Bleomycin sclerotherapy in patients with congenital lymphatic malformation in the head and neck

Bleomycin Congenital and Neck

Sclerotherapy in Patients With Lymphatic Malformation in the Head

Myung-Whun Sung, MD, Sun 0. Chang, MD, Joong Hwan Choi, MD, and Jin Young Kim, MD Congenital lymphatic malformations of the head and neck often present challenging problems to the otolaryngologist-head and neck surgeon. Although surgical excision was agreed to be the treatment of choice for this disease, the infiltrating nature of lymphatic channels often increases the frequency of operative complications and recurrences of this lesion. Purpose: Bleomycin sclerotherapy was attempted to avoid surgical risk and to cure this lesion. Materials and Methods: Clinical findings and treatment results were reviewed for patients with congenital lymphatic malformation and treated by bleomycin sclerotherapy. Results: Bleomycin sclerotherapy was a very effective therapeutic alternative. The best results were seen in cystic type I lesions in younger patients. Conclusions: Bleomycin sclerotherapy is a useful medical alternative, and we believe that it should be attempted before excision of the lesion. Copyright 0 1995 by W.B. Saunders Company

Congenital lymphatic malformations of the head and neck area present special challenges to the otolaryngologist-head and neck surgeon. Although this is a benign lesion, its infiltrating nature, the lack of definite demarcation, and the involvement of vital structures can sometimes lead to a variety of complicated clinical dilemmas. For many years, surgical excision has been considered as the treatment of choice.l*’ However, the infiltration of this lesion into adjacent structures, such as nerves and vessels, frequently makes total resection difficult, and resection is often met with nerve injury or other serious complications, such as wound infection, lymphorrhea, or recurrence.lm4 A number of therapeutic alternatives to surgery have been used to reduce the risk of surgical complications. Modalities tested include steroid therapy, radiotherapy, chemotherapy, and sclerotherapy, and the results of these triFrom the Departments of Otolaryngology and Pediatrics, Seoul National University, College of Medicine, Seoul, Korea. Address reprint requests to Myung-Whun Sung, MD, Department of Otolaryngology, Seoul National University Hospital, Yongon-dong 28, Chongno-gu, Seoul, Korea, 11 O-744. Copyright 0 1995 by W.B. Saunders Company 0196-0709/95/l 604-0003$600/O 236

American

Journal

of Otolaryngology,

als have shown marginal efficacy of these treatments.3V5-7 Recently, bleomycin, an antineoplastic agent, was found to have a sclerosing effect on the endothelial cells of the cyst of lymphangioma and has been used to treat cystic lymphangioma with several reports of promising results.4’8’g In this study, we present our recent experiences with bleomytin sclerotherapy of congenital lymphatic malformations of the head and neck, and discuss the complications and the role of bleomycin sclerotherapy in the treatment of this disease. MATERIALS

AND METHODS

At the Seoul National University Hospital, 10 patients (6 boys and 4 girls) with congenital lymphatic malformation were treated with bleomycin sclerotherapy during a d-year period from May 1990 to April 1993. Two of them underwent partial excision before the sclerotherapy; one case had been performed 1 month before and in the other, surgery preceeded the sclerotherapy by 12 years. Tracheostomy was electively performed for 3 patients to avoid the risk of airway compromise during sclerotherapy. The diagnosis of lymphatic malformation for every case was confirmed by computed tomography or magnetic resonance imaging. Once the diagnosis was made, bleomycin hydrochloride was adminis-

Vol 16, No 4 (July-August),

1995: pp 236-241

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tered in 1 mg/mL saline solution, after complete or near-complete aspiration of a thin yellow fluid from the cyst, using a 23G puncture needle. When the lesion was composed of several noncommunicating cavities, I to 2 mL of bleomycin solution was injected in each cavity. A dose of less than 6 mg was administered at intervals of at least 2 weeks, which varied depending on the effect achieved. Some injections were made under the guidance of ultrasound, especially when repeated injections were required to treat lesions consisting of multiple small cavities. Temporary local reactions such as swelling or redness were observed for a few days after the injection in some cases.

