Role of Bleomycin Sclerotherapy as a Non-surgical Method for the Treatment of Cystic Hygroma of Head and Neck Region-an Institutional Study

Abstract

Cystic hygroma is a benign congenital tumor of lymphatic origin. Most common location is head and neck region. Bleomycin is an antineoplastic glycopeptide antibiotic agent with sclerosing property. In our present study, we used bleomycin for intralesional sclerotherapy for cystic hygromas of head neck region, as an alternative to surgical excision. We also statistically analyzed the pattern of cystic hygroma in head and neck region. Our present study was a prospective observational study of 40 patients. The study period was 18 months. All patients were given intralesional bleomycin at the dose of 0.5 mg /kg body weight, not exceeding 10 units at a time. The injection was repeated if required, at an interval of 4 weeks up to 4–5 times. Each patient was followed up at regular interval up to 1 year. Most common age group was found to be between 0–7 years (55%). Mean age was 6.9 years. Posterior triangle of neck was the commonest site (35%). Excellent response was noted in 24 patients (60%) while good response was noticed in 11 patients (27.5%). Poor response in 5 patients (12.5%). No major side effects noted with bleomycin sclerotherapy. No recurrence was noticed in our study. Intralesional bleomycin is a safe, simple, relatively cheaper and effective nonsurgical treatment method for cystic hygroma of head and neck region. It can be used as a first line treatment modality. Still, a lot of research is needed to establish it as a gold standard treatment modality for cystic hygroma.

Electronic supplementary material

The online version of this article (10.1007/s12070-020-02273-2) contains supplementary material, which is available to authorised users.

Introduction

A cystic hygroma is a benign congenital tumor of lymphatic origin. It usually appears on a child’s neck or head.

The word “cystic hygroma” was coined by Werner in 1834. Hygroma in Greek means water containing tumor. They are soft tissue tumors of disputed origin reported for the first time by Redenbacker is 1828 [1]. The tumor is a multilocular one but occasionally it can be unilocular, where the term “hydrocele of neck” is used. It may be inflamed as a result of nasopharyngeal infection to cause some confusion in the diagnosis. There is no lymph node enlargement unless infected [2]_.

Totally three histopathological subtypes of cystic hygroma are noticed ie capillary lymphangioma, cavernous lymphangioma and cystic lymphangioma. The size of the lymphangioma is directly related to the degree of obstruction of veno-lymphatic drainage as evidenced by histologic examination [3].

The common sites of cystic hygroma in head and neck region are posterior triangle of neck, anterior triangle of neck, dorsum of tongue, oral cavity, cheek, parotid gland. Clinically they appear soft, compressible, non-tender, brilliantly transluminant and without any bruit. These cysts may produce milky, serous, sero-sanguineous or strawcolored fluid, when aspirated with a wide-bore needle [4, 5]. Ultrasonography reveals multicystic lesion with internal septations and no blood flow is detected on color Doppler study. Other modalities like CT Scan (Supplementary File:Image 1) and MRI Scan can be employed to evaluate the lesion in a better way.

In recent years, intralesional sclerotherapy has become an acceptable method of treatment for cystic hygromas in children. This treatment involves the use of a sclerosing agent that causes irritation of the endothelial lining of the cystic hygroma, there by leads to inflammation, fibrosis and involution. Previously reserved for treatment of unresectable cystic hygromas or in cases of tumor recurrence following surgery; intralesional sclerotherapy has gained popularity in recent years [6].

Before the present study, in our institute all cystic hygroma patients underwent surgical excision as treatment. We took up this study to evaluate the efficacy of bleomycin as a sclerosing agent and to promote it as a firstline modality of treatment.

The objectives of our present study were:

To evaluate statistically, cystic hygromas of head and neck region.

1. To evaluate the efficacy of bleomycin sclerotherapy as a non-surgical tool for the treatment of cystic hygroma of head neck region.

Materials and Methods

The present study is a prospective study of 40 cases of cystic hygroma of head and neck region. The study was conducted in ENT, surgery and radiology departments of our institute. The study period was from February 2018 to August 2019. Each patient’s age, sex, body weight, clinical symptoms, location of the swelling and size of the swelling were recorded. The diagnosis of cystic hygroma was made on the basis of clinical examination and imaging tools like ultrasonography (GE Voluson S8) and computer tomography scan (Toshiba,16slice, contrast as well as non-contrast study).

