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B. Tander1
M. Bankaoğlu2
Aim: We report here our experience with local bleomycin injection in lymphangioma. Patients and Methods: Nine patients
with lymphangioma were treated with locally injected bleomycin and followed prospectively. We performed an ultrasound
study in all cases to delineate the size, location, nature, and number of compartments of the cyst prior to the injection. Under ultrasound guidance, the content of the cystic cavity was aspirated
and 1 – 3 mg/kg bleomycin were injected. The patients were revisited monthly. No attempt at re-injection was made as long as
the mass continued to decrease in size. Results: Patients consisted of 4 boys and 5 girls aged between 14 days and 6 years.
The localisation of the mass was cervical in 6, cervical, sublingual, and lingual in 1, axillary in 1 and axillary and thoracic in 1.
In six children, the mass disappeared totally after a single injection. In one patient a second injection was needed, and surgical
excision was performed in two patients with residual solid component. No complication related to bleomycin was seen. Conclusion: Local application of bleomycin in children with lymphangioma is a simple, safe, and effective method. In the majority of
cases, total healing may be achieved with a single injection.
étude ultra-sonographique pour définir la taille, la localisation, la
nature et le nombre de kystes avant l’intervention. Sous contrôle
échographique: le contenu du kyste est aspiré et 1 à 3 mg/Kg de
Bléomycine sont injectés. Les patients étaient revus chaque mois.
Aucune ré-injection n’était faite tant que la masse continuait à
diminuer en taille. Résultats: Il y avait 4 garçons et 5 filles, âgés
de 14 jours à 6 ans. La localisation de la masse était cervicale
dans 6 cas, cervicale et linguale dans un, axillaire dans un, et axillaire et thoracique dans un. Chez 6 enfants, la masse disparaissait
totalement après une première injection; chez un patient, une
seconde injection était nécessaire et une excision chirurgicale a
été réalisée chez 2 patients avec l’exérèse d’un résidu fibreux. Aucune complication, liée à l’injection de Bléomycine, n’était observée. Conclusion: l’injection locale de Bléomycine chez l’enfant
avec un lymphangiome est une méthode simple, sûre et efficace
de traitement. Dans la majorité des cas, le traitement peut être
réalisé avec une simple injection.
383
Mots-clés
Hygroma cystique · bléomycine · lymphangiome
Resumen
Key words
Cystic hygroma · bleomycin · lymphangioma
Résumé
But: Nous rapportons notre experience de l’injection de Bléomycine dans un lymphangiome. Matériel et Méthodes: 9 patients
avec un lymphangiome étaient traités avec une injection locale
de Bléomycine et suivis. Dans tous les cas, nous réalisons une
1
Original Article
Abstract
Local Bleomycin Injection in
the Treatment of Lymphangioma
Objetivo: Presentamos nuestra experiencia con la inyección local
de bleomicina en el linfangioma. Material y Métodos: Tratamos
9 pacientes con linfangioma mediante inyecciones locales de
bleomicina. En todos los casos se realizó un estudio ecográfico
para delinear el tamaño, la localización, la naturaleza y el número de compartimentos del quiste antes de la inyección. Se aspiró
en contenido de la cavidad quística bajo control ultrasónico y se
inyectaron 1 a 3 mg/Kg de bleomicina. Los pacientes fueron vistos mensualmente. No se intentó reinyección alguna mientras la
Affiliation
Department of Pediatric Surgery, Şişli Etfal Education and Research Hospital, İstanbul, Turkey
2
Department of Radiology, Şişli Etfal Education and Research Hospital, İstanbul, Turkey
Correspondence
Dr. Didem Baskın · Pehlivanyanı Sok. 7/4 · 34934 Mecidiyeköy, İstanbul · Turkey · E-mail: [email protected]
Received: May 31, 2004 · Accepted after Revision: August 18, 2004
Bibliography
Eur J Pediatr Surg 2005; 15: 383 – 386 · © Georg Thieme Verlag KG Stuttgart · New York ·
DOI 10.1055/s-2005-872922 ·
ISSN 0939-7248
Downloaded by: University of Washington at Seattle. Copyrighted material.
D. Baskın1
Original Article
Palabras clave
Higroma quístico · bleomicina · linfangioma
Zusammenfassung
Zielsetzung: Ziel der Arbeit war es, die Erfahrungen der lokalen
Bleomycin-Injektion zur Behandlung von Lymphangiomen zu
überprüfen. Patienten und Methodik: Neun Patienten mit
Lymphangiom wurden mit lokalen Bleomycin-Injektionen behandelt und prospektiv untersucht. Bei allen Kindern wurde eine
Introduction
384
Lymphangiomas are congenital lymphatic malformations that
occur as large, soft cystic masses with distortion of the associated anatomic area. About 75 % occur in the neck with a predilection for the left side, mainly the posterior triangle, and 20 % occur
in the axillary region. The rest is usually distributed among the
mediastinum, retroperitoneum, pelvis, and groin [9].
