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ORIGINAL ARTICLE
Year : 2017  |  Volume : 5  |  Issue : 2  |  Page : 60-64

Efficacy of intralesional bleomycin as an alternative approach in the management of vascular anomalies


Department of Paediatric Surgery, Lilavati Hospital and Research Centre, Mumbai, Maharashtra, India

Date of Web Publication26-Jul-2017

Correspondence Address:
Rajeev Gurunath Redkar
Department of Paediatric Surgery, Lilavati Hospital and Research Centre, A-791, Bandra Reclamation, Bandra West, Mumbai - 400 050, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ssj.ssj_4_17

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  Abstract 

Aim: Cystic hygroma and hemangiomas are vascular anomalies which are mostly congenital in origin. The complications are increase in size of the swelling, infection, hemorrhage, dysphagia, respiratory distress, disfigurement, and recurrences. This study was done to assess the results of intralesional bleomycin.
Materials and Methods: A retrospective analysis of patient demographics, clinical response, treatment, and complications were recorded in vascular anomalies from 2009 to 2016. Nine children (53%) with hemangiomas and eight children (47%) with cystic hygroma were included in the study. The bleomycin injection was given as 1 mg/kg/dose intralesionally in all except for face lesions where it was given as 0.5 mg/kg/dose and was repeated after 4 weeks in case of nonresolving lesions. Two to six bleomycin injections were required in 14 cases and remaining three resolved after single injection. The lesions were assessed on first follow-up for resolution at 4–6 weeks.
Results: Out of the 17 children, 8 (47%) were male, and 9 (53%) were female. Sixteen children (94%) had lesions in the head, neck, and chest region and one had (6%) lesion on the hand. The lesions had completely resolved over 1–years in 14 (6 - hemangiomas and 8 - cystic hygroma) patients (82%) after bleomycin sclerotherapy, and one patient (hemangiomas) had 80% resolution and is on follow-up. Two patients (11%) had recurrence after six injections of bleomycin in chest cystic hygroma (1) and lip hemangiomas (1), and underwent surgical excision subsequently.
Conclusion: The bleomycin injection sclerotherapy is effective, safe, and economical.

Keywords: Bleomycin, cystic hygroma, hemangiomas, sclerosants


How to cite this article:
Redkar RG, Chigicherla S, Joshi S, Bangar A, Tewari S. Efficacy of intralesional bleomycin as an alternative approach in the management of vascular anomalies. Saudi Surg J 2017;5:60-4

How to cite this URL:
Redkar RG, Chigicherla S, Joshi S, Bangar A, Tewari S. Efficacy of intralesional bleomycin as an alternative approach in the management of vascular anomalies. Saudi Surg J [serial online] 2017 [cited 2017 Sep 24];5:60-4. Available from: http://www.saudisurgj.org/text.asp?2017/5/2/60/211611


  Introduction Top


In the 19th century, Virchow was the first to have categorized vascular anomalies on the basis of histologic features. In 1982, Mulliken and Glowacki proposed a biologic classification of vascular birthmarks on the basis of their clinical manifestations, histopathological features, and natural history.[1],[2] Vascular anomalies are characterized into tumors and malformations. Hemangiomas are vascular tumors with a growth phase, marked by endothelial proliferation and hypercellularity, and an involutional phase. Approximately 55% of these tumors are present at birth, and the remainder develops in the 1st week of life.[3] Although they frequently resolve spontaneously, approximately 5% produce complications such as bleeding, infection, consumption coagulopathy, and unesthetic appearance.[4]

In 1843, Wernher reported the first case of cystic hygroma. This term comes from the Greek word “hygroth” meaning fluid and “oma” meaning tumor.[5] Cystic hygroma is a multiloculated congenital malformation of the lymphatic system occurring in approximately 1 in 6000–12,000 births.[6] Surgical excision is the treatment of choice, but it is very difficult in some cases because of infiltrative nature of the thin-walled multiple cysts to the surrounding tissues. Complications (12%–23%) and recurrences (15%–53%) commonly occur after surgery.[7],[8],[9],[10],[11],[12] Coupled with a high recurrence rate, there is a search for effective and safe alternative or adjuvant methods of treatment. In 1977, Yura et al. were the first clinician to use bleomycin solution as a sclerosing agent for the treatment of cystic hygroma.[13] This agent produced extensive fibrosis and spontaneous resolution of vascular tumors. In recent years, two sclerosing agents, bleomycin, and OK-432 have been favored by some surgeons for the treatment of cystic hygroma.[8],[10],[11]