After the written and informed consent from parents of patients, the procedure of aspiration of cystic contents and injection bleomycin sclerotherapy was done in each patient. Most of the patients were given bleomycin sclerotherapy in outpatient department itself. Small children less than five years were given intravenous sedation with diazepam and sclerotherapy was done in operation theatre. All Patients were admitted for 24 h for monitoring possible immediate and delayed complications of sclerotherapy.

The cystic components of the swelling was aspirated with a hypodermic syringe and 23G needle using ultrasonographic guidance (GE Voluson S8). While keeping the tip of the needle in the lumen of cyst, 0.5 mg per kg body weight of bleomycin (not exceeding 10U) in aqueous solution was injected. 1 unit of Bleomycin is equivalent to 1 mg. Each patient was called after 4 weeks for assessing the size of the swelling. A repeat procedure was done when the cyst measured at least 1 cm in diameter. The procedure was repeated after 4 weeks and continued up to 4 to 5 times, if the swelling persisted.

The response to bleomycin was graded into 3 categories ie. excellent (complete resolution), good response (> 50% reduction in size) and poor response (< 50% reduction or no change in size). Recurrence was defined as reappearance of tumor after complete resolution or increase in size after initial reduction in size. Each patient was followed up after 3 months, 6 months, 9 months and up to 1 year. Patients who showed poor response were selected for surgery.

The statistical method used was the Wilcoxon Signed Rank Test. P value < 0.05 was considered to be statistically significant. The statistical findings are summarized along with results.

Inclusion Criteria

1. Cystic hygroma of head & neck region.

2. Age group between 0–16 years.

Exclusion Criteria

1. Cystic hygroma of other sites other than head & neck region.

2. Age group above 16 years.

3. Patients who underwent previous surgery for cystic hygroma.

4. Irradiated neck.

5. Children with systemic illness like congenital heart diseases, bronchial asthma, epilepsy.

Results

In our study, most common age group of cystic hygroma of head and neck region was found to be between 0–7 years (55%). Mean age was 6.9 years. Median was 6.75 years (Table1 & Fig. 1).

Table 1.

Age distribution

Age group	Number	%
0–5 years	17	42.5%
6–10 years	14	35%
11–16 years	9	22.5%
Total	40	100%

Fig.1.

Piechart Showing Age Distribution

22 patients were males and 18 were females. Male to Female ratio was 1.2:1.

Posterior triangle (35%) and anterior triangle (27.5%) of neck were the most common sites. Together they contributed 62.5% of patients. The other sites were tongue (15%), oral cavity (10%), cheek (7.5%), parotid (2.5%) and face (2.5%) (Table2 & Fig. 2).

Table 2.

Sites Cystic hygroma the head & neck region

Site	Number	%
Posterior triangle of neck	14	35%
Anterior triangle of neck	11	27.5%
tongue	6	15%
Oral cavity	4	10%
Cheek	3	7.5%
Parotid	1	2.5%
Face	1	2.5%
Total	40	100%

Fig. 2.

Piechart Showing Sites of Cystic Hygroma of Head & Neck

In this study of total 40 patients, 22 patients (55%) required single dose of intralesional bleomycin, 3 patients (7.5%) required 2 doses, 6 patients (15%) required 3 doses, 4 patients (10%) required 4 doses whereas, 5 patients (12.5%) received 5 doses of bleomycin.

Regarding response to bleomycin sclerotherapy, excellent response was noticed in 60% of patients, whereas good response noticed in 27.5%. Poor response in 12.5% (Table 3 & Fig. 3). The Wilcoxon signed rank test was applied to compare the initial and final volume. The initial mean volume before sclerotherapy was 107.75 ± 27.62 and the final volume after sclerotherapy was 26 ± 40.94. After applying the Wilcoxon signed ranks test, the P value was < 0.001, which is highly significant.

Table 3.

Response to Sclerotherapy

Type of response	Number	%
Excellent	24	60
Good	11	27.5
Poor	5	12.5
Total	40	100

Fig. 3.

Piechart Showing Response to Sclerotherapy

No major side effects to bleomycin sclerotherapy were seen in our study. Mild side effects like fever(5patients),local pain(9patients),erythema(3patients),hematoma(2 patients), cellulitis(1patient) were noticed(Table 4 & Fig. 4).

