Role of Bleomycin in Treatment of
Cystic Hygroma
Saxena S1, Hajela S2
1Dr. Sunil Kumar Saxena, Assistant Professor, Department of
Surgery,2Dr.Shalini Hajela, Assistant Professor, Department of
Pediatrics, Both are affiliated to Bundelkhand Medical College, Sagar,
MP, India
Address for correspondence:
Dr.Sunil Kumar Saxena, Email: sunilsaxena599@yahoo.com
Abstract
Introduction:
Cystic hygroma is a congenital multiloculated lymphatic lesion which
most commonly occurs in cervicofacial region (posterior triangle of
neck) and axilla. It is a benign cystic variety and the commonest form
of lymphangioma. It contains watery fluid consistent with lymph.
Bleomycin is a chemotherapeutic agent which acts by causing breaks in
DNA. We used bleomycin, an intralesional sclerosing agent as an
alternative to surgical excision. Methods:
After written informed consent of the guardians of the patients, all
the patients were given intralesional bleomycin injection at the dose
of 0.2 mg/kg body weight. Under all aseptic precautions, the lymphatic
fluid was aspirated completely and injection bleomycin was given from
same site. This injection was repeated at an interval of 4 weeks. Post
operatively compression dressing was done for 24 hrs. Results: Complete
resolution of cystic hygroma was seen in 21(42%) patients while partial
response in 18 (36%). No response, which is accumulation of lymphatic
fluid in the cyst after repeated injection of bleomycin for 4 times,
was noted in 11 (22%) patients. Complications such as local irritation,
redness at the injection site or fever occurred in 7 patients which
were controlled with antibiotic and antiallergic therapy. Conclusion:
Intralesional bleomycin can be used as first line of management in
patients with large cystic hygroma, since it avoids invasive surgery
and reduces risk of damage to vital organs. It is a safe, simple and
effective method and can be done on day care basis.
Keywords:
Asceptic Fibrosis, Bleomycin, Cystic Hygroma, Cystic Lymphangioma.
Manuscript received:
7st Feb 2014, Reviewed:
10th Feb 2014
Author Corrected: 19th
Feb 2014, Accepted for
Publication: 27th Feb 2014
Introduction
Cystic hygroma is a congenital malformation of the lymphatic system.
Hygroma in Greek means water-containing tumour. They are cystic variety
of lymphangioma. Cystic hygroma occurs more frequently as compared to
other types of lymphangioma, and may compose of single (unilocular) or
multiple (multilocular) macrocystic lesions having scarce communication
with normal lymphatic channels [1]. Lymphangiomas are usually
classified as capillary, cavernous or cystic lymphangiomas. They may
also be classified more conveniently, on the basis of size of the cysts
contained, as microcystic, macrocystic and mixed lymphangiomas.
Microcystic lymphangioma consists of cysts measuring less than 2 cm in
size, whereas the size of cysts in case of macrocystic lymphangioma is
more than 2 cm. The mixed lymphangioma is characterized by cysts of
variable sizes, i.e. some cysts are more than 2 cm in size and others
are less than 2 cm. The size of the lymphangioma is directly related to
the degree of obstruction of lymphatico-venous drainage as evidenced by
histologic appearance [2].
The common locations are cervico-facial regions (especially posterior
cervical triangle), axilla, mediastinum, groin and below tongue;
occasionally, these malformations occur in liver, spleen, kidney and
intestine [3]. On clinical examination, these lesions appear soft,
compressible, non-tender, transluminant and without any bruit.
Ultrasound of the lesion usually features multicystic lesion with
internal septations and no blood flow is detected on color doppler
ultrasonography. Other modalities like CT scan and MRI can be employed
to delineate the lesion, in a better way. A CT scan demonstrates
multicystic, homogeneous, non-invasive density with low attenuation.
These modalities are usually helpful in ascertaining the extent of the
lesion and their association with nerves and vessels and are
particularly useful, when surgical management of the lesion is
contemplated. These cysts may produce milky, serous, sero sanguinous or
straw-coloured fluid, when aspirated with a wide-bore needle [4].
Intralesional sclerotherapy has become an acceptable method of
treatment for lymphangiomas in children. It involves the use of a
sclerosing agent that causes irritation of the endothelial lining of
the lymphangioma, which leads to inflammation, fibrosis and involution.