Table 1 summarizes the patients with congenital lymphatic malformations treated with sclerotherapy. The majority of patients were less than 1 year old when first treated with bleomycin. One child was 2 years old and another 12 years old when treated. The E-yearold girl had undergone partial resection at 1 month of age. The approximate size of the lesion before treatment ranged from 5 x 8 to 10 x 12 cm and caused gross deformities in the face and neck. To determine the difference in response to sclerotherapy, we classified the lesions according to the classification of McGill and

Mulliken (1993),” in which type I lymphatic malformations are located below the level of the mylohyoid muscle with well-circumscribed and discrete cystic lesion and type II are poorly defined smaller lymphatic channels found above the level of the mylohyoid muscle, involving the oral cavity, lip, and tongue. Based on physical findings and imaging, 6 cases were classified to have mainly type I, 1 case was type II, and the other 3 had mixed lesions with properties of type I and II malformation. The number of injections ranged from 3 to 7. Complete or nearly complete shrinkage of the lesions were observed in 4 cases and marked reduction in size were noted in 3 cases. The remaining 3 cases showed partial or minimal reduction. Reduction in size of the mass was usually achieved in 2 weeks to 3 months. Some cases showed remarkable reductions in size after a single injection. All of type I lesions, except for a recurrent lesion in the l&year-old girl, demonstrated satisfactory results after 3 injections, whereas patients with lesions of type II or mixed type showed a marked response only in cysts in the lower neck and minimal responses in the submandibular region and the floor of the mouth. Illustrative cases of type I and type II are shown

TABLE 1.

With

RESULTS

Summary

of Bleomycin

Vwt

R

I + II

5X8

M

L

I

10 x 12

3

lwk lwk 4wks

F M F

Fl L B

I I I + II

10 x 10 6x9 10 x 12

3 3 7

2 yrs 3wks 4wks

M F M

L B L

II I + II I

lwk 12yrs

M F

R L

I I

Age’

Sex

Site

1

4wks

M

2

3wks

3 4 5 6 7

9 10

in Patients

Size (cm)

Case

6§

Sclerotherapy

No. of Treatment

Nearly complete Nearly complete Marked Marked Partial

7 7 3

6x8 10 x 5

Partial Marked Nearly complete Complete Stationary

3 4

12 years

before

Lymphatic

Outcome by BLM

3

9x6 7x9 6x5

Abbreviation: BLM, bleomycin sclerotherapy. * Age of initial sclerotherapy. t McGill and Mulliken’s classification (1993).” $ Partial excisions were performed 2 weeks and 9 Died with intercurrent pneumonia.

Congenital

the

first

Malformation

Surgery Tracheostomy Partial excision* Tracheostomy Partial excision Partial excision Partial excision -

Partial

sclerotherapy.

excision*

respectively.

Duration Follow-up (mos) 6 24 6 36 30 24 30 3 18 6

of

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ET AL

Fig 1. A typical case of a type I lymphatic malformation (case 9): (A) A 10 x 8 sized soft cystic mass was found on the right posterolateral neck at initial presentation. (B) Complete regression of the I-ion after three injections of bleomycin solution. (C and D) Coronal T,- (C) and axial T2-weighted (D) pretreatment MR images show a round homogenous cystic mass.

with pretreatment MRI findings (Figs 1 and 2). In patients who did not show satisfactory reduction of the lesion, surgical resection was attempted (cases 5, 6, and 7). When the operations were performed for partial responders, a moderately thickened fibrotic capsule surrounding the lesions made better demarcation of the lesions. One patient died of intercurrent pneumonia (case 8). DISCUSSION Congenital vascular lesions are currently classified into two major categories: hemangiomas and vascular malformations.‘-l* Hemangioma exhibits a history of rapid neonatal growth and slow involution. Vascular malformations can be subdivided into the following groups: capillary, venous, and arterial abnormalities, with or without fistulae and lymphatic anomalies’l Because vascular malformations grow in proportion to the child, fail to

regress, and fluctuate in size with growth spurts, surgical resection is generally recommended as the treatment of choice for control of congenital lymphatic malformation. However, complete and total resection of the lesion is not always possible and is rather difficult to achieve.5p15-18 Because these lesions are benign and are often difficult to resect without sacrificing important structures, a conservative rather than an aggressive approach is recommended to achieve functional alleviation of the airway obstruction or dysphagia, or to improve cosmesis in surgically incurable or difficult-to-cure patients. 1,4,16,19.20 Bleomycin was developed as an antitumor agent by Umezawa’l in 1966 and has been found to have antineoplastic activity against a variety of malignant tumors, including squamous cell carcinomas, lymphomas, and testicular tumors. In addition to its main antineoplastic activity mediated by the inhibition of DNA synthesis, bleomycin was found to have

