Bleomycin Therapy for Cystic Hygroma

By J. Orford, A. Barker, S. Thonell, P. King, and J. Murphy

Perth, Australia

l lntralesional bleomycin injection was used as sclerosant in diameter to “very large” (> 10 cm in diameter). Clinical
therapy for sixteen patients with cystic hygroma. An excel- photographs were taken before the procedure and were repeated
lent (complete clinical resolution) response was obtained in at a later follow-up visit.
seven (44%) patients, a good (>50% response) result in With the patient under general anesthesia, and using Doppler
seven (44%), and a poor or no response in two (12%). Minor ultrasound guidance and a sterile field, the cystic hygroma was
transient side effects (fever, vomiting, cellulitis, skin discolora- aspirated as completely as possible while maintaining the intra-
tion) were seen in six patients, and there were no serious cystic position of the needle (21 to 24 gauge). Bleomycin oil
side effects. The results suggest that bleomycin intralesional emulsion mixture (9 mg/mL) was injected at a dose of 0.3 to 0.6
sclerosant is effective therapy for cystic hygroma, with mg/kg in accordance with previously reported doses4
response rates comparable to those of surgical removal, but All were treated as hospital inpatients to allow close monitoring.
with the advantage of avoiding inadvertent nerve damage A standard proforma recorded patient details, including age,
and scarring. weight, site, size, clinical history, radiological studies, hospital stay,
Copyright 0 1995 by W.B. Saunders Company bleomycin dose, clinical response, side effects, and follow-up. The
mean follow-up period was 6 months (range, 1 to 17 months).
INDEX WORDS: Cystic hygroma, lymphangioma, sclerosing The response to therapy was determined clinically, as excellent
therapy, bleomycin. (complete clinical resolution), good (> 50% regression), poor
( < 50% regression), or no change.
YSTIC HYGROMA is a congenital lymphatic
C malformation that presents at birth in 50% to CASE REPORTS
65% of cases and manifests by 2 years of age in 80% The following 4 case reports illustrate the application of bleomy-
to 90%.1,2 Cystic hygroma can lead to morbidity tin injection in a variety of clinical settings. These are simple cystic
because of compression of adjacent organs (ie, respi- hygroma (case l), cystic hygroma in a young infant (case 2)
ratory obstruction, dysphagia, nerve compression, recurrent cystic hygroma after surgery (case 3), and the compli-
malocclusion) or can result in local inflammation, cated cystic hygroma (case 4).
infection, hemorrhage, and sinus formation.3 Sponta-
neous resolution occurs infrequently.3 The traditional Case 1
treatment is surgical excision, with its related prob- This boy was 7 years old when he presented with a left
lems of recurrence (10% to 15%) inadvertent nerve submandibular lump (Fig 1A) that rapidly appeared after tonsillec-
injury (12% to 33%), and death (2% to 6%).r tomy and adenoidectomy. The lesion was soft, cystic, and transillu-
Over recent years, intralesional bleomycin injec- minable. The clinical diagnosis was confirmed by ultrasonography.
tion has been used in Japan, with promising results. Five milliliters of fluid was aspirated, and 9 mg of bleomycin was
injected. Complete clinical resolution was noted at the 3-month
We have reproduced the bleomycin microsphere-in- follow-up examination (Fig 1B).
oil fat emulsion used by Tanaka et al4 and Tanigawa
et al5 and report our initial experience with this
therapy. Case 2
A 4-week-old full-term baby presented with swelling of the left
MATERIALS AND METHODS neck region, which had been present at birth and remained
Sixteen patients who had cystic hygroma between February 1991 asymptomatic and unchanged in size. Clinically, a large cystic
and March 1993 were treated with bleomycin injection. These hygroma was evident (Fig 2). Au ultrasound examination con-
patients are part of an Australia-wide study based at Princess firmed the diagnosis. After aspirating 3 mL of straw-colored fluid, 3
Margaret Hospital for Children in Western Australia; 13 of the mg of bleomycin was injected (using a more dilute solution [I5
patients were treated at this institution. There were 10 males and mg/5 my). After 48 hours there was moderate swelling of the
six females; the age at treatment ranged from 1 month to 13 years lesion, and it remained swollen and indurated for 2 weeks before
(mean, 5 years). gradually subsiding. At last follow-up examination (after 5 months)
The site of cystic hygroma was predominantly the neck (11 a “good” result (>50% reduction in size) was observed. The
patients, Table l), and the lesions’ maximum size ranged from 3 cm ultrasound assessment of the residual cystic hygroma showed the
main cystic space to be 25 mm x 13 mm, with several smaller
adjacent cysts of 5 to 10 mm in diameter. Repeat injection is being
considered.
From the Division of Swgev, Princess Margaret Hospital for
Children, Perth, Subiaco, Western Australia.
Address reprint requests to Mr A. Barker, Division of Surgery,
Princess Margaret Hospital for Children, Roberts Rd, Perth, Subiaco,
Case 3
Western Australia, 6008. A 9-year-old boy presented for bleomycin therapy of cystic
Copyright o 1995 by KB. Saunders Company hygroma. He had a right-sided preauricular and submandibular
0022-3468/95/3009-0009$03.OOiO cystic hygroma that was initially noticed at 3 months of age.

