Therapeutic Effects of Intralesional Bleomycin Sclerotherapy for Non-Invasive Management of Low Flow Vascular Malformations - A Prospective Clinical Study : Annals of Maxillofacial Surgery

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Original Article - Observational Study

Therapeutic Effects of Intralesional Bleomycin Sclerotherapy for Non-Invasive Management of Low Flow Vascular Malformations - A Prospective Clinical Study

Jan, Iram; Shah, Ajaz; Beigh, Shahid Hassan

Author Information
Annals of Maxillofacial Surgery 12(2):p 151-156, Jul–Dec 2022. | DOI: 10.4103/ams.ams_65_22
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Abstract

INTRODUCTION

Vascular anomalies represent the most widespread form of congenital and neonatal dysmorphogenesis, present with a wide spectrum of pathological conditions including different clinical features, natural course of progression and treatment approaches. Mulliken and Glowacki[1] based on the International Society for the Study of Vascular Anomalies broadly classified vascular anomalies into two categories as haemangiomas and vascular malformations (VMs)[2] which are further sub-divided depending upon their flow as high- or low-flow VMs (LFVMs).[3] VMs include high-flow malformations such as arteriovenous malformation, arterial malformation and arteriovenous fistula. Low-flow malformations include venous, capillary, lymphatic and combined malformations, i.e., venolymphatic malformation. They can occur anywhere in the body with a high preponderance for the head and neck region. In the cervical facial region, the most common vascular anomaly is VMs, previously known as ‘cavernous haemangiomas’. They may involve mucosa, skin and critical neuromuscular structures.[4] Ultrasonography helps in differentiating high-flow vascular lesions from low-flow lesions. It can also be used for guiding during sclerotherapy procedures.[5]

A number of treatment modalities for these VMs and anomalies have been reported including sclerotherapy, laser therapy, vessel embolisation, electrochemical therapy, copper needle treatment, surgical resection and a combination of these. Many sclerosing agents have been tried, thus far including sodium morrhuate, sodium tetradecyl sulphate, absolute ethanol, ethibloc, OK-432 and bleomycin.[6-8] Percutaneous sclerotherapy is a safe and effective treatment modality to reduce bleeding during surgery and shrink the size of the lesion.[9]

Traditional management involving surgical treatment may result in complications including wound infection, haemorrhage, unsightly scar, postoperative fluid accumulations, various nerve palsies and lymphorrhoea.[9] Bleomycin was developed as a cytotoxic antitumour agent in 1966 by Umezawa.[10] Intralesional bleomycin injection has been recently shown to be an effective treatment for vascular lesions and used extensively as a nonsurgical treatment because of its low cost, easy availability, low toxicity and high sclerosing effect on vascular endothelium. It has an apoptotic effect on rapidly growing immature cells inducing DNA degradation.[11,12]

The aim of our study was to evaluate the effect of intralesional bleomycin injection in VMs, especially venous and lymphatic malformations present extracranially on the face, lips and intraorally.

SUBJECTS AND METHODS

This was a clinical observational study comprising 30 patients who presented with vascular anomalies, especially LFVMs. This prospective study was conducted between September 2019 and November 2021. Patients for the study were selected from the Department of Oral and Maxillofacial Surgery, Government Dental College, Srinagar. Patients’ written consent was obtained for the use of intralesional bleomycin injection after explaining the possible risks and complications of the injection in detail. Ethical approval was obtained from the institutional review board of Government Dental College, Srinagar, vide approval no: ECC-GDC/0065 dated 05-08-2019. All procedures performed in the study were conducted in accordance with the ethical standards given in the 1964 Declaration of Helsinki, as revised in 2013. A total of 30 patients between the age group of 13 and 35 years having LFVMs on the basis of history and physical examination were included in this study. Computed tomography/magnetic resonance angiography and ultrasonography (USG) Doppler was done amongst few patients to confirm diagnosis and rule out high-flow VMs so that they could be excluded from the study [Figures 1a, b and 2a-d]. Immunocompromised patients and patients with blood dyscrasias were also excluded.

