Intralesional Sclerotherapy with Bleomycin in Lymphatic Malformation of Tongue an Institutional Experience and Outcomes.

INTRODUCTION: The management of lymphatic malformations (LMs) continues to improve with advancement in molecular genetics, imaging, and treatment options. However, the management of tongue LMs remains a challenge due to the location, function involved, and long-term disabilities. We propose injection sclerotherapy with bleomycin in the management of spectrum of tongue LMs.
METHODS: Children with LMs involving the tongue were prospectively treated with bleomycin sclerotherapy. Outcome measured was the efficacy of sclerotherapy, complications, and functional outcome.
RESULTS: A total of 11 children underwent sclerotherapy with bleomycin for varying tongue lesions. Excellent outcome was seen in children with macroglossia. Eight children with isolated (focal) lesions had a resolution of symptoms with a clearance of lesions. Specific complications related to bleomycin toxicity were not encountered in our series during the follow-up of 4 years.
CONCLUSION: In our series, children with macroglossia had an excellent outcome with normalization of tongue size and function. Children with focal tongue lesions also had good to excellent outcome. We recommend treatment of tongue LM with bleomycin sclerotherapy as the first line of management. Ease of treatment, early intervention, and excellent response makes it a favorable treatment option. Copyright:

INTRODUCTION

Lymphatic malformations (LMs) are localized or extensive lesions of malformed lymphatics in the skin or deeper regions most frequently involving the head and neck region.[1] They have been suggested to be sequestered segments of the primitive lymphatic system.[1]

In the oral cavity, the tongue is most commonly affected organ.[1] LMs involving the tongue tend to be microcystic, poorly defined, and diffuse. They occur as isolated lesions or extensions from adjacent structure. Isolated tongue involvement can present as raised granular lesions with multiple lymph filled cyst or as macroglossia.

Recurrent upper respiratory tract infections (URTIs) or accidental trauma commonly enlarge the LM or worsen the swelling. Macroglossia can cause airway obstruction, swallowing difficulty, malocclusion, and speech problems.

Various treatment modalities have been used for the management of the tongue LMs. Reduction surgery has been the procedure of choice. Other modalities used include laser ablation with long-pulsed Nd-YAG or CO2 laser, radiofrequency, and sclerotherapy. There is no consensus on the timing of surgery. Despite the variety of possible treatment modalities, the management of LMs of the tongue still represents functional and esthetic problems for the patients and can be challenging. We present our experience with the use of intralesional sclerotherapy with bleomycin for the management of tongue LMs and discuss its outcome.

METHODS

Children referred to our hospital between 2012 and 2018 were included in this study. We have had experience with the use of bleomycin, OK-432, doxycycline sclerotherapy, and surgery in the management of LMs involving cervicofacial and other regions. After the initial assessment, the parents were counseled regarding bleomycin sclerotherapy and appropriate consent obtained. Institutional ethical committee approval was also obtained. Clinical photographs were documented to assess the progression of the lesion. Age, sex, lesion location, size, weight, previous treatment history, and blood investigations were documented. Children with allergies and lung pathology were excluded from the study.

Technique

All procedures were done under sedation/general anesthesia. Children with macroglossia required nasotracheal intubation [Figure 1a]. Bleomycin with strength 15 IU was diluted with 0.9% normal saline to make a strength of 1 IU/ml. Dosage given was based on weight - 0.2 mg/kg (0.2U/KG). None of the children received more than 10 IU in a single session. Injections were given using a tuberculin syringe with 26G hypodermic needle.

Figure 1

(a) Difficult airway with nasotracheal intubation. (b-d) Shows serial response with reduction of size in a child with macroglossia

In children with macroglossia, intralesional sclerotherapy was initially started at the tip of the tongue and progressed proximally during the subsequent sessions.

For focal lesions, sclerosant was instilled intralesionally accessed through normal tissue in four to six sites around the lesion.

Postinjection the children were observed for increase in swelling, breathing, or swallowing difficulties. The children with isolated/focal tongue lesions were usually discharged after overnight observation. Those children with macroglossia were observed for 48–72 h before being discharged.

