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Successful treatment of juvenile hemangiomas with prednisone
March, 1968 T h e Journal of P E D I A T R I C S
351
Successful treatment of juvenile bemangiomas witb predn isone Six children with extensive hemangiomas were treated with oral prednisone. All except one showed dramatic regression within two weeks after starting therapy; the failure was in the oldest patient, 16 months of age, who had scarring due to extensive resection prior to administration of corticosteroids. Three patients relapsed after termination of therapy but were controlled by a second course; one of these had a second exacerbation after reduction of the dose. The advantages of a short course of systemic corticosteroids over other modes of therapy in hemangiomas requiring intervention are discussed.
Norman C. Fost, M.D.,* and Nancy B. Esterly, M.D.** BALTIMORE,
T ~ E
MD.
M A J o R I T Y
0 V
capillary
and
cavernous hemangiomas involute spontaneously with good cosmetic results, 1-a but difficulty arises when intervention is forced by involvement of a vital structure, excessively rapid growth with marked disfigurement and tissue destruction, or associated symptomatic thrombocytopenia. Several modes of therapy have been employed in these complicated cases, and each has disadvantages. Surgical excision may result in unsightly scarring or recurrence of tumor in the wound, and entails the risks of anesthesia and postoperative wound infection. 4 Injection of sclerosing solutions is From the Department of Pediatrics, The Children's Medical and Surgical Center, The Johns Hopkins University School of Medicine. *Department of Pediatrics, The lohns Hopkins Hospital. Present address, United States Army Hospital, Fort Jackson, S. C. ***Fellow, Division of Dermatology, Department of Medicine, The ]ohns Hookins University School o] Medicine.
undependable and painful, and the use of refrigerants may cause severe atrophy. 2 Irradiation has been associated with damage to the epiphyses, 5 breasts, gonads, skin, 6 lensf and thyroid, 8 and, in a large series, yielded no better results than in untreated controlsY Not only are these methods ineffective in some cases, but the incidence of complications in treated patients has been reported to be more than ten times that in untreated individuals? Systemic corticosteroids have been used in an attempt to control the bleeding diathesis in patients with giant hemangioma and thrombocytopenia (Kassabach-Merritt syndrome). In a few of these patients regression of the hemangiomas as welI as control of the thrombocytopenia has been noted, 1~176 but the effect of steroids is difficult to assess because it has been combined with other forms of therapy, particularly irradiation. Vol. 72, No. 3, pp. 351-357
352
Fost and Esterly
A
The Journal o[ Pediatrics March 1968
B
Fig. 1. Patient T. M. (in Case 1). (A) at 12 months of age, one month prior to initiation of prednisone therapy; and (B) at age 14 months after one month of prednisone therapy.
I n addition, the capricious n a t u r a l history of these tumors dictates caution in overinterpreting the response to therapy. T h e purpose of this paper is to report 6 patients with mixed capillary a n d cavernous hemangiomas who were treated with prednisone alone, 5 of whom showed p r o m p t a n d dramatic regression of their lesions shortly after initiation of therapy. T w o of the cases have been included in a previous report3 a CASE R E P O R T S Case 1. Patient T. M. (JHH 114-77-36), a full-term Caucasian boy, was noted at birth to have a small nodule on the right anterior frontal area and a pinhead-sized mark on the right pinna. During the first months of life there was gradual growth of these lesions as well as development and coalescence of satellite hemangiomas throughout the right temporal area. At 5 months of age extensive ulceration of the superficial lesions and compression of the external auditory canal by enlargement of the cavernous component prompted intervention. An unknown dose of irradiation was given; however, no change was noted in the size of the lesion. At 12 months of age the patient was referred to this hospital because of increasing prominence and distortion of the right ear. An elevated reddish-purple, confluent, roughened hemangioma involving the right ear and tempo-
ral area measured 9 by 14 cm. (Fig. 1, A). Gray-white sclerotic areas were scattered throughout the lesion and no ulceration was seen. The right tympanic membrane was not visible. The patient was observed for a month and no change in the hemangioma was noted. Prednisone, 30 mg. every day, was started and a decrease in the size of the lesion was noted within a few days. After two weeks of therapy, the cavernous component had been reduced significantly (Fig. 1, B) and the ear canal was patent. The dosage of prednisone was gradually reduced, and discontinued after three months of therapy. Two years later there has been no recurrence of ttimor. Case 2. Patient C. Co. (JHH 113-02-19) was noted at birth to have a left facial bruise which became raised and red during the subsequent several days. She was first seen at this hospital at age 1 month with an extensive capillary and cavernous hemangioma of the left face and head. By 2!/2 months of age extension and swelling of the tumor resulted in proptosis of the left eye and marked enlargement of the upper lip. The upper lip was partially excised because constant contact with the nose had produced ulceration of the nasal tip. At 6 months of age continued progression (Fig. 2, A) prompted institution of prednisone, 20 rag. every day, for 1 month. At 1 week there was slight but definite improvement, and at 1 month, dramatic regression. Prednisone was discontinued after 4 months, at which time the lesion was still re-
Volume 72 Number 3
Prednisone and hemangiomas
353
A
Fig. 2. Patient C. Co. (in Case 2), (A) at age 6 months at initiation of prednisone therapy; and (B) at 11 months, one month after termination of therapy.