The treatment of lymphangioma depends on the clinical presentation, the size of the lesion, the anatomic localization, and the
complications. Although surgical excision has been considered
as a mode of treatment by the majority of surgeons, the patient
can be affected by several morbid conditions such as nerve injuries, prolonged lymphatic drainage, recurrence, wound infections, unacceptable scar formation, and incomplete resections
due to infiltration of adjacent vital structures [3].
The use of sclerosing agents as an alternative to surgical excision
has been met with some scepticism. Recently, two sclerosing
agents, bleomycin and OK-432, have been favoured by some surgeons in the treatment of lymphangioma [3, 9]. A prospective
clinical trial was conducted to evaluate the efficacy of single injection of bleomycin for the treatment of lymphangioma in children.
Patients and Method
A prospective clinical trial was conducted in the Department of
Paediatric Surgery of the Şişli Etfal Education and Research Hospital between 1997 and 2003.
Baskın D et al. Local Bleomycin Injection … Eur J Pediatr Surg 2005; 15: 383 – 386
Ultraschalluntersuchung vorgenommen, um die Größe, Lokalisation und Art des Lymphangioms sowie die Anzahl der Zystenkompartimente vor der Injektion festzulegen. Unter Ultraschallführung wurde dann die Zystenhöhle punktiert und 1 – 3 mg/kg
Bleomycin nach Aspiration von Flüssigkeit injiziert. Die Patienten wurden dann monatlich nachkontrolliert. Wenn die Zystengröße kontinuierlich abnahm, wurde keine Reininjektion vorgenommen. Ergebnisse: Insgesamt wurden 4 Knaben und 5 Mädchen im Alter von 14 Tagen bis 6 Jahren behandelt. Die Lokalisation des Tumors war bei 6 Kindern zervikal, bei einem zervikal
und sublingual, bei einem axillär und bei einem weiteren axillär
und thorakal. Bei 6 Patienten verschwand die Zyste vollständig
nach einer einzigen Injektion. Ein Patient benötigte eine zweite
Injektion, bei zwei weiteren Kindern musste die Zyste wegen eines soliden, verbleibenden Anteiles exzidiert werden. Nach der
Bleomycin-Behandlung wurden keine Komplikationen beobachtet. Schlussfolgerung: Die lokale Applikation von Bleomycin im
Kindesalter bei Lymphangiom ist eine sichere und effektive Methode, die in den meisten Fällen zu einer vollständigen Heilung
nach einer einzigen Injektion führt.
Schlüsselwörter
Zystisches Hygrom · Bleomycin · Lymphangiom
Diagnosis of lymphangioma was made by physical examination,
and Doppler ultrasonography (USG), computerized tomography
(CT), and/or magnetic resonance imaging (MRI) were employed
to identify the nature and the dimensions of the lesion. Details
of the treatment were explained to the family of each patient
and their consent was obtained.
Patients were hospitalised before injection. Complete blood
count and chest X-rays were taken. Allergic status of the patient
was noted.
Under general anaesthesia or sedation, depending on the patient’s age, cystic fluid was aspirated under the guidance of ultrasonography. Meticulous care was taken to perform the aspiration
atraumatically in order to minimise the absorption of bleomycin
systemically. After aspiration of the cystic fluid, bleomycin was
injected into each separate cystic cavity. A single vial of bleomycin hydrochloride (Bleocin 15 mg, Nippon Kayaku Co. Ltd.) was
used on each patient at a rate of 1 – 3 mg/kg, with the total dose
ranging between 6 and 15 mg. Bleomycin was diluted with 10 ml
of normal saline. Injection of 1 – 2 mg of bleomycin was performed for each cavity regardless of the amount of fluid aspirated. The total dose never exceeded 15 mg.
After the injection of bleomycin, a pressure dressing was applied
to the cyst. The patient was observed for 24 hours for any sign of
adverse reactions to bleomycin such as fever, cough, and dyspnoea. If no problem was encountered, the patient was discharged and subsequently recalled for monthly follow-up. A
chest X-ray was requested on the first visit. The size of the lesion
was measured at each visit using ultrasonography. If any residual
cystic mass was found, a second bleomycin injection was performed. Any solid residual component was excised after the disappearance of the cystic compound.
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masa continuó decreciendo. Resultados: Tratamos 4 varones y 5
mujeres de entre 14 días y 6 años. La localización de la masa era
cervical en 6, cervical y sublingual en 1, axilar en 1 y axilar y torácica en 1. En 6 niños la masa desapareció totalmente tras una
única inyección. En un paciente se requirió una segunda inyección y se realizó excisión quirúrgica en 2 que tenían un componente sólido residual. No hubo complicaciones relacionadas con
la bleomicina. Conclusión: La aplicación local de bleomicina en
niños con linfangioma es un método simple seguro y eficaz. En
la mayoría de los casos se puede obtener una curación completa
con una sola inyección.
