Bleomycin electrosclerotherapy: new treatment to manage vascular malformations



British Journal of Oral and Maxillofacial Surgery, 2017-11-01, Volume 55, Issue 9, Pages 977-979, Copyright © 2017 The British Association of Oral and Maxillofacial Surgeons

Abstract

Venous malformations are congenital anomalies of the vascular system. The injection of bleomycin (a cytotoxic, antitumour drug) into the lesion is a safe and effective treatment for low-flow (venous and lymphatic) malformations, but its use systemically has been associated with pulmonary fibrosis. Intralesional injection of bleomycin is considered to have a lower risk, but caution should be used when planning treatment, with particular regard to respiratory function. Electroporation is the temporary application of an electrical field across a tissue to increase (briefly) the permeability of the cell membrane in that tissue. We successfully treated a venous malformation in a patient with severe respiratory compromise with a low dose of bleomycin into the lesion, which we augmented using electroporation. To the best of our knowledge, this is the first reported use of bleomycin electrosclerotherapy in the management of a venous malformation.


Introduction

Vascular malformations are congenital anomalies of the vascular system and are a challenge both therapeutically and diagnostically. Current management mainly consists of techniques of intralesional sclerotherapy. Bleomycin is a cytotoxic, antitumour drug with sclerosant properties, and the use of it intralesionally is safe and effective for the treatment of venous malformations. There is an established link between its systemic use and pulmonary fibrosis, and a single case report shows this complication with intralesional injection of bleomycin also. We give our patients a specialist respiratory assessment, (which involves testing their pulmonary function) before treatment, to provide a baseline for comparison and diagnose any pre-existing respiratory conditions.

Intralesional injection of bleomycin is also used to manage various types of skin cancer, and is typically combined with the technique of electroporation (known as “electrochemotherapy”). Electroporation applies an electrical field across cells to increase the permeability of the membranes. We apply pulsed, short, high-intensity electrical fields to the tissues through electrodes placed into the lesions, and inject a drug (in this case, bleomycin), either systemically or intralesionally.


Case study

A 76-year-old man, who was a retired plant operator, presented to our clinic with a venous malformation. It had been noted in childhood, affected both cheeks, and extended into the mouth and tongue. Excision had been attempted twice in the past, and he had had a course of radiotherapy, neither of which had worked. He had lived with the malformation ever since, and sought referral to us only because of a steady increase in its size and symptoms. Ultrasound examination supported the physical findings of a venous malformation that affected the entire tongue and involved the cheeks bilaterally ( Fig. 1 ).

Clinical photograph showing the venous malformation before treatment.
Fig. 1

Clinical photograph showing the venous malformation before treatment.

The malformation was accessible percutaneously and was therefore ideal for treatment with injection of intralesional bleomycin. The patient had poor respiratory function secondary to severe chronic obstructive pulmonary disease because of a history of smoking and exposure to coal dust.

We devised a management plan after discussion with him that involved a reduced dose of intralesional bleomycin, and we did serial pulmonary function tests between injections. We repeated treatment over a course of six sessions with six-week intervals, and continued it based on the response. Small improvements were seen after each session, but the overall response was minimal. We think that this was probably because of the reduced dose of bleomycin (a third of the standard) used.

After further discussion with him we did one more session of injections (still at a reduced dose) accompanied by electroporation. On review one month later, the malformation had reduced considerably in size, his symptoms had eased, and he had had no complications ( Fig. 2 ). No deterioration in respiratory function was seen throughout the duration of treatment.

Clinical photograph showing considerable improvement in the venous malformation after treatment.
Fig. 2

Clinical photograph showing considerable improvement in the venous malformation after treatment.


Discussion

Electrochemotherapy with bleomycin has been used extensively in the treatment of cutaneous malignancies without serious adverse events.

The use of intralesional bleomycin in the treatment of venous malformations is well established and associated with a favourable ratio of benefit:risk. A recent meta-analysis showed good to excellent rates of response in 87% of those treated.

In this instance, electrosclerotherapy enabled us to use a reduced dose of bleomycin. For units with access to electroporation devices, this may also be a simple way of improving response to intralesional bleomycin when treating venous malformations and the approach will be an exciting direction for future research.