Fig. 3. Patient M. M. (in Case 3) at 8 months, three months after resection of hemangioma.
gressing (Fig. 2, B). Two years later there was no recurrence. Case 3. Patient M. M. ( J H H 111-31-69) was first admitted to this hospital at 4 weeks of age because of increasing respiratory distress. Hoarseness and blue discoloration of the face were noted at birth. At two weeks of age it became apparent that an extensive hemangioma
was present. When admitted at the age of I month there were raised hemangiomas over the tongue, palate, buccal vermilion, and perioral surfaces and scattered lesions elsewhere on the face, neck, and trunk. Tracheostomy was required, at which time redness of the epiglottis and arytenoids was noted. Ulcerated skin lesions with superimposed staphylococcal infection were treated with topical and systemic antibiotics. Three months later he was readmitted because of feeding difficulties secondary to extension of the tumor. Partial removal of hemangioma from the head and neck was accomplished in a 3 stage operative procedure. Transient right facial nerve palsy was a complication, and a feeding gastrostomy tube was required for 3 months. When examined at 1 year of age the hemangioma was static but the patient was severely disfigured (Fig. 3). There was extensive fibrosis and scarring involving the tissue of the lower jaw; the mouth remained open. At 16 months and again at 23 months he received a 2 week course of steroids without noticeable change in the hemangiomas. At 23 months laryngoscopy showed that the airway was obstructed below the vocal cords by hemangioma bulging into the tracheal lumen. At 3 years of age he continues to require a tracheostomy because of occasional stridor associated with vigorous play and with upper respiratory tract infections.
354
Fost and Estcrh,
A
The Journal of Pediatrics March 1968
B
Fig. 4. Patient H. M. (in Case 4), (A) at 6 weeks of age, first course of prednisone started: and (B) 5 ~ months of age, regression on prednisone therapy is apparent.
Redness of the tracheal wall and reduction in the size of the lumen below the vocal cords are still observed on laryngoscopy. Case 4. Patient H. M. ( J H H 120-52-97) was noted to have a small hemangioma on the chest at birth. One week later there were lesions on the lower face and neck; at two weeks of age the lower lip became involved. She was first seen at this hospital at 6 weeks of age, having been hospitalized elsewhere and treated with a topical antibiotic for ulceration of the lip. The face was markedly disfigured by a firm subcutaneous mass in the left preauricular area. There were multiple raised red hemangiomas involving both ears, the face, anterior neck, and thorax. Small lesions were present on the tip of the tongue and the buccal mucosa. The lower lip was eroded and weeping. The hemangiomas on the neck and chest were ulcerated and infected (Fig. 4, A). The patient was started on prednisone, 20 mg. every day, and tapered to 7.5 mg. daily over a 3 week period, at which time there was noticeable regression, particularly of the cavernous component of the lesion. The ulcerated areas healed rapidly with topical therapy. Prednisone was discontinued at 3 months of age because of the excellent response, but one month later she was readmitted for further therapy
because of striking regrowth of the hemangiomas. Once again there was prompt and dramatic flattening of the lesions when prednisone, 20 mg. daily, was given (Fig. 4, B). At 6 months of age enlargement of the lesions in the parotid areas was again observed. Prednisone had been reduced to 5 ms. daily. The dosage was increased to 10 ms. every day for 6 weeks and then reduced to 5 mg. daily. It has been maintained at this dosage since the age of 9 months and there has been no regrowth of the tumor. The parotid areas have become flat and the capillary lesions have faded considerably. Mild growth retardation has been the only untoward effect of therapy. Case 5. Patient J. W., a full-term male infant, was first noted to have a small hemangioma of the lower lip at 8 months of age. Three months later the patient was started on prednisone 20 rag. daily because of continued rapid growth of the lesion. After 2 weeks of therapy there was definite improvement, and the dosage was gradually reduced and discontinued over a 2 week period. At 13 months of age, one month after discontinuation of therapy, the lesion was observed to be enlarging. A 6 week course of prednisone, 10 mg. daily, resulted in a decrease in the size of the hemangioma. Case 6. Patient C. C. developed nmltiple
Volume 72 Number 3
