 60% to 70% of the cases with Ethibloc, these sclerotherapy sessions were followed by surgical excision and they did note that the sclerotherapy made the surgery easier because it decreased the amount of bleeding during surgery and helped to define the margins for resection. There are multiple factors affecting how well the sclerotherapy works in venous malformations. One is drainage patterns: whether the venous malformation has very little drainage or no drainage, if it drained through a normal venous system or if it has an ectatic venous drainage system, and whether or not the lesion is localized or diffuse. Also, in some instances, a history of previous procedures has been shown to be detrimental although other papers demonstrate that such a history has no real effect on outcome. Complications associated with alcohol use are pain, swelling and ecchymosis, as with all the sclerosing agents. Acute blistering was seen in 25% of patients overlying the lesion that was treated. Skin necrosis with ulcerations is fairly common, occurring iin about 21%, either from reflux from superficial venous channels into distinct capillaries overlying the lesion or, if some of the alcohol leaks out into surrounding tissues, this can cause skin necrosis. However, these problems are usually correctable with reconstructive surgery and typically lead to an acceptable outcome. Another complication is hemolysis, which occurs in a quarter to half the cases. This requires aggressive IV hydration to protect from hemoglobinuria. Also, neuropraxia can result once the lesion becomes inflamed. Ethibloc has similar complications including pain, swelling and ecchymosis. It has a lower incidence of skin necrosis probably because it has a lower alcohol concentration. However, another complication is fistulization to the skin from the venous malformation leading to leakage of the Ethibloc from the wound. However no one has reported any serious or negative outcomes from this fistulization, which usually resolves spontaneously. Sometimes infection will occur but usually no further intervention is required. In addition, because Ethibloc is so viscous it can have a tendency to migrate into distal veins and cause phlebitis - so some authors actually dilute the Ethibloc with some absolute alcohol to help prevent this complication. Ethibloc has also been used to treat lymphatic malformations. Like venous malformations, lymphatic malformations are difficult to treat - for many of the same reasons. They can involve important structures, they have infiltrating growth pattern and they can grow in areas that are difficult to dissect. Lymphatic malformations are seen at birth about half the time and by two years of age have expressed themselves in 89% of patients. They most commonly involve the head and neck region but can also involve the axilla and the mediastinum. They are typically slow growing via hypertrophy as the patient ages and they have a history of changing in size or having rapid growth in the setting of an upper respiratory tract infection or if the lesion itself becomes infected during periods of hormonal change and after trauma. These lesions are classified in two basic categories: microcystic and macrocystic. Macrocystic lesions tend to be localized and microcystic lesions tend to be diffuse. Sometimes these lesions are mixed having both macrocystic and microcystic components. Indications for treatment of lymphatic malformations are the same as those for venous malformations. They include severe cosmetic deformity, air obstruction, infection and functional impairment. Again, the treatment options include surgery, which is considered the gold standard. There are well-accepted surgical statistics cited in multiple different articles. The recurrence rate is anywhere from 15% to 53%, and inadvertent nerve injury is between 12% to 33% and mortality is between 2% to 6%. The numbers are on the higher side in patients that are younger, especially infants, and in floor of mouth and tongue lesions that tend to be the most difficult to treat. Again, these issues have led to people seeking treatment alternatives. This included radiotherapy in the early 20s and 30s, which was associated with esophagitis, tracheitis and a distant formation of malignancy. Today, treatment options include carbon dioxide and neodymium yag laser ablation, basically used for localized laryngeal lesions. Radio frequency ablation and interstitial laser treatment and, of course, sclerotherapy are also being used. The idea of using sclerotherapy came after it was noted that lymphatic malformations will spontaneously involute after they become infected and the infection resolves. In 1933, Dr. Harrower in the British Medical Journal published the first known case of using sclerotherapy for lymphatic malformations. He treated a one-month-old Chinese baby with a rapidly enlarging left neck mass, which had increased from the size of an orange to the size of a grapefruit within six weeks time. The agent he chose was sodium moroate, which is cod liver oil. The patient was treated with two injections with intermittent aspiration of the lesion and Dr. Harrower noted complete resolution in six