Bleomycin sclerotherapy in lymphangiomas of the head and neck region: a prospective study Tiwari P, et al. Int J Oral Maxillofac Surg (2020) Lymphatic malformations (LMs), traditionally called lymphangiomas, are developmental disorders of the lymphatic system and one of the most common vascular malformations. Around 50% of affected children present with an asymptomatic mass at birth, while 90% of LMs manifest within the first 2 years of life. The site of involvement and symptoms at presentation vary. lesions in the head and neck region with significant extension may cause severe respiratory distress. The functional and cosmetic problems caused by these lesions and their progressive nature are bothersome for parents, and such patients have long warranted treatment. Excision was the most common treatment modality used in the past, but was associated with high morbidity due to the close relationship of the lesion with the vital structures. Excision was also associated with scarring along with very high recurrence rates With the advent of sclerotherapy, the treatment results have improved and response rates have been excellent. Different agents have been used as sclerosants and have shown good results in different studies. Sclerotherapy has the added advantage of better cosmesis and lesser associated morbidity. Bleomycin is one of the most common sclerosants used in the head and neck region. This study was performed to evaluate the role of Bleomycin sclerotherapy in the management of the different radiological variants of lymphangiomas of the head and neck. Patients and methods A prospective study was conducted in the Department of Oral and Maxillofacial Surgery in collaboration with the Department of Paediatric Surgery from July 2015 to December 2019. Patients who presented during the study period with lymphangioma of the head and neck region were included after informed and written consent. The diagnosis was made on clinical and ultrasound examination of the lesion. On the basis of ultra-sound, the lesions were classified as (1) macrocystic LMs, i.e. single or multiple cysts of >2 cm3 in size; (2) microcystic LMs, i.e. single or multiple cysts <2 cm3 in size; or (3) mixed LMs, with both macrocystic and microcystic components. The patients were assessed by clinical examination for local and systemic infection and complete blood counts were performed. Children with severe respiratory distress at the time of presentation and features of infection on clinical examination or abnormal blood counts were excluded from the study. Further, all patients who failed to give consent and who were lost to follow-up were excluded from the study. Treatment All of the patients were managed by intra-lesional injection of bleomycin (commercially available mixture of bleomycin A2 and B2) at a dose of 0.5 mg/kg (1 unit of bleomycin =1 mg), not exceeding 10 units at a time. All procedures were performed under sedation with sevoflurane and the

1. Bleomycin sclerotherapy in
lymphangiomas of the head and
neck region: a prospective study
Tiwari P, et al. Int J Oral Maxillofac Surg (2020)
PRESENTED BY : BHANU PRIYA

2.  Lymphatic malformations (LMs), traditionally called
lymphangiomas, are developmental disorders of the
lymphatic system and one of the most common
vascular malformations.
 Around 50% of affected children present with an
asymptomatic mass at birth, while 90% of LMs
manifest within the first 2 years of life.
 The site of involvement and symptoms at
presentation vary.
 lesions in the head and neck region with significant
extension may cause severe respiratory distress.

3.  The functional and cosmetic problems caused by
these lesions and their progressive nature are
bothersome for parents, and such patients have
long warranted treatment.
 Excision was the most common treatment
modality used in the past, but was associated
with high morbidity due to the close relationship
of the lesion with the vital structures.
 Excision was also associated with scarring along
with very high recurrence rates

4.  With the advent of sclerotherapy, the treatment
results have improved and response rates have been
excellent.
 Different agents have been used as sclerosants and
have shown good results in different studies.
 Sclerotherapy has the added advantage of better
cosmesis and lesser associated morbidity.
 Bleomycin is one of the most common sclerosants
used in the head and neck region.

5.  This study was performed to evaluate the role of
Bleomycin sclerotherapy in the management of
the different radiological variants of
lymphangiomas of the head and neck.

6. Patients and methods
 A prospective study was conducted in the Department of
Oral and Maxillofacial Surgery in collaboration with the
Department of Paediatric Surgery from July 2015 to
December 2019.
 Patients who presented during the study period with
lymphangioma of the head and neck region were included
after informed and written consent.
 The diagnosis was made on clinical and ultrasound
examination of the lesion.

7. On the basis of ultra-sound, the lesions were classified as
(1) macrocystic LMs, i.e. single or multiple cysts of >2 cm3 in
size;
(2) microcystic LMs, i.e. single or multiple cysts <2 cm3 in
size; or
(3) mixed LMs, with both macrocystic and microcystic
components.

8.  The patients were assessed by clinical examination for
local and systemic infection and complete blood counts
were performed.
 Children with severe respiratory distress at the time of
presentation and features of infection on clinical
examination or abnormal blood counts were excluded
from the study.
 Further, all patients who failed to give consent and who
were lost to follow-up were excluded from the study.

9. Treatment
 All of the patients were managed by intra-lesional
injection of bleomycin (commercially available mixture of
bleomycin A2 and B2) at a dose of 0.5 mg/kg (1 unit of
bleomycin =1 mg), not exceeding 10 units at a time.
 All procedures were performed under sedation with
sevoflurane and the patients were observed for 24 hours
for any complications.