Other modes of treatment that have been employed with variable results
include complete surgical resection, incision and drainage,
aspirations, radiation therapy [5], laser excision, radio-frequency
ablation and cauterization [4]. Complete surgical resection, which was
considered ideal treatment, is impossible in many cases due to the
nature of cystic hygroma, which has propensity to infiltrate tissue
planes and encircle important neurovascular structures. Tumour
recurrences and nerve injuries are common complications following
surgery. Previously reserved for treatment of unresectable
lymphangiomas or in cases of tumour recurrence following surgery,
intralesional sclerotherapy has gained popularity over recent years.
Several studies using bleomycin and a newer agent OK-432 as
sclerosants, have shown that this method of treatment produces
favourable results compared to surgery [5]. We have used bleomycin for
intralesional sclerosant therapy of cystic hygroma, and the primary
reason for choosing to use bleomycin is because it was available while
OK-432 is not yet available in India.
Materials
and methods
This was a prospective review of 50 successive cases of lymphangioma .
The procedures were conducted in the Surgery Department of Bundelkhand
Medical College, Sagar between January2010 and January 2012.The
diagnosis of lymphangioma in these patients was made on the basis of
clinical examination and imaging findings , mainly ultrasound (USG) and
computed tomography (CT). Ultrasonographic assessment was performed on
all patients. Patients’ age, sex, body weight, symptoms,
lesion location and lesion size were recorded. Under the effect of
general anaesthesia in some patients and under local anaesthetic in
others, and with strict aseptic precautions, the cystic components of
the tumour were aspirated with a hypodermic syringe and 23G needle
using ultrasonographic guidance. While keeping the tip of aspiration
needle within a cyst lumen, 0.2 mg per kg body weight of bleomycin
aqueous solution (1.5 mg/ml water) was injected. When more than one
cyst was aspirated, the calculated dose was divided by the number of
cysts aspirated and the divided dose was injected into each cyst. This
procedure was repeated after 4 weeks if the cystic component persisted
and measured at least 1 cm in diameter. The maximum cumulative dose of
bleomycin allowed was 5 mg per kg body weight. Patients were admitted
for at least 24 hours following the procedure and monitored for
possible immediate and delayed complications of the treatment. After
discharge, patients were followed-up after 2 to 4 weeks when clinical
assessment and measurements were made. If the lesion was still present,
it was assessed with USG to see if further intralesional bleomycin was
feasible. A repeat procedure was done when there were cysts that
measured at least 1 cm in diameter. This was the minimum cyst size
where the radiologists felt confident to aspirate and maintain tip of
the needle within the cyst lumen for the bleomycin injection. Follow-up
and additional injections were given until the lesion completely
resolved or intralesional bleomycin was no longer feasible (cysts
measured less than 1 cm).
The response was graded as complete resolution (total disappearance),
good response (showing > 50% reduction in size) and poor
response (showing < 50% reduction or no change in size).
Recurrence was defined as reappearance of the tumour after complete
resolution or increase in size after initial significant reduction in
size. When bleomycin sclerotherapy was no longer required or no longer
feasible, the follow up period was increased to 3 monthly, then 6
monthly until the size of the lesion was stable, and then yearly.
Patients who showed poor response were offered surgery.
Results
During the 2 yr study period, 50 patients were included in the study,
with ages ranging from 6 years to 15 years. Out of 50 patients, 34
patients were male and 16 patients were female. All patients had a
swelling. Other symptoms included pain, tenderness and skin erythema.
The most common site of lesion was the neck, followed by face, axilla,
chest, buttocks and thigh. Lesions of the face were sited over the pre
and post-auricular regions. Chest lesions were sited at the
sub-clavicular region. The number of procedures per patient varied from
once to 6 times, with a cumulative dose of 1 to 20 mg bleomycin. Total
follow-up period from the time of 1st injection ranged from 2 to 24
months.
Table-1: Site of Lesion
|
|
Total
|
%
|
|
Neck
|
28
|
56
|
|
Axilla
|
5
|
10
|
|
Parotid
|
4
|
8
|
|
Chest wall
|
3
|
6
|
|
Buttock
|
4
|
8
|
|
Abdomen & Upper thigh
|
6
|
12
|
Complete resolution was seen in 42 %( 21/50) of lesions, 36
% (18/50) had good response and the remaining 22 % (11/50) had poor
response or no response. The observations were recorded at the end of
follow-up or at the time the patient was last seen in the clinic, the
first patient who failed intralesional sclerotherapy had six injections
and minimal reduction in size was achieved. . After six injections,
there were no further cysts large enough for aspiration and injection.