  Materials and Methods Top


From 2009 to 2016, the study was carried out on 17 children with cystic hygroma (9 patients) and hemangiomas (8 patients). The patients were admitted for 24–48 h. A standardized data collection sheet included the patient's age, sex, size and location of the lesion, clinical history, investigations, bleomycin dose, clinical response, side effects, and follow-up. Out of 17 children, 8 were male, and 9 were female, with age between 3 months and 16 years. The sizes of the lesions were ranged from 5 cm × 4 cm × 3 cm to 15 cm × 10 cm × 4 cm. The sites of the lesions were face (out of nine, six were cystic hygroma, and three were hemangiomas), chest (one cystic hygroma), neck (two hemangiomas), hand (one cystic hygroma), lip (two hemangiomas), orbit (one hemangioma), and mouth (one hemangioma). The lesions were asymptomatic in 12 children, and 5 children were symptomatic with respiratory distress and dysphagia and secondary complications such as infection and hemorrhage. Ultrasonography was done to see the extent and depth of the lesion. Computed tomography and magnetic resonance imaging were required in four children to confirm the depth and extension of the lesions and involvement of vital structures. Out of 17 children, two children had recurrent lesions after six bleomycin injections and underwent surgical excision. All children underwent injection bleomycin sclerotherapy at 1 mg/kg/dose except the children with lesions on the face who received 0.5 mg/kg/dose. One vial of bleomycin (15 mg) was reconstituted in 10 ml normal saline (1 ml = 1.5 mg). Required amount was measured on the basis of weight of the child and cyst size. Prepared bleomycin solution was injected into the cyst after aspiration of the contents. In hemangiomas, a 25-gauge needle was inserted through the places close to the lesion for avoiding bleeding until the hemangiomas became pale. The bleomycin was injected in a radial fashion [Figure 1]. In cystic hygroma, a 22-gauge needle was inserted at a site of maximum fluctuation, and the cystic hygroma fluid was aspirated. All the patients were observed and treated for any immediate problems such as fever and pain. Mild fever, swelling, and pain at the injection site occurred in four patients and disappeared within 24–48 h. Patients were discharged and asked to come after 4 weeks for follow-up. On follow-up visit, the lesions were inspected for decrease in size, color, and appearance. The size and blood flow of the hemangiomas were evaluated with color ultrasonography when appropriate. X-ray chest was done in all patients to rule out pulmonary fibrosis as it is long-term side effect of bleomycin. Repeated injections were given at an interval of 4 weeks.
Figure 1: Hemangioma - before bleomycin injection

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  Results Top


Out of 17 children, 8 were male, and 9 were female treated from the age group of 3 months to 16 years. The results after the first injection were divided into three categories, as “excellent” response if the masses had disappeared completely, (100% resolution) as a “good” response if the masses had reduced considerably (more than 50% reduction) with some residual lesions, and as a “poor” response if the masses reduced only slightly (<50% reduction) or did not change in size [Figure 2]. Of the 17 patients, 6 (35%) had resolution of <50%, 8 (47%) had resolution of 50%–75%, and 3 (17%) had resolution of 100% after first bleomycin injection. Three patients (hemangiomas: 17%) required only one injection, two patients required (cystic hygroma: 11%) two injections, four patients (hemangiomas: 23%) required three injections, (one had 80% resolution who is under follow-up) two patients (one hemangiomas and one cystic hygroma: 11%) required five injections, and four patients (cystic hygroma: 23%) required six injections with 4 weeks gap in between each injection. Two children (one hemangiomas and one cystic hygroma: 11%) had recurrent lesions after six bleomycin injections and underwent surgical excision.
Figure 2: Hemangioma - after bleomycin injection

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Sixteen children had complete resolution of the tumor with one child having 80% resolution after three injections and are under follow-up. Postinjection complications such as fever, increase in redness, and pain were seen in four children. No major complications were seen in any of the patients. No patients had pulmonary fibrosis.


  Discussion Top


Vascular anomalies are categorized into vascular tumors and malformation depending on clinical behavior and cellular kinetics. Vascular tumors are characterized by endothelial hyperplasia, and vascular malformations arise due to vascular dysmorphogenesis and exhibit normal endothelial turnover. In our study, we reported nine vascular malformations (cystic hygroma) and eight vascular tumors (hemangiomas). The management of these lesions is sclerotherapy and surgical excision.

Hemangiomas grow by endothelial cell hyperplasia and should be differentiated from vascular malformations, which are not true neoplasms but are localized defects of vascular morphogenesis caused by dysfunction in embryogenesis and vasculogenesis. The Greek suffix “oma” means cellular proliferation of a tumor, and thus, the term hemangioma is erroneous when used for malformations. Hemangiomas are the most common benign soft-tissue tumor of infancy and childhood, occurring in 12% of all infants and are found in greater frequency in girls, whites, premature infants, twins and are usually born to mothers of higher maternal age. They occur most frequently in the head and neck region (60%), followed by the trunk (25%), and the extremities (15%), which are grouped into infantile hemangiomas and congenital hemangiomas. Conrad Pienaar et al. treated hemangiomas with a standard injection of bleomycin at 0.3–0.6 mg/kg per injection. Bleomycin acts on S-stage of cell cycle to snip DNA chain during cell mitosis and disturb the cell proliferation. Therefore, the effects of bleomycin on hemangiomas are believed to destroy the proliferation of vascular endothelial cells. The onset of involution is usually heralded by a change in color from bright red to purple or gray after treated with bleomycin for several times. We used bleomycin as sclerosing agent to modulate angiogenesis of the hemangiomas and achieved good effects. There are several well-established treatments which include corticosteroids (either intralesional or systemic corticosteroids), interferon-alpha, laser therapy, cryotherapy, and surgical excision.[14],[15],[16]