10.  In patients with macrocystic lesions, the lesion was palpated
and a 10-ml syringe was introduced with negative suction.
 Once inside the cystic cavity, the maximum amount of fluid
was aspirated; the needle was then left in place and a
different syringe with bleomycin diluted in 4 ml of normal
saline was injected.
 Compression dressings were applied with a cotton ball at the
site of the lesion and strapped with micropore tape for 10–12
hours.
 The site was checked, especially in the neck region, for any
excessive compression and inadvertent respiratory
compromise

11.  In patients with microcystic and mixed variant lesions,
the lesions were divided arbitrarily into four equal
quadrants.
 They were entered from one quadrant with the desired
dose of bleomycin diluted in 4 ml of normal saline.
 Once at the centre, the syringe was withdrawn and
bleomycin was simultaneously injected into the lesion.
 The same procedure was repeated for the other three
quadrants.

12.  The patients were given oral Paracetamol for 3–5 days and
recalled after 4 weeks for evaluation.
 In those with an inadequate response, the intralesional
therapy was repeated after 4 weeks, for a maximum of
five additional doses.
 The response was recorded using the clinical response and
by taking clinical photographs of the lesion

13. Evaluation
 Color photographs of the patients were taken before the onset of
treatment and at each monthly visit.
 The response was assessed using these photographs at an interval
of 4 weeks; this was done independently by two consultants who
were blinded to the type of lesion.
 The patients were classified as ‘complete responders’ ‘excellent
responders’ ‘partial responders’ ‘non-responders’
 USG was repeated in all children at the completion of treatment
for correlation with the clinical response.

14. Results
 142 children were included in the study: 71 had the
macrocystic type (type 1), 43 had the microcystic type
(type 2), and 28 had the mixed type (type 3).
 The male to female ratio was 1.25:1.
 The median age at the onset of treatment was 5.0 months
for those with type 1 lesions, 6.0 months for those with
type 2 lesions, and 5.0 months for those with type 3
lesions.

17.  In the patients with the macrocystic variant, 76.1% had an
excellent response, 19.7% had a good response, and 4.2% had
no response after the first dose of bleomycin.
 This was better when compared to those with the microcystic
and mixed variants.
 Patients with the macrocystic variant also showed a better
response as compared to those with the microcystic and
mixed variants following the second dose of bleomycin, with
7.0% being complete responders.
 After the third dose of bleomycin, 16.7% of patients showed a
complete response.

18.  The response was statistically better than that in the
patients with the microcystic and mixed variants
 After the fourth dose, patients with macrocystic variant
continued to show significant differences in the response
compared to the patients with the microcystic and mixed
variants .
 However, with fifth and sixth doses of bleomycin, there
was no statistically significant difference between the
macrocystic, microcystic, and mixed variants of LMs

19.  In children with the mixed cystic variant, 35.7% had an
excellent response, 57.1% had a good response, and 7.1%
had no response after the first dose of bleomycin.
 The response was better when compared to those with
the microcystic variant.
 Similarly, patients with the mixed variant had a better
response than those with the microcystic variant after the
second dose .
 However, for the third, fourth, fifth, and sixth doses, the
response was similar to that for the micro-cystic variant

20.  The microcystic variant showed a poor response for the
first two doses and first four doses as compared to the
mixed variant and macrocystic variant, respectively.
 However, for the fifth and sixth doses, the patients with
the microcystic variant showed a similar response to those
with the others types

21. Macrocystic lymphangioma

23. Mixed

25.  The mean number of doses in the macrocystic group was
4.4 ±1.2 per patient.
 In the microcystic and mixed variant groups, the doses
required per patient were 5.3 ± 0.8 and 5.4 ± 0.7,
respectively.
 The mean numbers of doses required in patients with the
microcystic variant and mixed variant were significantly
higher when compared to the number of doses required in
the patients with macrocystic lesions.
 The patients in all three groups received a dose of 0.5
mg/kg body weight to a maximum of 10 mg (10 U) at a
time.

27. Follow-up and complications
 The median follow-up in the macrocystic group was 18 months (9–30
months).
 The median follow-up of children with microcystic lesions and mixed
cystic lesions was 24 months and 18 months respectively.
 During followup, 16 children with the macrocystic variant and nine with
the mixed variant presented with symptoms of pain and swelling (29
episodes) at the site of the lesion following episodes of upper respiratory
tract infection.
 The pain and swelling resolved in all cases following management of the
upper respiratory tract and with anti-inflammatory drugs.
 No such episodes were reported in children with microcystic lesions.

28.  The most common complication in this series was the
development of induration, erythema over the lesion, and fever.
 These symptoms developed typically within 24–48 hours of
intralesional therapy and affected 50 (35.2%) children.
 The median age of the children with these clinical symptoms
was 3.5 months which was significantly younger than the median
age of the children without these symptoms at 6.0 months.