1282 JournalofPed/afric Surgery, Vol30, No 9 (September), 1995: pp 1282-1287

BLEOMYCIN THERAPY FOR CYSTIC HYGROMA 1283

Table 1. Lesion Site

No of Patvmts Site

10 Neck
3 Face
2 Floor of mouth
2 Limb
1 Axilla
1 Meciiastinum

Excision had been performed at 12 months of age. with a good

cosmetic result until the preauricular component recurred at age 3
years, when further surgical excision was undertaken (which was
incomplete). At 9 years of age he presented with the asymptomatic
cystic hygroma shown in Fig 3A. An ultrasound scan showed
multiple cysts of varying sizes that extended through the superficial
soft tissue of the preauricular region and also below the mandible.
The carotid and jugular vessels were seen at the lower end of the
cystic lesion.
Bleomycin oil emulsion (15 mg) was injected after emptying the
cyst of 10 mL. The response was good (>50% regression)
particularly around the angle of the jaw. Nine months later a
second injection of bleomycin (15 mg) was administered, and an
excellent result (complete clinical resolution) was obtained (Fig
3B). The follow-up period is 16 months.

Case 4
A
This girl had a complicated cystic hygroma and presented at 12
months of age with a 3-day history of an upper respiratory tract
infection followed by 2 days of increasing stridor and swelling of
the left part of the neck. There was no history of stridor or swelling
previously. An emergency tracheostomy was performed, and dur-
ing the procedure the trachea was found to be markedly deviated to
the right. Aspiration of the cystic swelling obtained blood only.
Subsequent microscopy and culture of the fluid content were
negative for bacterial infection.
Computerized tomography was performed the following day and
showed a large retrophatyngeal cystic mass with recent hemor-
rhage. The cystic area extended from the base of the skull to the
superior mediastinum on the left, distorting the esophagus, tra-
chea, and carotid sheath. It measured 6.6 x 5.6 x 6.5 cm (Fig 4A).
Eighty millihters of blood-stained fluid was aspirated under ultra-
sound guidance. Within 10 days the fluid had reaccumulated (Fig
4B); therefore, 16 days after admission the cystic hygroma was
reaspirated, followed by injection of 4 mg of bleomycin emulsion.
The size of the cystic hygroma decreased gradually over the next 2
weeks.
Extubation was performed 2 months later and was uncompli-
cated (Fig 4C). A neck ultrasound examination before extubation
showed only one small 12-mm-diameter cyst in the left neck region.
At the &month follow-up vistt her result was excellent, with no
clinical evidence of cystic hygroma.

RESULTS
Eleven single treatments were performed, and five
patients required additional injections. A total of 22
injections were performed, and there were no major
or life-threatening complications. Simple cystic hy-
groma was present in 14 (88%) patients, one patient
had a mixed capillary/cystic lymphangioma, and one Fig 1. (A) Case 1. This submandibular cystic hygroma in a 7-year-
had a cavernous lymphangioma. Two patients had old boy resolved after a single injection of bleomycin emulsion. (B)
Three rr months after treatment.
1284 ORFORD ET AL

(4), vomiting (2) cellulitis (2) skin discoloration of

the foot (1).
The inpatient stay was 1 or 2 days for 12 of the
patients (range, 1 to 38 days; mean, 4.5 days).