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Fig 2. A typical case of a type II lymphatic malformation (case 71: (A) This patient had a huge beardliko lymphatic malformation involving both sidea of the neck end the floor of the mouth before sclerotherapy (3-week-old). (6) After 7 courses of sclsrotherepy (15-month-old), mess lesions could not be grossly seen except for a mild bulging of the left floor of the mouth. (C and D) Axial T2(C) and sagittal T,- (D) pretreatment MR images show a lobulated inhomogeneous multi-cystic mess lesion involving the entire neck.

a local sclerosing effect on endothelial cells of the cyst wall of lymphatic malformations with nonspecific inflammatory reaction.g Histological examination of the tissues from patients

who received preoperative bleomycin injections have shown loss of normal lymphatic epithelial lining and prominent infiltration of lymphocytes and other inflammatory cells

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with proliferation of stromal connective tissue.4*e*g When Yura et al9 introduced bleomycin as an effective therapeutic sclerosing agent for lymphangiomas, they injected bleomycin into the surrounding tissue. In 1987 Tanigawa et ala recommended bleomycin in microspherein-oil emulsion for better confinement of bleomycin in the injected space. We injected soluble bleomycin into aspirated cyst cavities with satisfactory results. Previous reports have discussed the overall response rates of bleomycin sclerotherapy without providing detailed descriptions of the nonresponsive cases. Although there is still confusion in terminology and classification of the congenital vascular malformations, we found McGill and Mulliken’s classification” to be useful for our analysis. We observed that congenital lymphatic malformations involving a higher cervical region (type II) were less responsive to sclerotherapy, because they were usually composed of smaller multiple cysts, sometimes with deep infiltration into the adjacent tissue, such as the floor of the mouth and tongue. For lesions in the lower neck (type I), sclerotherapy with bleomycin provided excellent results in most cases. In these instances, we believe that the larger cysts communicate well with one another, making conditions favorable for sclerotherapy. Hellman et al3 commented that cysts with hemorrhage within them or evidence of prior hemorrhage appeared to have a greater response to percutaneous sclerotherapy. Younger patients who started bleomycin sclerotherapy before 1 year of age appeared to do better than older children. However, it is difficult to compare the significance of the age because we had only two patients in the group older than 1 year. Side effects of bleomycin sclerotherapy were minimal, except for mild transient local swelling and inflammation in a few cases. Although several previous reports of bleomycin sclerotherapy also showed negligible systemic or local side reactions, one of the patients in our series died of intercurrent oneumonia, and it cannot be entirely ruled out that this was secondary to the use of bleomycin. In this case, physical and radiological findings suggested a diagnosis of pneumonia and they

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ET AL

were not compatible with pulmonary fibrosis. Unfortunately, an autopsy could not be performed for that patient. Because of this fatal complication of bleomycin, which is usually seen in accummulated doses higher than 300 mg but sometimes not dose-dependent, especially in lymphoma patients,22*23 some precautions should be stressed. For sclerotherapy, bleomycin was recommended to be injected in a dose of less than 1 mg/kg, and at intervals of not less than 2 weeks, with the total dose limited to 5 mg/kg.4 However, because little is known about the potential risk of long-term complications using bleomycin sclerotherapy, we believe that it is imperative to follow this guideline strictly and that we need to study more patients with longer follow-up. In this study, we found that bleomycin sclerotherapy for congenital lymphatic malformations in the head and neck to be an effective therapeutic alternative for reducing the size of lesions with complete regression in some instances. The best results were seen in the cystic type I lesions in younger patients. Bleomytin sclerotherapy was less effective in treating type II lesions that infiltrated the submandibular area and tongue. However, we think bleomycin sclerotherapy is a useful initial step in the treatment of this disease because it not only reduced the lesion size but also lessened the complicating resection of lesions that did not regress completely. Because the responses of bleomycin sclerotherapy in this presentation are of short duration at the present time, these data need to be reviewed again when the patient information matures over the next several years and with more patients. Furthermore, we believe that trials of alternative sclerosing agents with fewer side effects are warranted because of the potential toxicities of this agent. REFERENCES 1. Rlcciardelli EJ, Richardson MA: Cervicofacial cytic hygroma: Patterns of recurrence and management of the difficult case. Arch Otolarvngol_ Head Neck Surg 117:546553.1991 2. Emery PJ, Bailey CM, Evans JNG: Cystic hygroma of the head and neck: A review of 37 cases. J Laryngol Otol 96:613-619, 1964 3. Hellmann JR, Myer CM III, Prenger EC: Therapeutic