weeks time. The agents used today for lymphatic malformations include bleomycin, OK-432 as well as Ethibloc. Bleomycin was an antibiotic discovered in 1965 by Dr. Umezawa, which is a product of streptomyces vertilicus. Interestingly, it has never really been used as an antibiotic after it was found to cause incision of single stranded DNA. Since that time it has been used to treat malignancy due to its anti-neoplastic property, usually lymphoma, squamous cell carcinomas, testicular cancers and malignant pleural effusions. It was noticed that in the treatment of malignant pleural effusions, bleomycin caused fibrosis and scarring. They also noted that bleomycin was a relatively safe drug. So, in 1977 Dr. Yura in Japan was the first to use bleomycin in the treatment of lymphatic malformation. He treated eight patients who either had incomplete resection or recurrence. This also included four patients who were simply non-resectable and had no other treatment option. Dr. Yura noticed good results. Complications with bleomycin also include pain, swelling and fever. There is a2% to 4% association with diarrhea and vomiting. The most dreaded complication of bleomycin, pulmonary fibrosis, is dose dependent. It is associated with single doses greater than 30mg per square meter. However, this complication has never been reported in any paper with sclerosing therapy. OK-432, also known as Picibanil, is classified as a potent biological response modifier. This is because it activates natural killer cells, it causes production of cytotoxic factors and cytokines and was first used in clinical trials in 1967 by Dr. Kunimoto as a biological response modifier for the treatment of head and neck cancers. OK-432 is a product of low virulent bacteria strain, Type III, Group A streptococcus biogonese that has been incubated with penicillin G. After it’s incubated it is then lyophilized, which results in the complete disappearance of the streptolysin S producing ability that makes the bacteria virulent. It cannot be used in patients that have severe penicillin allergies because it is incubated with penicillin G. In 1987, Dr. Ogita in Japan was the first person to publish a treatment using OK-432 for lymphatic malformations. He got his idea after reading a couple papers by Dr. Torisu and Kondo in 1982 and 1983. They used OK-432 to treat malignant, pleural and peritoneal effusions and found it to be 90% effective. They postulated the mechanism of action as being activation of the complement system, release of anaphylic toxins and chemotactic factors. This results in the inflammation of the pleural and peritoneal lining. This caused a decrease in the fluid production secondary to damage of endothelial cells and the resultant deposition of fibrotic tissue. They found the drug to be very safe and none of their patients had any serious side effects. They also published the LD50s for OK-432 and saw that it had very acceptable LD50 values for various types of different modalities of treatment. The technique for injecting these into lymphatic malformation is similar to venous malformations. Both are done under general anesthesia. It requires a sterile technique: either ultrasound or fluoroscopy since there is no need to worry about a venous drainage pattern. Directly puncture the cyst, then inject some contrast material to help identify the anatomy and also to see the communication between the different macrocysts. At this point aspirate as much of the cyst as possible and then inject the sclerosing agent. Now, how much an agent do you inject? Well, for bleomycin the recommended and published concentrations are 0.3mg to 0.6mg per kg, with a maximum of 5mg per injection. For OK-432 it is 0.1mg per cc and the maximum you should inject per session is 20cc or 2mg. For Ethibloc, people are typically injecting up to one vial. Patients are monitored in-house afterwards and are treated symptomatically for fever and pain. In Dr. Ogita’s original paper in 1987, he treated nine patients at various sites and noted complete regression in eight and marked regression in one patient, with only half the patients requiring more than one injection. He noted the side effects as I mentioned before and he also noted that there was no damage to the overlying skin or residual scar. In an extensive literature search looking for results of OK-432 with lymphatic malformations, I was able to come up with eight articles covering 139 children. Overall, 66% had either an excellent or a good outcome and about one-third of the patients had minimal or no response. Usually, only one or two injections were required, but very large lesions required more injections. Again, the only side effects noted were fever and swelling. However, if you look at this data in another way and divide the patients into those with either macrocystic lesions or microcystic lesions, there were 100 patients, so it was roughly 50/50. There was an excellent or good response in 95% of the patients with macrocystic lesions versus 50% excellent or good response in patients with microcystic lesions. A good response does not mean the complete disappearance of lymphatic malformation but that it is definitely much