Fig 2. Left cervical cystic hygroma in a l-month-old boy (case 2).

previous surgery, and one has undergone subsequent

surgery.
Seven patients (44%) had an excellent response,
seven (44%) had a good response, and two (12%) had
a poor or no response. Of the five patients who
received additional injections, three had a good
result, one had an excellent result, and one had a
poor result.
Simple cystic hygromas of the neck (four patients),
neck and face (one patient with post surgical recur-
rence [case 3]), mouth (one patient), and axilla (one
patient) resulted in excellent responses, with com-
plete clinical resolution.
A good response to bleomycin treatment was ob-
tained in six patients who had simple cystic hygromas:
four of the neck, one of the face, and one of the
forearm. Unexpectedly, one patient with an extensive
cavernous lymphangioma of the foot also had a good
response.
There was no response in a patient who had ex-
tensive facial and cervical cystic hygroma, nor in a
patient with large cervicomediastinal cystic/capillary
lymphangioma. Fig 3. (A) Nine-year-old boy with an unsightly cystic hygroma. This
facial and cervical cystic hygroma recurred despite two previous
Minor side effects were seen after six of the 22 attempts at surgical excision. (B) Sixteen months later. An excellent
bleomycin injections (27%). These consisted of fever result was achieved after bleomycin emulsion injection.
BLEOMYCIN THERAPY FOR CYSTIC HYGROMA 1285

‘,,(’