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alternatives in the treatment of life-threatening vasoformative tumors. Am J Otolaryngol 13:48-53, 1992 4. Okada A, Kubota A, Fukuzawa M, et al: Injection of bleomycin as a primary therapy of cystic lymphagioma. J Pediatr Surg 27:440-443, 1992 5. Hancock BJ, St-Vi1 D, Luks FI, et al: Complications of lymphangiomas in children, J Pediatr Surg 27:220-228, 1992 8. Dickerhoff R, Bode U: Cyclophosphamide in nonresectable cystic hygroma. Lancet 335:1474-1475, 1990 7. Seashore JH, Gardiner LJ, Ariyan S: Management of giant cystic hygromas in infants. Am J Surg 149:459-486, 1985 8. Tanigawa N, Shimomatsuya T, Takahashi L, et al: Treatment of cystic hygroma and lymphangioma with the use of bleomycin fat emulsion. Cancer 60:741-749, 1987 9. Yura J, Hashimoto T, Nakamura T, et al: Bleomycin treatment for cystic hygroma in children. Arch Jpn Chir 46:607-612, 1977 10. McGill TJ, Mulliken JB: Vascular anomalies of the head and neck. in Cumminns CW. Friedrickson IM, Harker LA, et al (eds): Otola&ngology-Head and Neck Surgery, vol 1 (ed 21. St Louis, MO, Mosby, 1993, pp 333-346

11. Mulliken JB, Young AE: Vascular Birthmarks: Hemangiomas and Malformations. Philadelphia, PA, Saunders, 1988 12. Stal S, Hamilton S, Spira M: Hemangiomas, lymphangiomas, and vascular malformations of the head and neck. Otolaryngol Clin North Am 19:769-796, 1986 13. Finn MC, Glowacki J, Mulliken JB: Congenital vascular lesions: Clinical application of a new classification. J Pediatr Surg 18:894-900, 1983 14. Mulliken JB, Glowacki J: Hemangiomas and vascu-

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lar malformations in infants and children: A classification based on endothelial characteristics. Plast Reconstr Surg 69:412-422, 1982 15. Kennedy TL: Cystic hygroma-lymphangioma: A rare and still unclear entitiy. Laryngoscope 99:1-g, 1989 (suppl49) 16. Cohen SR, Thompson JW: Lymphangiomas of the larynx in infants and children: A survey of pediatric lymphangioma. Ann Otol Rhino1 Laryngol 95:1-20, 1986 (suppl 127) 17. Ward PH, Harris PF, Downey W: Surgical approach to cystic hygroma of the neck. Arch Otolaryngol 91:508514,1970 18. Dingman

RO, Grabb WC: Lymphangioma of the tongue. Plast Recontr Surg 27:214-223, 1961 19. April MM, Rebeiz EE, Friedman EM, et al: Laser therapy for lymphatic malformations of the upper aerodigestive tract: An evolving experience. Arch Otolaryngol Head Neck Surg 118:205-208,1992 20. Balakrishnan A, Bailey CM: Lymphangioma of the tongue. A review of pathogenesis, treatment and the use of surface laser photocoagulation. J Laryngol Otol 105: 924-930, 1991 21. Umezawa H: Recent studies on biochemistry and action of bleomycin, in Carter SK, Crooke ST, Umezawa H (eds): Bleomycin: Current Status and New Developments, New York, NY, Academic, 1978, pp 15-20 22. Eisenberger M: Chemotherapy in head and neck cancer, in Mvers EN, Suen IY (edsl: Cancer of the Head and Neck. New York, NY, Churchill Livingstone, 1989, pp 979-1004 23. Levy RL, Chiarillo S: Hyperpyrexia, allergic-type response and death occurring with low-dose bleomycin administration. Oncology 37:318-317, 1980