In addition, children with macroglossia presented to us with varying degree of ulceration and infection. They were initially treated with antibiotics before starting sclerotherapy. The interval between each session was 4–6 weeks.

Postsclerotherapy, these children were assessed for clearance of the lesions. Preintervention and sequential photographs taken during treatment were used to assess outcome. Complete response was considered as excellent outcome, 60%–80% reduction/clearance of the lesion was considered as good outcome, 40%–60% was considered as fair outcome, and <40% was considered as no response.

RESULTS

Eleven children underwent bleomycin sclerotherapy for tongue LM [Table 1].

Table 1

Demographic details of the patients

Age at presentation and gender	Diagnosis	Duration of symptoms	Number of sessions
10 yearsFemale	Cervicofacial lymphatic malformation with tongue ulceration and edema	2 years	1
11 yearsMale	Isolated tongue lesions-vesicles with ulcers and edema	1 month	3
10 yearsMale	Isolated tongue lesions with bleeding ulcers	1½ years	2
7 monthsMale	Macroglossia	Since birth	4
2½ yearsFemale	Macroglossia	Since birth	6
11 yearsFemale	Isolated tongue lesions with bleeding ulcers with edema	Since birth	2
2 yearsFemale	Cervicofacial lymphatic malformation with tongue ulceration and edema	1 month	3
8 yearsMale	Cervicofacial lymphatic malformation with tongue lesions with bleeding ulcers	1 month	4
3 yearsMale	Isolated tongue lesions-vesicles with ulcers and edema	6 months	2
10 yearsMale	Isolated tongue lesions-vesicles with ulcers and edema	1 year	2
2 yearsFemale	Macroglossia	Since birth	2

Two children with macroglossia had excellent outcome [Figure 1b–d]. They were able to keep the tongue completely intraorally with maintained function. They received between 4 and 6 injection sclerotherapy over a 1-year period. There was no recurrence in this group on a mean follow-up 4 years. One child with macroglossia received two sessions of sclerotherapy. She had achieved a partial reduction in size, however, was lost on follow-up.

Six of the eight children with focal tongue lesions had good outcome with amelioration of swelling and symptoms and clearance of lesion [Figure 2].

Figure 2

Isolated lesions involving dorsum, margins, and tip of the tongue with edema (a) at presentation (b) during treatment (c) follow-up

Two among them had an initial response with decrease in size of the lesion. However, they developed a recurrence of the lesion on the dorsum of the tongue and tip, respectively. They are being followed up for further sclerotherapy [Figure 3].

Figure 3

Lesions involving undersurface of tongue along with ulceration and edema (a) at presentation (b) on treatment

Overall outcome and complications are shown in Table 2. There were no airway-related complications in our group. One child had bluish discoloration of the tongue which cleared in the immediate postoperative period. There were no skin changes seen or clinical features of lung involvement due to bleomycin in our series during the follow-up.

Table 2

Results, outcome, and follow-up details

Follow-up	Outcome	Complications
Complete resolution of lesions	No recurrence, good	Nil
Complete resolution of lesions	No recurrence, good	After 2nd session- discoloration of the tongue which resolved with conservative measures
Residual, stable lesions, asymptomatic	Fair	Nil
Complete resolution of oral lesions, after 4 years new lesion in the left parotid region	Good	Nil
Complete resolution of lesions	Good	NIL
Complete resolution	Good	Nil
Complete resolution	Good	Nil
Residual, stable lesions, asymptomatic	Fair	Nil
Residual, stable lesions, asymptomatic	Fair	Nil
Clearance of lesion, stable	Excellent	Nil
Partial reduction	-	Lost on follow-up

DISCUSSION

LMs are malformations of the lymphatic system occurring as a result of the sequestration of lymphatic tissue, which retain growth potential. Approximately 50%–75% of LMs are in the head and neck region. Virchow gave the first accurate description of a lymphangioma of the tongue in 1854.[2] The involvement of the tongue though rare is the most common cause of true macroglossia.[3]

It is classified into macrocystic (cavities larger than about 2 cm), microcystic (cavities smaller than about 2 cm), or mixed lesions (combining these two types). Tongue lymphangiomas are almost always microcystic in nature [4] (cysts <1 cm in diameter).