‘, ‘1,

Fig 4. (A) Case 4. Transverse upper cervical computerized tomog-

raphy scan ShOwS extensive cystic hygroma containing a fluid level
indicative of recent hemorrhage. Note the tracheal deviation to the
right (arrow}. (B) Twelve-month-old girl with a huge left cewica) cystic
hygroma and tracheostomy, photographed just before bleomycin
emulsion injection. (C) Same patient 2 months later, after tracheos-
tomy tube removal. There was complete clinical resolution of the
cystic hygroma.
1286
DISCUSSION
A variety of nonsurgical treatment methods have
been used for cystic hygroma including aspiration,d-
rainage procedures, radiation, and injection of sclero-
sants, all without much success.l Surgical excision has
been advocated as the treatment of choice, although
there is significant risk of morbidity and morta1ity.l
The recurrence rate is high (10% to 15%)l because it
is technically difficult (and sometimes impossible) to
remove all involved tissue and preserve the important
anatomic structures.
We have found intralesional bleomycin to be as
effective as surgery, with 88% regression (44% com-
plete resolution). In only one of our 16 patients has
there been recurrence after apparent resolution. In
this patient, repeat injection has produced a good
response (noted at the 3-month follow-up). For
patients whose initial response to the bleomycin is not
complete, a repeat injection after 6 weeks may be of
value, as suggested by Tanaka et a1.4 Longer fol-
low-up is required before our recurrence rate can be
determined; however, we are encouraged by the low
rate (14%, ie, similar to that with surgery) reported
with follow-up periods of 3 and 6 years.2%4
A planning ultrasound examination is always per-
formed to confirm the clinical diagnosis and assess
the suitability for bleomycin injection. Doppler ultra-
sound assessment is always used at the time of
bleomycin injection. This is particularly important in
the neck to determine the relationship of the cystic
hygroma to the vessels, which allows safe injection of
the bleomycin emulsion.
The side effects experienced from bleomycin injec-
tion were relatively minor, did not prolong the hospi-
tal stay, and were in keeping with the inflammatory
sclerosant effect of bleomycin. We found that after 24
to 48 hours there was often marked swelling, indura-
tion, and erythema of the cystic hygroma, with less
associated pain than one would expect with the
degree of inflammation. One patient had vesiculation
followed by gray skin color after her second bleomy-
tin injection into the foot. No serious side effect was
experienced, and the doses are far lower than those
used for oncology purposes. Pulmonary toxicity is the
most serious potential side effect of bleomycin therapy.
The risk is related to the dose, with an increased
incidence associated with a total dose of more than
400 U, or single doses exceeding 30 mg/m2. Elderly
patients and those with underlying pulmonary disease
also are at risk.6 The clinical studies from Japan, in
which a total of 92 patients were treated with intrale-
sional bleomycin, did not show pulmonary fibrosis to
be a complication.2T4,5 There is potential for airway
compromise after bleomycin injection of some cervi-
ORFORD ET AL
cal cystic hygromas.5 After the procedure, close moni-
toring is advised for lesions of the anterior neck or
floor of the mouth.
Patient selection for this mode of therapy is impor-
tant. Bleomycin injection is more likely to produce a
good response in cases of cystic lesions than in those
of cavernous and other more complex lymphangioma-
tous lesions. This is supported by the literature4,5 as
well as this study. Of the two cases with a poor
response, one involved a huge cervicomediastinal
mixed capillary and cystic lymphangioma. One week
after bleomycin injection without response, the tumor
was excised via median sternotomy, with a good
result. The other patient had an extensive facial cystic
hygroma extending bilaterally from the intraorbital
margins to the thoracic inlet. Extensive cervical exci-
sion had been performed at 3 months of age, and
lower lip debulking was performed at 4 years of age.
Two bleomycin injections also were administered at
age 4 (to the lower lip and right lower face) with
minimal, if any, response.
The patient with a cavernous lymphangioma was
selected because of gross generalized involvement of
the foot, which was not amenable to surgery, and a
good response ( > 50% decrease in tumor size) was
achieved after two injections.
We believe that surgery is still the best option for
intraabdominal or life-threatening cases of cystic
hygroma. In addition, the swelling that follows bleo-
mycin injection poses a significant risk for the cervico-
mediastinal hygroma, and we support the opinion of
Tanaka et al that intralesional bleomycin injection is
contraindicated in such cases.4
In summary, with regard to patient selection, ac-
cording to our experience and that reported in the
literature, a patient can be considered for intrale-
sional bleomycin therapy if they had a primary or
recurrent simple cystic hygroma that did not involve
the mediastinum or intraabdominal site, was not
immediately life threatening (although our successful
case 4 does not comply with this), and did not require
treatment in the neonatal period.
Recently, promising results have been reported
with the use of OK-432, a low-virulence Su Strain
group A streptococcus pyogenes cultured with penicil-
lin. Ogita et a17,* reported favorable results, without
recurrence or significant side effects (transient fever
and inflammatory reaction only). The final report on
these results and the details of OK-432 production
are not yet available.
Bleomycin intralesional sclerosant appears to be a
safe and effective alternative to surgery in the treat-
ment of cystic hygroma. It is suitable for use as a
primary therapy, in preference to operative resection,
BLEOMYCIN THERAPY FOR CYSTIC HYGROMA
because it avoids the risk of inadvertent nerve dam-
age, there is no surgical scar, and the therapeutic
results are equally good.
REFERENCES
1. Cystic hygroma. Lancet 335:511-512,199O (editorial)
2. Okada A, Kubota A, Fukuzawa M, et al: Injection of
bleomycin as a primary therapy of cystic lymphangioma. J Pediatr
Surg 27440~443,1992
3. Ravitch M, Rush B: Cystic hygroma, in Ashcraft KW, Holder
TM (eds): Paediatric Surgery, chap 53. Philadelphia, PA, Saun-
ders, 1993, p 533
4. Tanaka K, Inomata Y, Utsunomiya H, et al: Sclerosing
therapy with bleomycin emulsion for lymphangioma in children.
Pediatr Surg Int 5:270-273,199O
5. Tanigawa N. Shimomatsuyz T, Takatrashi K, et al: Treatment
1287
ACKNOWLEDGMENT
The authors thank Princess Margaret Hospital pharmacy for
their reproduction of the bleomycin preparation.
of cystic hygroma and lymphangioma with the use of bleomycin fat
emulsion. Cancer 60:741-749, 1987
6. Goodman and Gilman’s The Pharmacological Basis of Thera-
peutics (ed 8). New York, NY, Pergamon, 1991, p 1246
7. Ogita S, Tsuto T, Takahashi T: Intracystic injection of OK
432: A new sclerosing therapy for cystic hygromas in children. Br J
Surg 74:690-691,1987
8. Ogita S, Tsuto T, Nakamura K, et al: OK-432. Therapy in 64
patients with lymphangioma. Presented at the Annual Meeting of
the British Association of Paediatric Surgeons Manchester, En-
gland, 1993 (abstr)