Table 2: Response to treatment
|
|
N
|
%
|
|
Complete resolution
|
21
|
42
|
|
Good response
|
18
|
36
|
|
Poor/No Response
|
11
|
22
|
Immediate complications reported include skin erythema at
injection site, local swelling, mild tenderness and fever, which were
controlled by oral antipyretics. However, no life- threatening
complications such as respiratory obstruction and severe
hypersensitivity reaction to bleomycin were observed. No patient
developed excessive scarring as a result of the procedure.
Table 3: Complications
|
|
Number
|
%
|
|
Fever
|
7
|
35
|
|
Local pain
|
10
|
50
|
|
Erythema
|
3
|
15
|
|
Hematoma and cellulitis
|
0
|
0
|
Discussion
First described by Wermer in 1843, Cystic hygroma is a cystic
lymphatoid lesion, also called as cystic lymphangioma and macrocystic
lymphatoid malformation, first described in 1828 by Redenbacker [6].
Cystic Hygroma manifests at birth in up to 65% and presents by the age
of 2 years in 80–90% of cases. The incidence of lymphangioma
is reported to be from 1.5–2.8 per 1000, and it has no
predilection for either sex or any race [5]. The reported incidence of
these tumors is quite variable ranging from 1 in 1000 to 1 in 16000
live births [7]. Embryologically, these lesions are believed to
originate from sequestration of lymphatic tissue from lymphatic sacs,
during the development of lymphatico-venous sacs. These sequestered
tissues fail to communicate with remainder of the lymphatic or venous
system. Later on, dilatation of the sequestered lymphatic tissues
ensues, resulting in the cystic morphology of these lesions [2].
The common locations in 75% cases are cervico-facial regions
(especially posterior cervical triangle), in 20% cases axilla and rest
5% being superior mediastinum, groin, retroperitoneum, pelvis, bones,
scrotum and below tongue. Occasionally, these malformations occur in
liver, spleen, kidney and intestine. Omental cyst in omentum and
mesenteric cyst in the mesentery of intestine represents parallel
lesions at these locations [3].Lymphatic malformations can be
congenital or acquired. Acquired lesions generally arise from
obstruction of the lymphatic system due to trauma or infection. This
might represent dormant cystic hygroma that can appear at any age,
trauma being a coincident event [8]. Cystic hygroma may be associated
with Turners Syndrome, Noonan Syndrome, Trisomies (Down’s
Syndrome {Trisomy 21},Trisomy 18,Trisomy 13), cardiac anomalies, Fetal
hydrops [1,4]. A lethal version of this condition is known as Cowchock
Wapner Kurtz syndrome that, in addition to cystic hygroma, includes
cleft palate and lymphedema, a condition of localized edema and tissue
swelling caused by a compromised lymphatic system [9].
The most common symptoms are swelling and cosmetic deformity. A large
lesion in the neck can compress vital structures, cause respiratory
obstruction, dysphagia and symptoms of nerve compression [5]. The main
indications of treatment are respiratory distress, recurrent
infections, cosmetic reasons and compression of local structures like
airway, blood vessel and upper gastrointestinal tract. Intralesional
sclerotherapy has become the preferred modality of treating cystic
hygroma with increasingly documented remarkable results for management
of such lesions with sclerosant agents although complete surgical
excision used to be the ideal treatment in the pre-sclerotherapy times.
The other treatment modalities that have been employed with variable
results include simple drainage, aspirations, radiation, laser
excision, radio-frequency ablation and cauterization [10].
The idea of using sclerotherapy in the treatment of lymphangioma
occurred when it was noted that lymphatic malformations spontaneously
involute when they became infected and the infection resolved. The
first case of lymphangioma treated by sclerotherapy was reported in
1933, using sodium morrhuate [5]. Complete tumour regression was noted
in 6 weeks following intralesional injection [10]. Other sclerosing
agents that have been used previously, namely iodine, ethanolamine
oleate, alcohol, ethibloc, sodium tetradecyl sulfate, tetracycline and
cyclophosphamide [5,9]. Bleomycin and OK-432(Picibanil) are currently
the most popular sclerosants. However, only bleomycin is available in
India. Bleomycin is an anti-neoplastic antibiotic, produced by the
fermentation of streptomyces verticillus. Discovered in 1965 by
Umezawa, this drug was found to cause single strand and double strand
DNA breaks and inhibition of DNA and RNA synthesis. Initially, when
this anti-neoplastic drug was used in the treatment of malignant
pleural effusion, it was observed that bleomycin caused marked fibrosis
and scarring. This sclerosing property was first put to use in 1977 by
Yura in the treatment of cystic hygroma [4]. Studies using bleomycin
have produced promising results in cases of cystic hygroma [5].