Table 4.

Types of Complications

Type of complications	Number	%
Fever	5	25
Local Pain	9	45
Erythema	3	15
Hematoma	2	10
Cellulitis	1	5
Total	20	100

Fig. 4.

Piechart Showing Types of Complications

Discussion

The incidence of cystic hygroma is 1.2 to 2.8 per 1,00,000 infants [7]. It does not show any gender preference; both males and females are equally affected [8].

Cystic hygroma can involve any anatomical subsites in human body [9, 10]; but mostly they are seen in head and neck region (75%); probably because of rich lymphatics in the head and neck area. 80–90% of cystic hygromas present before the end of second year of life.

In embryonic period at eighth week of gestation, six lymphatic sacs are noticed in the developing embryo. These are two jugular sacs, two iliac sacs, one at the base of root of mesentery and one dorsal to the abdominal aorta. Later on, a network of lymphatics develops that communicate with lymphatics of various regions [11, 12].

Numerous theories are proposed to explain the pathophysiology of cystic hygroma. Embryologically, these tumors are believed to originate from sequestration of lymphatic tissue from lymphatic sacs, during the development of veno -lymphatic sacs, these sequestrated lymphatic tissues later undergo dilatation to take the morphology of cystic hygroma.

Sabin in 1990 proposed the theory of centrifugal lymphatic system development. The embryological derivatives of lymphatic tissues as arising from six primitive lymphatic buds and postulated that abnormal sequestration of these lymphatic buds give rise to lymphatic malformations. Other theories like centripetal theory also has been postulated [13].

Genetic disorders like Turnes’s syndrome, Noonan’s syndrome, Trisomies (Trisomy 21, Trisomy 18, Trisomy 13), fetal hydrops may be associated with cystic hygroma. A lethal version is known as Cowchock Wapner Kurtz syndrome, where cystic hygroma is assosiated with cleft palate and lymphedema of local tissues due to compromised lymphatic drainage [14].

The major indications for treatment of cystic hygroma are respiratory obstruction, recurrent infections, cosmetic reasons and compression of local structures like trachea, blood vessel and upper gastrointestinal tract [15].

Complete surgical excision is treatment of choice for cystic hygroma of any location. Recently, intralesional sclerotherapy has become a preferred modality with increasingly documented remarkable results.

The other different modalities of treatment employed with variable results are simple aspiration, radiation, laser excision, radio–frequency ablation and cauterization [16].

The novel idea of using sclerotherapy in the treatment of lymphangioma occurred when it was noticed that these malformations spontaneously involute when they got infected and the infection resolved. In 1933, the first case of sclerotherapy for cystic hygroma was done using the agent, sodium morrhuate [17].

The sclerosing agents available are bleomycin, iodine, OK-432 (Picibanil), absolute alcohol, ethibloc, iodine, tetracycline, doxycycline, cyclophosphamide, ethanolamine oleate, sodium tetradecyl sulfate. Bleomycin and OK-432 (Picibanil) are currently the most popular sclerosants for sclerotherapy of cystic hygroma [17]. However, only bleomycin is commercially available in India.

Bleomycin was discovered by Japanese scientist Dr Hamao Umezawa in 1965. Its mechanism of action is breakage of single and double stranded DNA and there by inhibition of RNA and DNA synthesis. It is an antineoplastic glycopeptide antibiotic produced by the fermentation of Streptomyces verticillus. It chelates copper or iron, produces superoxide ions and intercalates between DNA strands causing chain scission and inhibits repair. In initial days of usage as antineoplastic drug for malignant pleural effusion, it was noticed that bleomycin caused marked fibrosis and scarring. This sclerosing action of bleomycin was first put to use in 1977 by Yura in the treatment of cystic hygroma [18, 19].

The major side effects bleomycin therapy are fever, transient increase in size of the swelling, hemorrhage, hematoma formation, leukocytosis, local infection and pulmonary fibrosis. Among these, pulmonary toxicity is of major concern. This risk is dose related; with as increased incidence associated with total dose exceeding 30 mg /m² of body surface area or total cumulative dose of 400 U given intravenously to cancer patients. Although high-grade lung injury is very rare with cumulative dose of less than 400 U, injury can occur at doses less than 50U. Rapid intravenous infusion may also increase the risk of pulmonary toxicity. Elderly cancer patients, those with underlying pulmonary pathology and renal failure are at greater risk for pulmonary toxicity [19]. The sclerotherapy dose of 0.5 mg/kg body weight not exceeding 10 U at a time given intra-lesionaly in our study is negligible to cause pulmonary toxicity. Others have used it in doses varying from 0.3 to 3 mg/ kg [20].