F1-7
Figure 1:
(a and b) Ultrasonography Doppler images confirming hypoechoic lesions with multiple septations below the surface of tongue. (c-e) Pre-, during and post-sclerotherapy image of Tongue lesion showing complete reduction
F2-7
Figure 2:
(a-d) Ultrasonography Doppler images showing hypoechoic lesion of heterogeneous echotexture with multiple internal septa seen at clinical site. (e and f) Pre- and post-sclerotherapy showing marked improvement

A standardised detailed case history sheet recording the particulars of the patient including name, age, gender, weight, location of the lesion, size of the lesion, special investigations, any drug allergy and previous treatment for the same was completed for each case. The patients with LFVMs were selected for intralesional bleomycin injection. The response to treatment was recorded by serial photography and measurements taken before, during and after completion of the therapeutic session. Bleomycin powder (15 mg) was reconstituted with 15 mL of normal saline. Dilution of 0.6 mg/mL to 1 mg/mL was used. In adults, a dose of 1–15 mg was injected intralesionally at each session. The volume of bleomycin injected was matched to the lesion size initially and later standardised to a degree. A single dose of 15 mg per appointment was never exceeded. After application of a topical anaesthetic cream 15 min before, bleomycin was injected in a radial fashion.

Percutaneous puncture was accomplished by introducing the needle through normal skin and then advancing through the VM in subcutaneous and deep tissue plane. Blanching of the overlying skin during puncture was a good indicator of a fair injection.[13] Injection was followed by application of local pressure for about 5–10 min. Furthermore, a pressure dressing was applied. Patients were kept under observation for about 30 min to 1 h. The patients were discharged 1 h post-injection with mild analgesia. Three- to 4-week duration between sessions was maintained. Considerable reduction in size was noted after the first injection in many cases and in a few it was noted after the second or third injection. Colour changes also could be appreciated after 3–4 weeks of the first injection. A total of 3–4 sessions were carried out, if necessary. The follow-up of the patients was done in an outpatient setting, and parameters such as size, colour and texture of the lesion were evaluated after treatment. Pre-injection and post-injection serial photography was taken for the evaluation of aesthetic appearance. Patients were followed for a period of 6–12 months [Figures 1c-e, 2e, f and 3a and b].

F3-7
Figure 3:
(a and b) Pre- and post-sclerotherapy image showing complete reduction

The results were scored based on a 4-point scale that was modified by Achauer et al.[14] and Hassan et al.[15]

This scale took volume, colour and texture of the lesion after treatment into consideration.

  1. No response, that is, no change in the size or continued to enlarge
  2. Mild improvement, that is, the lesions decreased in size, but <50% with improvement in appearance
  3. Marked improvement, that is, the lesions decreased in size more than 51%, but <100% with remarkable improvement in appearance
  4. Cured, that is, the lesions disappeared completely without recurrence at least 6 months after treatment.

Statistical analysis

The recorded data was compiled and entered into a spreadsheet (Microsoft Excel). Continuous variables were expressed as mean ± standard deviation and categorical variables were summarised as frequency and percentages.

RESULTS

This prospective study was conducted between September 2019 and November 2021 amongst 30 patients. The participants included 18 males and 12 females. Their ages ranged from 13 to 35 years with a mean age of 24 years. They were treated with percutaneous bleomycin sclerotherapy under local anaesthesia on an outpatient basis and analysed prospectively. Patients were followed up for a period ranging from 6 to 12 months.