smaller. Ethibloc results: I wasn’t able to find too many papers on the use of Ethibloc for lymphatic malformations. Many of the initial papers are by Riche from Paris. In 1993 he published the paper of his experience with 70 patients. Eighty percent of these lesions were in the maxillofacial region and 62% of the patients had a good outcome. Sixteen of these patients had continued progression and he noted that 11 of the 16 had mixed cystic or microcystic lesions. The only other paper is by Dubois from 1997 in France. She looked at 14 patients with lymphatic malformations. The average age of the patient was six-years-old. Half the patients had macrocystic lesions and half of them had mixed lesions. She had two-year follow-ups on her patients and all the patients had either an excellent or good response. Only three patients required two injections. However, she noted that 10 out of her 14 patients had fistulization to the skin with leakage of the Ethibloc and this occurred anywhere from 2 weeks to 3 months after injection. However again, no serious complications came from this fistulization. And finally, bleomycin, I found four papers covering 125 patients. Forty-five percent had a complete response and 41% had a partial response. On the chart, the numbers in parentheses are patients who underwent surgery following injection and all of these patients had surgery following injection because they had no change. Bleomycin was also found to be very safe. The only side effects noted were pain and swelling. There was no skin ulceration or scarring and there were no documented cases of pulmonary fibrosis. In conclusion, vascular malformations pose an extremely challenging treatment dilemma for physicians and for their patients. There is no magic bullet. No one treatment is going to treat all vascular malformations and the treatment needs to be tailored to each individual patient. I think sclerotherapy offers another avenue for physicians to explore - but just a few reminders about each agent. Alcohol is very good at what it does but you need to make sure that you get it in the right place because it’s also very good at what it does in the wrong places as well, although skin ulceration, a fairly common complication, seems quite manageable. Ethibloc basically acts like a less potent absolute alcohol. It seems to have approximately equal efficacy but the fistulization issue is a little bit worrisome and one wonders why you would use Ethiloc if you have alcohol so readily available. Bleomycin appears to be very safe and effective but it has the potential complication of pulmonary fibrosis. All these agents cause post-injection fever, swelling and varying degrees of discomfort and multiple injections are required for large lesions. Remember that macrocystic lesions often have a much better result than microcystic lesions and these lesions often need a team approach. Case Presentation: M.A. is a 10-year-old white male whose parents noted a left-sided neck and angle of mandible mass, which was first noticed at age 2, and which had been slowly increasing in size over the past 7-8 years. They noted that it intermittently increased in size in association with viral URI's. It had never been infected and there was no history of trauma. The mass has become an increasing social issue but caused no functional impairment. The patient was referred by his pediatrician for evaluation. Exam revealed a soft, compressible, mass without discoloration, tenderness, or pulsation. The mass trans-illuminated. MRI with contrast showed no contrast enhancement. Bright on T2. One large macrocystic mass, 9cm in greatest dimension, was appreciated abutting the carotid sheath and extending to the lateral pharyngeal wall. Diagnosis of a lymphatic malformation was made based on imaging and history and exam. Treatment options considered were surgical excision vs. sclerosis. It was recommended to the parents that the child undergo sclerotherapy with OK-432. Four injections were performed at 6-week intervals. After the first injection, a small hard lesion remained that was injected three more times. At one-year follow-up, the mass had completely resolved with minimal evidence of residuum on exam. A small area of persistence was noted on MRI, which did not enhance on T2 weighted images and is presumed to represent lymphatic tissue residuum. Bibliography: American Society of Health-System Pharmacists, Inc. Bleomycin. Drug Digest. Available online at http://www.drugdigest.org/DD/DVH/Uses/0,3915,82|Bleomycin,00.html. Accessed 07/20/02. 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Radiol 1989;170:1059-1066. Yakes WF, Luethke JM, Parker SH, Stavros AT, Rak KM, Hopper DK, Dreisbach JN, Griffin DJ, Seibert CE, Carter TE, Guilliland JD. Ethanol embolization of vascular malformations. Radiographics 1990;10:787-796. Yakes WF, Parker SH, Gibson MD, Haas DK, Pevsner P, Carter TE. Alcohol embolotherapy of vascular malformations. Sem Intervent Radiol 1989;6:146-161. Grand Rounds Archive | Department Home pageBCM Public | BCM Intranet | Privacy Notices | Contact BCM | BCM Site Map | ©2001-2005 Baylor College of Medicine
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