Lymphangiomas are a common developmental anomaly of the lymphatic system. It is characterized by the formation of a multilocular cystic mass of variable size. The majority of lymphangiomas occur in the head and neck area.[17] Other site includes the mediastinum, axilla, arm, chest wall, abdomen, inguinal region, and leg. Lymphangioma has been classified into three varieties: (a) Lymphangioma simplex composed of capillary sized, thin-walled lymphatic channels, (b) cavernous lymphangioma, and (c) cystic lymphangioma, composed of cysts of few millimeters to several centimeters in diameter. Because of surgical complications, multiple nonsurgical strategies have been attempted to cure the lesion with minimal complications.[18] After spontaneous infection, lymphangiomas were noted to shrink or even completely regress. The epithelium lining the cystic spaces is destroyed after injection with subsequent decrease in lymph fluid production and collapse of the cysts. Many different drugs were used to mimic what may occur naturally after infection. In cystic hygroma, bleomycin causes damage of epithelial lining, fibrosis resulting in resolution of the lesions.

In recent years, two sclerosants are in use for the management of vascular anomalies (cystic hygroma and hemangiomas) instead of surgical excision. They are bleomycin and OK-432 (a low virulence strain of Streptococcus pyogenes cultured with penicillin-G). Bleomycin was discovered as an antibiotic in 1965 by Dr. Umezawa from Tokyo. Bleomycin is known to have some antitumor activity and also have local sclerosing effect on endothelial cells of cysts wall of lymphangiomas. Interestingly, it has never been used as an antibiotic after it was found to cause incision of single-stranded DNA.[19] OK-432 has no recurrence or significant side effects, but its availability and cost factor limits its use.[20] The other sclerosants are doxycycline (a broad-spectrum antibiotic), acetic acid at a 40%–50% concentration, absolute ethanol, hypertonic saline, alcoholic solution of zein (ethibloc), fibrin sealant, and triamcinolone.

Bleomycin has been shown to be more effective for cystic-type of hygroma as compared with capillary or cavernous lymphangiomas.[8],[21],[22] Cervical, facial, and axillary lymphatic malformations are more commonly composed of the cystic type. The desired effect of the drug locally is dependent on the availability of the drug per unit surface area of the lesion;[23],[24] hence, the amount of drug given should depend on the size of the lesion and not only on the weight of the patient. Another factor that can influence the final dose of the solution is the ability to aspirate the lesion before injecting. Evacuation of most of the fluid out of the lesion is a crucial step for success as it facilitates more contact between the sclerosants and the endothelial lining of the lymphangiomas. The amount injected must not distend the lesion markedly as this may precipitate inflammation. The total dose of injection must not exceed 10 mg per injection setting; otherwise, there may be a risk of development of pulmonary interstitial fibrosis, a well-documented complication for this sclerosant.[25]

In our series, the resolution of lesions was 35% who had resolution of <50%, 47% had resolution of 50%–75%, and 17% had resolution of 100% after one bleomycin injection which was seen in most of the studies. Fourteen patients required multiple injections (2–6) which was similar to another study done by Dr. J. D. Rawat et al. from King George Medical University, Lucknow, Uttar Pradesh, India.

Intralesional bleomycin therapy is more effective for vascular anomalies. A minimum dose of 1 mg/kg of bleomycin has been recommended in the literature for each injection of bleomycin.[8] We preferred bleomycin as a sclerosant because of its easy availability, low cost, good response and minimal side effects when used in low-dose intralesionally in vascular anomalies. Minor side effects of bleomycin such as local swelling, redness, pain, and low-grade fever were noted in four patients after injection, which mostly recovered within 24–48 h. Pulmonary toxicity is a potential side effect of bleomycin therapy. This risk is related to the dose, an increasing incidence being associated with the total dose of more than 400 units or a single dose exceeding 30 mg/m 2 of body surface area. The pulmonary fibrosis of intralesional bleomycin therapy is not reported so far. No such major adverse effect was seen in our series.

Even the use of bleomycin as a sclerosant in the intrauterine fetus with cystic hygroma is under trial, and some centers have noted promising results.[11],[17]


  Conclusion Top


Our study concludes that intralesional bleomycin as sclerosant appears to be a safe and effective alternative to surgical treatment of vascular tumors (cystic hygroma and hemangiomas). However, repeated injection may be required till continuous resolution. Follow-up is required for recurrences. Hence, it may be suitable for use as a primary therapy in large lesions or lesions at sites where resection is difficult to avoid the risk of inadvertent damage by surgery as well as for cosmetic reasons.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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2.
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7.
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Rothenberg SS, Pokorny WJ. Use of argon beam ablation and sclerotherapy in the treatment of a case of life-threatening total abdominal lymphangiomatosis. J Pediatr Surg 1994;29:322-3.  Back to cited text no. 14
    
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Dubois J, Garel L, Abela A, Laberge L, Yazbeck S. Lymphangiomas in children: Percutaneous sclerotherapy with an alcoholic solution of zein. Radiology 1997;204:651-4.  Back to cited text no. 15
    
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25.
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