A study was done by M. Hazim, S S Moses and I P Tan on intralesional use of OK-432 in cystic hygroma in six patients. Total shrinkage was achieved in one patient, marked shrinkage in three patients, there was slight shrinkage in one patient, whereas one patient was non-responsive [21]. Pietro Impellizzeri et al. in their study of eight children with 98% sterile ethanol as a sclerosing agent, found complete disappearance of lesion in 7 (87.5%) patients. One patient (12.5%) with satisfactory result required a second alcohol injection with an excellent outcome [22]. Both OK-432 and 98% sterile ethanol are equally potent sclerosing agent as compared to bleomycin. But OK-432 is not available in India and 98% sterile ethanol is not commonly available due to abusive reason, so we opted bleomycin as sclerosing agent in our present study.

In our presnt study, after intralesional bleomycin sclerotherapy, complete resolution (excellent response) was noticed in 60% (24/40) of lesions, 27.5% (11/40) had good response and remaining 12.5% (5/40) had poor response. our present study shows that intralesional bleomycin sclerotherapy is very effective and the results are comparable to various published study series (Supplementary file: Image2 & Image3). Other authors have also quoted success rates between 36 and 63% for complete tumor regression, of up to 88% significant tumor regression and poor response between 12 and 23 using either bleomycin or ok–432. Rozman etal noted excellent and good response in 63% (15/24) of lesions and 21% (5/24) patients. Niramis et al. noted 83% of respone [23]. whereas Baskin et al. noted about 95% of respone [24] suggesting good sclerosing activity of bleomycin for therapeutic purpose.

Orford et at observed an excellent response in seven (44%) patients, a good response in seven (44%) patients, and a poor or no response in two (12%) patients suggesting that bleomycin intralesional sclerotherapy is effective for cystic hygroma treatment with response rates comparable to those of surgical excision; but with advantage of avoiding inadvertent neuro-vascular damage and scarring [25].

In our present study of 40 patients, no serious complications were noticed as a result of intralesional bleomycin sclerotherapy. However, some patients complained of fever, mild tenderness, local swelling, erythema and cellulitis. These symtoms were transient and did not prolong their stay in hospital. Niramis et al. noted complications in about 43% of patients in their study.

Even though, complete surgical excision is considered as the treatment of choice for this type of tumor; it is associated with tedious dissection, lot of morbidity in the form of disfigurement and damage to vital structures like neuro—vascular bundle, chylous fistula, chylothorax, pneumothorax, wound seroma, ugly scar and recurrence. If any residual tissue is left behind after dissection, the expected recurrence rate is apploximately 15%. Post operative complications occur in as many as 30% after surgical excision. Therefore, sclerotherapy with agents like bleomycin, ok-432 has gained popularity in recent years.

In our study we found a satisfactory response in 87.5% of cases (Excellent response in 60% and good response in 27.5% of cases) as observed in various studies. In short term follow up of 1 year, no recurrence was noticed, which is consistent with recent studies. Although mortality was reported by Orford etal [25], it was absent in present study.

Conclusion

Posterior triangle of neck is the commonest site of cystic hygroma of head and neck region. Intralesional bleomycin sclerotherapy is simple, safe, relatively cheaper and effective method of treatment for cystic hygroma of head and neck region. This non-surgical treatment method is met with less complications as compared to complete surgical excision.

So intralesional bleomycin sclerotherapy can be recommended as first line treatment modality in place of surgery. Surgical excision has to reserved for those tumors failed to respond to sclerotherapy. Still lot of research is needed to establish it as a gold standard treatment modality for treatment of cystic hygroma.

Electronic supplementary material

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Funding

Nil.

Compliance with Ethical Standards

Conflicts of interest

None.

Ethical Approval

The permission was taken from Institutional Ethics Committee prior to staring the project. All procedures performed in studies involving human participant were in accordance with the ethical standards of the institution and /or national research committee and with the 1964 Helsinki declaration ant its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.