A total of 11 lesions measured <2 cm and 19 lesions measured between 2 and 4 cm. There was complete resolution in 11 patients (36.66%) and marked improvement in 17 patients (56.66%) and a mild improvement in two patients (6.66%) [Table 1 and Graph 1]. Local complications that were seen after intralesional bleomycin injection were superficial ulcerations that were seen in 14 patients (46.66%). It improved after a week of injection and only one patient (3.33%) presented with hyperpigmentation initially but it resolved after the last session. No other complaints were reported by the patients in our study. Uneventful healing with no post-injection complications was seen in around 15 patients (50%). None of the patients reported any haematological adverse effects or signs of pulmonary fibrosis, a feature reported to be present with systemic bleomycin therapy [Table 1 and Graph 2]. The effect of percutaneous bleomycin sclerotherapy treatment showed statistically significant results (Chi-square=52.5, P-value= <0.001).

T1-7
Table 1:
Comparison based on outcomes and adverse effects
F4-7
Graph 1. Comparison based on outcomes
F5-7
Graph 2. Comparison based on adverse effects

DISCUSSION

Nowadays the treatment options for VMs include sclerotherapy, surgical excision, cryotherapy, laser therapy and irradiation. Surgical excision of extensive lesions is associated with high recurrence rates, significant functional impairments and cosmetic disfigurement.[16] There are a number of sclerosing agents currently in use for the treatment of LFVMs and haemangiomas. Sclerotherapy is the process of injecting a sclerosing agent directly through the skin into a lesion. They vary in mechanism of action, toxicity and complication rates.

Intralesional sclerotherapy is a minimally invasive treatment modality for low-flow VMs and macrocystic lymphatic malformations.[17] In the present study, we performed intralesional sclerotherapy in patients of low-flow VMs. Percutaneous sclerotherapy is an injection of sclerosing agent directly through the skin into the lesion for venous or lymphatic malformation. Various sclerosants have been used in the past for haemangioma and VM.

Bleomycin was discovered by Umezawa[10] as an antitumour agent in 1966 which acts through inhibition of DNA synthesis. Later on, Yura et al.[18] in 1977 first studied its intralesional sclerosing effect in macrocystic lymphangioma and achieved good result in all eight cases. Sarihan et al.[19] were the first to use it in cutaneous haemangioma in 1997.

Alcohol is the most widely used sclerosing agent because of its rapid availability, relatively lower cost, ease of use and longer shelf life. Alcohol acts by causing dehydration and subsequent sloughing of the dysmorphic endothelial cell lining.[20] It leads to intralesional thrombosis and oedema. The efficacy of sclerotherapy using alcohol injections ranges from 75% to 95%.[21]

Most of the cases in the present study were adults with VMs (n = 30), out of which 18 were males and 12 were females which was contrary to other studies where female ratio was higher as compared to males.[15,22] Lips, oral cavity and tongue were the most common sites for slow-flow VMs. The number of injections required ranged from 2 to 5 which was similar to Pienaar et al.[22] and Hassan et al.[15]

Our study reported complete cure in 11 patients (36.66%) and marked improvement in 17 patients (56.66%). These patients did not require any surgery. This is in accordance with the study conducted by Hassan et al.[15] Furthermore, in our study mild improvement was recorded in two patients (6.66%). These patients were later taken up for surgery after the bleomycin therapy reduced the size of the lesion and vascularity. This facilitated aesthetic closure at a later date. This is also in accordance with Hassan et al.[15] and Bhardwaj et al.[23] Results of this series were comparable with other studies[24] and it was similar or even better compared to surgical modality.[15] Complications such as nerve palsy and bad scar were thus avoided. Percutaneous intralesional bleomycin injection causes destruction of the vascular endothelial cells, hence producing sclerosing effect. The injection was repeated every 3 weeks in this study as the duration of 3 weeks was found to be consistent with the expected changes in the haemangioma and slow-flow VM. Intralesional bleomycin has been successfully used to treat haemangiomas and VMs with a success rate of 87% and 84% respectively.[25] In another study, lymphangiomas were treated by percutaneous bleomycin sclerotherapy and it was found to be an effective treatment for lymphangiomas.[9]