Table 1 Patients receiving bleomycin treatment
Age
Localisation
Time in
hospital
(days)
Result
1
2 months
axillary and
thoracic
90
partial resection of
the solid component
2
14 days
cervical
1
disappeared
3
2.5 months
cervical
1
disappeared
4
1 month
cervical
1
disappeared
5
6 months
axillary
1
disappeared
6
2 months
cervical
2
disappeared on 2nd
injection
7
2 months
cervical and
sublingual and
lingual
8
6 years
cervical
1
disappeared
9
10 days
cervical
1
disappeared
10
Original Article
No.
solid rest removed by
ENT surgeons
Results
Nine patients were included in the study (Table 1). Their ages
ranged from 14 days to 6 years. There were 5 girls and 4 boys.
The localisation of the mass was cervical in 6, cervical, sublingual, and lingual in 1, axillary in 1, and axillary and thoracic with
an extension to the arm in 1.
A single injection was effective in 6 patients (Figs. 1, 2, and 3). Hygroma disappeared in all. In one patient with a cervical mass,
there was a recurrence 2 months later which disappeared after
the second injection. The median period of follow-up of these patients is 6 months.
Fig. 2
Appearance of patient 2 prior to injection.
Discussion
Fig. 3
Appearance of patient 2 at 5 months of age.
Lymphangioma or cystic hygroma is one of the most common
benign lesions of childhood. Surgical excision has been considered the treatment of choice. However, the lesion often infiltrates
the adjacent structures such as nerves and vessels, resulting in
incomplete resection or inadvertent nerve injury. Furthermore,
incomplete resection may lead to lymphorrhoea, wound infection, or recurrences.
Sclerotherapy is an alternative to surgery, and bleomycin and
OK-432 are the two most commonly used agents for sclerotherapy of lymphangioma. The lesion may disappear completely or
undergo a reduction in size that permits a complete surgical removal. Although more readily available than OK-432 in many
countries, the use of bleomycin has been restricted due to fear
Residual solid components were removed in 2 patients. In patient 1 with a giant hygroma that involved the neck, axilla, thorax, and arm without intrathoracic extension, the lesion decreased in size following bleomycin injection. Because of the intimate relation of the solid components with the axillary structures, only partial removal of the mass could be accomplished
after insertion of a tissue expander. In patient 7, the sublingual
solid component was removed by ear-nose-throat surgeons,
with bleomycin injection into the lingual cysts. The patient has
no residual disease 1 year after surgery.
No complications related to bleomycin were seen in any of the
patients. There was no mortality in the series.
Baskın D et al. Local Bleomycin Injection … Eur J Pediatr Surg 2005; 15: 383 – 386
385
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Fig. 1 MRI of patient
2, showing large cervical cystic lesion.
The standard dosage for bleomycin as a single agent in cancer
treatment is 0.25 – 0.5 mg/kg IV, IM or SC given one or two times
per week [2]. Doses between 0.25 and 0.6 mg/kg for each injection [7, 9,10], with a total amount of bleomycin injected up of to
50 mg [4] or 5 mg/kg [6], and up to 16 injections [6, 9] with intervals of between 2 weeks and 2 months have been reported in the
literature for the treatment of lymphangiomas [6, 9]. The total
dose we used for each patient was between 1 mg/kg and 3 mg/
kg. A second bleomycin treatment after 6 weeks has been recommended for patients whose initial response is not satisfactory
[9]. We did not consider a second injection in a patient as long
as the cysts continued to decrease in size and preferred to wait.
Although the cyst size decreased over 2 months, we needed to
wait 4 months in some patients for complete disappearance. A
second injection was needed in only one patient, whose cysts began to enlarge during follow-up. Ultrasonography-guided treatment of each separate cystic cavity may be the reason for the
successful results.
Induration and erythema of the overlying skin are the other wellknown side effects of the drug [2, 7]. Although we did not see
these complications during our 24 hours of observation, they
may have occurred after discharge. Some families described enlargement of the lesion in the first few weeks to the size prior to
the injection, probably due to inflammation. Signs of inflammation such as erythema and oedema should be expected because
inflammation is probably the main mechanism of action in
sclerotherapy with bleomycin [7]. This effect should limit the
use of bleomycin in enclosed spaces such as the thorax, because
there is not sufficient space to accommodate swelling if oedema
occurs and this may lead to respiratory distress [7].
Bleomycin injection is a simple and effective method for the sclerotherapy of lymphangioma, but surgeons should be aware of the
possible side effects and dose limitations of the drug. Information about the serum levels of the drug when injected into cystic
lesions needs to be made available.