The tongue involvement can occur as an isolated lesion or in continuity with cervicofacial lesions. Lymphangioma of the tongue may present as macroglossia, discrete circumscribed lesions, or as ulcerations. Of the 11 children, eight presented with reactionary swelling of tongue along with vesicular lesions on dorsum and the lateral border of tongue. Two among these had small ulcers with bleeding from these lesions. The tongue involvement causing macroglossia was seen in three children presenting to us in early infancy.

As seen in our series and available reports,[15] all children presented with tongue swelling, difficulty in swallowing, or speech disorder. Secondary complications such as infection, bite injuries, and malocclusion were seen in most. Those with focal tongue lesions had minimal symptoms only related to bleeding and pain during episodes of enlargement.

Two children with macroglossia presented with airway obstruction causing breathing difficulty and requiring ICU support. The tongue enlarges with each episode of URTI, and when protruding through the lip margin is also exposed to frequent trauma. These repeated episodes of infection and trauma lead to fibrous tissue being laid down. This thus leads to further dilatation of lymphatic channels and enlargement of the tongue.[5]

The tongue lymphangioma presents specific therapeutic problems because of the microcystic character of the lesions, marked functional problems, and a high recurrence rate due to multifocal lesions and failure to address the deeper component.

The management of these lesions is challenging and controversial. Conservative approaches are used initially. Various techniques have been described including laser, radiofrequency ablation, radiation therapy, electrocoagulation, cryosurgery, steroids, and injection of sclerosants with varying success. The mainstay of treatment has been surgery. Perkins in his survey reported that the cosmetic and psychosocial aspects of tongue reduction procedures and their perceived outcomes vary widely.[5] The timing of treatment is also not clear with an average age of 3–4 years for surgical intervention. Furthermore, surgery is usually radical leaving gross deformities and still cannot result in complete eradication.

Being microcystic in nature, these lesions are assumed to be not amenable for sclerotherapy.

Bleomycin, an antineoplastic antibiotic which acts by damaging endothelial cells with a nonspecific inflammatory reaction and occlusion of vessels has a proven role for the treatment of macrocystic LMs.[6]

We noted that part of the microcystic LMs, especially if involving the inner lip had a favorable response to bleomycin. All the oral mucosal lesions disappeared after sclerotherapy. Contemplating a favorable outcome,[7] we used bleomycin sclerotherapy in focal tongue lesions and subsequently extended its use to children with macroglossia.

For the treatment of lymphangiomas, intralesional bleomycin in doses of 0.75–1.8 U/kg has been suggested. These injections are given at 2-week–2-month intervals, and the cumulative amount of injected bleomycin is up to 15 U/kg.[89] The dosage used in our patient was given in dose of 0.2 mg/kg. Total number of sessions required in our series ranged from 2 to 6, keeping the cumulative dose well within acceptable limits.

Two children who presented with macroglossia had normalization of tongue size and were able to keep tongue completely intraorally. No relapse/increase in size of the tongue was seen during a mean follow-up of 4 years.

Rest of the eight children who had swelling of the tongue with vesicles and ulcer (lateral border and dorsum) responded favorably with almost complete remission of vesicles, healing of ulcers, and reduction in size of the tongue. These patients are presently in follow-up with no symptoms/relapse.

The main side effects of bleomycin described are pulmonary toxicity, mucocutaneous effects such as skin erythema, pigmentation, edema and alopecia, and fever.[10]

Pulmonary toxicity is a potentially life-threatening condition occurring in ages more than 70 years and is related to cumulative dose. This toxicity is rare at total doses below 450 U, occurring only in 3%–5% of patients.[8] The total dose used in our patients was considerably lower, and no side effects were observed in the mean follow-up of 4 years.

CONCLUSION

We found that sclerotherapy with bleomycin was effective in the management of microcystic LM of the tongue. Children with macroglossia had excellent outcome with normalization of tongue size and function. Children with focal tongue lesions also had good to excellent outcome. We recommend the treatment of tongue LM with bleomycin sclerotherapy as the first line of management. Ease of treatment, early intervention, and excellent response makes it a favorable treatment option.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.