Very few minor complications encountered in this study were hyperpigmentation of overlying skin. Concerns have been raised regarding the potential of systemic bleomycin therapy to cause pulmonary fibrosis. However, no cases have been reported in the literature with bleomycin used as a sclerosing agent. Furthermore, the risk of this complication is explained to be minimal, if the dose per session is kept under 1 mg/kg per session.[26] In our study, the dosage per session was maintained at 1 mg/kg and the interval between injections was fixed at 3–4 weeks. The recommended dose for intralesional bleomycin injection (IBI) is 1 mg/kg/dose or summated dose should not exceed 5 mg/kg. The dose we employed in this study was 0.5 mg/kg/dose, which was much lower to cause pulmonary complications. To date, no cases of pulmonary fibrosis have been reported in the literature following its use as sclerotherapy. This is likely because it does not go into the circulation as opposed to patients treated systemically.

IBI is the modality of choice for all head-and-neck haemangioma and slow-flow VM in our centre before considering surgical excision. This was reported to lessen the chances of intravascular administration, anaphylactic reactions and enhanced therapeutic effect of the drug. However, no such complications were reported in our study despite intralesional bleomycin injection being performed without any USG guidance. This was in accordance with the study conducted by Bhardwaj et al.[23] All the 30 patients in our study were done in an outpatient setting without the need of general anaesthesia. Thus, intralesional sclerotherapy should be considered as the modality of choice for all head and neck haemangioma and slow-flow VM before considering surgical excision.

One of the limitations of this study is that the detailed genetic perspective was not taken into consideration as various genetic syndromes are often associated with VMs such as Kasabach–Merritt syndrome, Servelle–Martorell syndrome, Klippel–Trénaunay syndrome and Parkes Weber syndrome, though these were ruled out with a detailed case history. Further research is warranted to assess the genetic influence and effect of mutations on VMs.

CONCLUSION

It was concluded that intralesional bleomycin injection is a safe, effective sclerosing agent with minimal complication rate. It is a noninvasive tool in the treatment of LFVMs and precludes surgery, in most cases if not all and thus the subsequent scarring, especially in lesions present on the face. Thus, this treatment modality has to be considered before surgical excision as the aesthetic outcome of the therapy is also superior with higher patient satisfaction.