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Bleomycin electrosclerotherapy: new treatment to manage vascular malformations

L. McMorrow
, M. Shaikh
, G. Kessell
and T. Muir

British Journal of Oral and Maxillofacial Surgery, 2017-11-01, Volume 55, Issue 9, Pages 977-979, Copyright © 2017 The British Association of Oral and Maxillofacial Surgeons

Abstract
Venous malformations are congenital anomalies of the vascular system. The injection of bleomycin (a cytotoxic, antitumour drug) into the lesion is a safe and effective treatment for low-flow (venous and lymphatic) malformations, but its use systemically has been associated with pulmonary fibrosis. Intralesional injection of bleomycin is considered to have a lower risk, but caution should be used when planning treatment, with particular regard to respiratory function. Electroporation is the temporary application of an electrical field across a tissue to increase (briefly) the permeability of the cell membrane in that tissue. We successfully treated a venous malformation in a patient with severe respiratory compromise with a low dose of bleomycin into the lesion, which we augmented using electroporation. To the best of our knowledge, this is the first reported use of bleomycin electrosclerotherapy in the management of a venous malformation.

Introduction
Vascular malformations are congenital anomalies of the vascular system and are a challenge both therapeutically and diagnostically. Current management mainly consists of techniques of intralesional sclerotherapy. Bleomycin is a cytotoxic, antitumour drug with sclerosant properties, and the use of it intralesionally is safe and effective for the treatment of venous malformations. There is an established link between its systemic use and pulmonary fibrosis, and a single case report shows this complication with intralesional injection of bleomycin also. We give our patients a specialist respiratory assessment, (which involves testing their pulmonary function) before treatment, to provide a baseline for comparison and diagnose any pre-existing respiratory conditions.
Intralesional injection of bleomycin is also used to manage various types of skin cancer, and is typically combined with the technique of electroporation (known as “electrochemotherapy”). Electroporation applies an electrical field across cells to increase the permeability of the membranes. We apply pulsed, short, high-intensity electrical fields to the tissues through electrodes placed into the lesions, and inject a drug (in this case, bleomycin), either systemically or intralesionally.

Case study
A 76-year-old man, who was a retired plant operator, presented to our clinic with a venous malformation. It had been noted in childhood, affected both cheeks, and extended into the mouth and tongue. Excision had been attempted twice in the past, and he had had a course of radiotherapy, neither of which had worked. He had lived with the malformation ever since, and sought referral to us only because of a steady increase in its size and symptoms. Ultrasound examination supported the physical findings of a venous malformation that affected the entire tongue and involved the cheeks bilaterally ( Fig. 1 ).

Fig. 1

Clinical photograph showing the venous malformation before treatment.

The malformation was accessible percutaneously and was therefore ideal for treatment with injection of intralesional bleomycin. The patient had poor respiratory function secondary to severe chronic obstructive pulmonary disease because of a history of smoking and exposure to coal dust.
We devised a management plan after discussion with him that involved a reduced dose of intralesional bleomycin, and we did serial pulmonary function tests between injections. We repeated treatment over a course of six sessions with six-week intervals, and continued it based on the response. Small improvements were seen after each session, but the overall response was minimal. We think that this was probably because of the reduced dose of bleomycin (a third of the standard) used.
After further discussion with him we did one more session of injections (still at a reduced dose) accompanied by electroporation. On review one month later, the malformation had reduced considerably in size, his symptoms had eased, and he had had no complications ( Fig. 2 ). No deterioration in respiratory function was seen throughout the duration of treatment.

Fig. 2

Clinical photograph showing considerable improvement in the venous malformation after treatment.

Discussion
Electrochemotherapy with bleomycin has been used extensively in the treatment of cutaneous malignancies without serious adverse events.
The use of intralesional bleomycin in the treatment of venous malformations is well established and associated with a favourable ratio of benefit:risk. A recent meta-analysis showed good to excellent rates of response in 87% of those treated.
In this instance, electrosclerotherapy enabled us to use a reduced dose of bleomycin. For units with access to electroporation devices, this may also be a simple way of improving response to intralesional bleomycin when treating venous malformations and the approach will be an exciting direction for future research.

Conflict of interest
We have no conflicts of interest.

Ethics statement/confirmation of patient’s permission
N/A. We obtained the patient’s permission for the use of the clinical images in this paper, and all have been anonymised.

References

1. Mulliken J.B., Glowacki J.: Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 1982; 69: pp. 412-422.

2. Horbach S.E., Rigter I.M., Smitt J.H.S., et. al.: Intralesional bleomycin injections for vascular malformations: a systematic review and meta-analysis. Plast Reconstr Surg 2016; 137: pp. 244-256.

3. Atwa K., Abuhasna S., Shihab Z., et. al.: Acute pulmonary toxicity following intralesional administration of bleomycin for a lymphovenous malformation. Pediatr Pulmonol 2010; 45: pp. 192-196.

4. Gothelf A., Mir L.M., Gehl J.: Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation. Cancer Treat Rev 2003; 29: pp. 371-387.

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