Side effects of Bleomycin are fever, transient increase in
size of swelling, hemorrhage, leukocytosis, infection, and pulmonary
fibrosis. The primary concern of bleomycin therapy is its risk of
pulmonary toxicity. The risk is dose related with an increased
incidence associated with a total dose exceeding 30 mg/m2 of body
surface area or total cumulative dose of 400 mg given intra-venously to
oncology patients. Elderly oncology patients and those with underlying
pulmonary disease and renal failure were at greater risk [5]. Bleomycin
doses used in sclerotherapy are small in comparison, typically 1% to 5%
of the lowest dose associated with possible pulmonary fibrosis. [11] We
used 0.2 mg/kg of dose. Others have used it in doses ranging from 0.3
to 3 mg/kg. [12]. In our study, after intralesional bleomycin therapy,
complete resolution was seen in 42 %( 21/50) of lesions, 36 % (18/50)
had good response and the remaining 22 % (11/50) had poor response or
no response. Our study indicated that intralesional bleomycin therapy
was very effective and the results were comparable to various published
series. Other authors have also quoted success rates of between 36 to
63% for complete tumour regression, of up to 88% significant lesion
regression, and poor response of between 12 to 23% using either
bleomycin or OK-432. Rozman et al noted excellent and good response in
63% (15/24) of lesions and 21% (5/24) patients [5]. Niramis et al noted
83% of response [13] where as Baskin et al noted about 95% of response
[14], suggesting good activity of bleomycin for the purpose. Okada
observed 86% (25cases) showed significant reduction of the mass and 55%
(16 cases) showed complete disappearance in a study on intralesional
sclerotherapy in 29 cases [10]. Orford observed an excellent (complete
clinical resolution) response in seven (44%) patients, a good (>
50% response) result in seven (44%), and a poor or no response in two
(12%) suggesting that bleomycin intralesional sclerosant is effective
therapy for cystic hygroma, with response rates comparable to those of
surgical removal, but with the advantage of avoiding inadvertent nerve
damage and scarring [15].
No serious complications were seen as a result of intralesional
bleomycin therapy. Most patients complained of mild skin erythema,
local swelling, induration, mild tenderness and fever. These symptoms
lasted for a day or two but did not prolong their stay in hospital. In
this study, few complications were noted as also noted by Rozmann [5],
whereas Niramis et al noted complications in about 43% of patients
[13]. Clinical studies done at various places in which patients were
treated with intralesional bleomycin did not report pulmonary fibrosis
as a complication. Although surgical excision has been considered to be
treatment of choice by most of the surgeons, it is associated with
tedious dissection along with lot of morbidity in the form of
disfigurement and damage to vital structures adjacent to the mass
including damage to a neurovascular structure (including cranial
nerves), chylous fistula, chylothorax, hemorrhage, infection, wound
seroma, ugly scar and recurrence. Recurrence rates vary depending on
the complexity of the lesion and the completeness of excision. If
residual tissue is left behind, the expected recurrence rate is
approximately 15%. Most recurrences occur within the first year but
have been reported to occur as long as 10 years after excision.
Postoperative complications occur in 30% or more of cases. Therefore,
sclerotherapy of lymphangioma has gained popularity during recent
years. In this prospective study, we found the response satisfactory in
almost 78% of cases (Complete resolution in 42% and Good response in
36%) as also observed in various case series. In short term follow up
no recurrence was encountered. Others have also not found recurrence to
be of much concern [5, 12]. Although mortality has been reported by
Niramis et al [13], it was not seen in this series.
Conclusion
Intralesional bleomycin therapy is a safe and effective method of
treatment for lymphangioma. The results from our series are comparable
with other published series and support the continued use of
sclerotherapy with bleomycin in the treatment of lymphangioma. No
serious side effects from intralesional bleomycin therapy were
observed. Sclerotherapy is recommended in place of surgery as the
first-line treatment modality. The latter must be reserved for those
lesions where sclerotherapy had failed. However continued trials and
long term follow up is required to establish intralesional
sclerotherapy with bleomycin as the gold standard for the treatement of
cystic hygroma.
Funding:
Nil, Conflict of
interest: Nil
Permission from IRB:
Yes
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How to cite this article?
Saxena S, Hajela S. Role of Bleomycin in Treatment of Cystic Hygroma.
Int J Med Res Rev 2014;2(4):344- 348.doi:10.17511/ijmrr.2014.i04.015