29.  The development of induration, erythema, and fever was
not related to the type of lesion
 Among the children with these reactions, eight (5.6%)
developed respiratory distress (tachypnoea and nasal
flaring with the use of accessory muscles for breathing).
 All of these cases presented within 48 hours of the
administration of intralesional bleomycin and were
managed with intravenous fluids and oxygen
supplementation (by low-flow nasal prongs), following
which three (2.1%) children improved over a period of 24–
72 hours.

30.  In the remaining five (3.2%) children, there was no
improvement and they rapidly developed acute
respiratory failure (stridor and central cyanosis).
 These children required intubation and mechanical
ventilation for a duration of 3–4 days, following which all
were successfully weaned and extubated.
 Twelve (8.5%) patients developed pigmentations, most
commonly involving the dorsal aspect of the hand and
foot, which resolved spontaneously once treatment was
completed.

31. Discussion
 The surgical excision of lymphangiomas is associated with
high rates of morbidity and recurrence.
 A nerve injury was reported in about 33% of cases
following the excision of LMs of the head and neck.

32.  The evidence of healing of LMs follow-ing infection led to
the theory of inflammatory fibrosis.
 Fukase et al. showed that there was an inflammatory cell
infiltration and surge in cytokines in the cavity of the LM
following injection of OK-432.
 This causes fibrosis and atrophy of the epithelium and
leads to the resolution of the lesion.
 Bleomycin has been suggested to cause similar fibrosis in
the lesion in a non-inflammatory manner, although the
mechanism is not fully understood

33.  Intralesional therapy with bleomycin provides a distinct
advantage in the man-agement of LMs.
 Traditionally, most stud-ies have shown the effectiveness
of bleomycin in macrocystic lesions.
 This may be because the contact with bleomy-cin in
lymphangioma and resulting fibrosis is only possible in
these lesions.
 A scoping review by Churchill et al. published in 2011
showed that the macrocystic variant responded better to
sclerotherapy than either the mixed or microcystic
variant.
 In their study, picibanil (OK-432) showed better results as
compared to bleomycin and an alcoholic solution of zein
(ASZ

34.  In 2011, Rozman et al. conducted a retrospective study on
24 children with LMs.
 Their study revealed a better response with the
macrocystic variant as compared to the microcystic and
mixed variants.
 Upad-hyaya et al., in 2018, concluded that the majority
of macrocystic lymphangiomas showed complete remission
after the first dose.
 Zhong et al. reported successful treatment in 97% of the
cases, without serious complications.

35.  In a study by Qin involving 200 patients with
lymphangiomas, bleomycin sclerotherapy led to a
significant response in 86%.
 In the present study, although only following the initial
doses, macrocystic lymphangiomas responded better than
both the microcystic and mixed variants.
 However, after the fourth dose, the microcystic and mixed
variants responded almost equally, and after the sixth
dose, all variants of lymphangioma responded similarly.
 This may have resulted from the technique of instillation
of bleomycin, making it also penetrate the smaller cysts.

36.  The most dreaded complication of bleomycin therapy is pulmonary
fibrosis.
 This is a dose-related complication, occurring with a cumulative dose of
more than 400 U (400 mg), or with a single dose exceeding 30 mg/m2.
 In cystic hygroma, the dose should be restricted to 5 mg/kg21,22.
 The mean weight of the children in the present series was 8.2 ± 2.7 kg
and the mean number of doses required ranged from four to five across
the three groups.

37.  So, on average the children received a cumulative dose of
approximately 20 mg over the whole treatment duration.
 This is much lower than the problematic threshold.
 No case of pulmonary fibrosis was encountered in this
series.
 With restrictions to the total dose, pulmonary fibrosis may
be avoided in children treated with bleomycin injection
for the management of cystic hygroma.

38.  The typical complications of intralesional bleomycin
treatment are erythema, oedema, pigmentation of the
skin, and transient hair loss.
 The erythema, in-duration, and fever result from the
non- inflammatory fibrosis induced by bleomycin.
 In the present series of patients, the incidence was
higher in the younger children.
 The upper airway in neonates and younger children is
small in calibre and is more prone to collapse following
compres-sion from the outside (poorly developed tracheal
cartilage).

39.  The induration and oedema following bleomycin injection
into lesions in close relation to the upper airway may lead
to their compression.
 Even slight compression and a slight decrease in the
airway diameter will lead to an exponential increase in
the airway resistance (Poi- seuille’s law).
 This can cause respiratory distress and in severe cases
may require ventilation.
 We suggest that children younger than 3 months of age
should be admitted for at least 48 hours after the
administration of bleomycin to avoid unattended upper
airway obstruction.

40. CONCLUSION
 Bleomycin sclerotherapy is an effective treatment
modality for the management of lymphangiomas of the
head and neck in children.
 Overall, patients with the mixed and microcystic variants
showed the same response to intralesional bleomycin
treatment as those with macrocystic lesions.
 Children under 3 months of age are at higher risk of
respiratory obstruction following intralesional bleomycin.

41. Merits Demerits
Prospective study There was no control group
Proper inclusion and exclusion
criteria.
Lacked an objective assessment
of the response by serial USG
during the treatment.
Adds to the limited literature. Limited sample size

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