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

1. Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: A classification based on endothelial characteristics. Plast Reconstr Surg 1982;69:412–22.
2. Churojana A. Bleomycin: An effective drug for intralesional injection treatment of vascular anomalies. Pharm Pharmacol Int J 2020;8:38–40.
3. Mohan AT, Adams S, Adams K, Hudson DA. Intralesional bleomycin injection in management of low flow vascular malformations in children. J Plast Surg Hand Surg 2015;49:116–20.
4. Sheng L, Yu Z, Li S, Cao W, Jiang Z. Bleomycin sclerotherapy for large diffuse microcystic lymphatic malformations. Gland Surg 2021;10:1865–73.
5. Chen YN, Chen CP, Lin CJ, Chen SW. Prenatal ultrasound evaluation and outcome of pregnancy with fetal cystic hygromas and lymphangiomas. J Med Ultrasound 2017;25:12–5.
6. Erikci VS. Intralesional bleomycin sclerotherapy in children with lymphangiomas: A review article. Ann Plast Reconstr Surg 2020;4:1069.
7. Bagrodia N, Defnet AM, Kandel JJ. Management of lymphatic malformations in children. Curr Opin Pediatr 2015;27:356–63.
8. Regmi D, Bista M, Shrestha S, Shrestha D, Mahato NB. Comparative study on efficacy of intralesional bleomycin injection in head and neck lymphangioma and vascular malformation. J Clin Diagn Res 2017;11: MC04–6.
9. Bilici S, Avci V, Öztaş T, Asena M, Çelik K. The treatment of lymphangiomas with bleomycin in childhood: A retrospective observational study. Haydarpasa Numune Med J 2019;59:315–9.
10. Umezawa H. Recent study on biochemistry and action of bleomycin Carter SK, Crook ST, Umezawa H Bleomycin: Current Status and New Development. New York: Academic Press NY;1978:15–20.
11. Regmi D, Bista M, Shrestha S, Shrestha D, Mahato NB. Comparative study on efficacy of intralesional bleomycin injection in head and neck lymphangiomas and vascular malformation. J Clin Diagn Res 2017;11: MC04–6.
12. Horbach SE, Rigter IM, Smitt JH, Reekers JA, Spuls PI, van der Horst CM. Intralesional bleomycin injections for vascular malformations: A systematic review and meta-analysis. Plast Reconstr Surg 2016;137:244–56.
13. Upadhyaya VD, Bhatnagar A, Kumar B, Neyaz Z, Kishore JS, Sthapak E. Is multiple session of intralesional bleomycin mandatory for complete resolution of macrocystic lymphatic malformation?. Indian J Plast Surg 2018;51:60–5.
14. Achauer BM, Chang CJ, Vander Kam VM. Management of hemangioma of infancy: Review of 245 patients. Plast Reconstr Surg 1997;99:1301–8.
15. Hassan Y, Osman AK, Altyeb A. Noninvasive management of hemangioma and vascular malformation using intralesional bleomycin injection. Ann Plast Surg 2013;70:70–3.
16. Regmi D, Bista M, Shrestha S. Intralesional bleomycin injection in head and neck haemangioma and vascular malformation: A nonsurgical treatment. J Kathmandu Med Coll 2017;6:20;43-6..
17. Bhatnagar A, Upadhyaya VD, Kumar B, Neyaz Z, Kushwaha A. Aqueous intralesional bleomycin sclerotherapy in lymphatic malformation: Our experience with children and adult. Natl J Maxillofac Surg 2017;8:130–5.
18. Yura J, Hashimoto T, Tsuruga N, Shibata K. Bleomycin treatment for cystic hygroma in children. Nihon Geka Hokan 1977;46:607–14.
19. Sarihan H, Mocan H, Yildiz K, Abes M, Akyazici R. A new treatment with bleomycin for complicated cutaneous hemangioma in children. Eur J Pediatr Surg 1997;7:158–62.
20. Sachraswaty R, Laidding, Marthin SW, Josh F, Prihantono P. Intralesional Sclerotherapy Using Absolute Alcohol for Management of Haemangioma.”. American Journal of Medical Sciences and Medicine 2017;5:67–70.
21. Lee BB, Do YS, Byun HS, Choo IW, Kim DI, Huh SH. Advanced management of venous malformation with ethanol sclerotherapy: Mid-term results. J Vasc Surg 2003;37:533–8.
22. Pienaar C, Graham R, Geldenhuys S, Hudson DA. Intralesional bleomycin for the treatment of hemangiomas. Plast Reconstr Surg 2006;117:221–6.
23. Bhardwaj A, Gupta S, Moirangthem R, Anant A, Bharadwaj N. Intralesional bleomycin as therapeutic modality for low-flow venous malformations: Treatment on outpatient basis. Int J Head Neck Surg 2017;8:112–7.
24. Zhao JH, Zhang WF, Zhao YF. Sclerotherapy of oral and facial venous malformations with use of pingyangmycin and/or sodium morrhuate. Int J Oral Maxillofac Surg 2004;33:463–6.
25. Muir T, Kirsten M, Fourie P, Dippenaar N, Ionescu GO. Intralesional Bleomycin Injection (IBI) treatment for haemangiomas and congenital vascular malformations. Pediatr Surg Int 2004;19:766–73.
26. Pawar NM, Singh AP, Gupta AK, Chaturvedi V, Barolia DK. Comparison of intralesional bleomycin with/without doxycycline in the primary management of pediatric lymphangiomas. Formos J Surg 2021;54:177–82.
Keywords:

Intralesional bleomycin injection; sclerotherapy; vascular malformation

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