Acknowledgement
We thank Prof. Dr. Nebil Büyükpamukçu for his critical review of
the paper, and Mr. Christopher Embleton for native language editing.
References
1
2
3
The main side effects of the drug are pulmonary toxicity, mucocutaneous effects such as erythema, oedema and alopecia, and
fever [8]. There is no known special side effect in newborns. The
late pulmonary toxicity of the drug is related to the cumulative
dose used [1, 2]. It has been reported that pulmonary toxicity is
more common in patients over 70 years, in those receiving prior
pulmonary radiation, in those receiving supplemental oxygen,
and when total doses greater than 400 U are used [2]. At total
doses of below 150 mg or 450 U, life-threatening pulmonary toxicity is rare [1, 2], occurring in 3 % to 5 % of patients [1]. Patients
with pulmonary toxicity present with a persistent dry cough
and exertional dyspnoea that can progress to tachypnoea, hypoxia, and death. The chest X-ray typically shows reticulonodular
infiltrates at the base [1, 2]. Acute pulmonary reactions are unpredictable, however, and have occurred at much lower doses.
The highest total dose we used was one third of the stated danger
level and we did not observe any of the signs or symptoms of pulmonary toxicity in our patients, but of course this is a small series. The advantages of our protocol are fewer injections for the
patient and a significant reduction in total hospitalisation time.
Baskın D et al. Local Bleomycin Injection … Eur J Pediatr Surg 2005; 15: 383 – 386
4
5
6
7
8
9
10
Balis FM, Holcenberg JS, Blaney SM. General principles of chemotherapy. In: Pizzo PA, Poplack DG (eds). Principles and Practice of Pediatric
Oncology. 4 th ed. Philadelphia, Baltimore, New York, London, Buenos
Aires, Hong Kong, Sydney, Tokyo: Lipincott Williams & Wilkins, 2002:
274 – 275
Dorr RT, von Hoff DD. Drug monographs, bleomycin sulfate. In: Dorr
RT, von Hoff DD (eds). Cancer Chemotherapy Handbook. 2 nd ed. Norwalk, Connecticut: Appleton & Lange, 1994: 227 – 235
Feins NR. Lymphatic disorders. In: O’Neill JA, Rowe MI, Grosfeld JL,
Fonklasrud EW, Coran AG (eds). Pediatric Surgery. 5th ed. St. Louis,
Baltimore, Boston, Calsbad, Chicago, Minneapolis, New York, Philadelphia, Portland, London, Milan, Sydney, Tokyo, Toronto: Mosby,
1998: 1973 – 1981
Jiang JP. Local injection of bleomycin A% in lymphangioma in children.
Analysis of 100 cases. Chung Hua Wai Ko Tsa Chih 1989; 27: 741 – 742,
781
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 – 773
Okada A, Kubota A, Fokuzawa M, Imura K, Kamata S. Injection of bleomycin as a primary therapy of cystic lymphangioma. J Pediatr Surg
1992; 27: 440 – 443
Orford J, Barker A, Thonell S, King P, Murphy J. Bleomycin therapy for
cystic hygroma. J Pediatr Surg 1995; 30: 1282 – 1287
Skeel RT, Lachant NA. Antineoplastic drugs and biologic response
modifiers: Classification, use and toxicity of clinically useful agents.
In: Skeel RT, Lachant NA (eds). Handbook of Cancer Chemotherapy.
4th ed. Philadelphia: Lippincott Williams & Wilkins, 1995: 142 – 144
Sanlialp I, Karnak I, Tanyel FC, Senocak ME, Büyükpamukçu N. Sclerotherapy for lymphangioma in children. Int J Pediatr Otorhinolaryngo
2003; 67: 795 – 800
Stringel G. Hemangiomas and lymphangiomas. In: Ashcraft KW (ed).
Pediatric Surgery. 3 rd ed. Philadelphia, London, New York, St. Louis,
Sydney, Toronto: W.B. Saunders Company, 2000: 965 – 986
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Original Article
386
of pulmonary toxicity. There is no standard dosage for the sclerosing therapy with bleomycin. Bleomycin is currently used for
the treatment of various cancers such as lymphomas, testicular
cancer, and other germ cell tumours. Bleomycin also has been
administered regionally into the pleural space for malignant
pleural effusions and intravesicularly for bladder tumours [2]. A
recent report details its use in haemangiomas and vascular lesions [5]. Serum levels of the drug are well known with intravenous, intra-arterial, intrapleural, intraperitoneal, intravesicular, or intratumoural administration [2], but there is no published information on the serum levels of bleomycin when administered into cystic lesions. About 45 – 50% of the drug is systemically absorbed with an intracavitary injection. Thus, in our
series sedation and ultrasonographic guidance were used to inject the drug as atraumatically as possible into the cysts and not
into any other tissue.