capillary hemangiomas on the lower lip and in the parotid areas at the age of 3 weeks. By 8 weeks of age these lesions had coalesced, and enlargement of deep hemangiomas in the parotid areas resulted in compression of the external auditory canals. Prednisone therapy, 20 rag. daily, was initialed and 2 weeks later there was definite decrease in the size of the hemangiomas. The dosage was decreased to 10 mg. every day; however, after 1 month, slight enlargement of the lesions was again noted. The dosage was increased to 15 mg. daily, and there has been no change in the size of the tumor. DISCUSSION The natural history of most juvenile hemangiomas is one of spontaneous but irregular regression. Although spontaneous resolution may be expected in the vast majority of patients, 1-3 certain situations preclude an expectant approach. Rapid growth of an hemangioma, particularly those about the face and neck, is not only cosmetically distressing but may interfere with vital functions. Associated thrombocytopenia may be life-threatening. Ulceration is not usually an indication for intervention, since significant hemorrhage is extremely rare, but scarring is more frequent when ulceration is severe. Our patients were treated with systemic corticosteroids in the hope that the more commonly used therapeutic methods could be avoided. In this series all of the patients except one showed a striking regression of lesions within 2 weeks after therapy was instituted. Furthermore, 3 of these patients (in Cases 4, 5, and 6) had regrowth of hemangioma tissue after reduction in dosage or discontinuation of therapy. These patients were adequately managed with a second course of steroids. Although the follow-up is brief, their lesions are now arrested or involuting. We feel that the course of these patients offers additional evidence that regression of the hemangiomas resulted from steroid therapy rather than to spontaneous resolution. Patient M. M. (in Case 3), the one unresponsive patient, still requires a trache-
Prednlsone and hemangiornas
3 55
ostomy at the age of 3 years and has a cosmetically poor result from surgery. Since there was massive involvement of the head and neck structures some type of intervention was necessary at the time of resection. However, had corticosteroid therapy been instituted prior to the extensive resection of his lesion, some of the sequelae might have been avoided. Because of this experience Patients 4, 5, and 6 were treated earlier in the course of their disease. The series of Zarem and Edgerton 21 from the plastic surgery service of this institution includes two of the patients in this report (in Cases 1 and 2) and describes an additional 5 patients with rapidly growing hemangiomas who responded to systemic corticosteroid therapy. In Table I are listed 13 other patients from the English Literature 1~ who were also treated with systemic corticosteroid therapy alone or in combination with another modality. It is difficult to evaluate the response in some of these cases and to segregate the possible role of steroids in this response. Nevertheless, the over-all findings support the impression that steroids may be an effective means of therapy in certain situations. The mechanism of action of systemic corticosteroids on hemangiomas is unknown. Zweifach, Shorr, and Black 22 have shown that corticosteroids maintain arteriolar tone and heighten vascular sensitivity to vasoconstrictive agents in the adrenalectomized rat. Arteriolar constriction and narrowing of the precapillary sphincters have been demonstrated in the hamster cheek pouch during treatment with intramuscular cortisone acetateY 3 These animals also showed resistance to formation of petechiae and susceptibility to white thromboembolism in the cheek pouch venules (leukocytic coating of the endothelial wall). In addition, steroids may significantly alter fibroblasts, ground substance, and collagen formation. '-'~-26 Although these effects have not been studied in reference to vascular structures, the immature and rapidly proliferating vessels of hemangiomas may well be par-
356
Fost and Esterly
The Journal o[ Pediatrics March 1968
T a b l e I. R e p o r t e d cases of h e m a n g i o m a s t r e a t e d w i t h c o r t i c o s t e r o i d s
Dosage
Duration o[ treatment
Other treatment
Effect
--
Regressed slightly in 1 mo,, subsequently continued to regress
Author
Age
1. Dargeon, H . W . , and associates 1~
2 Yr.
Hydrocortisone (25 mg. daily)
2 Wk.
2. Dargeon, H . W . , and associates x~
1 Mo.
Cortisone (75 rag. daily)
1 Mo.
Tumor grew; later regressed with irradiation
3. Paletta, F . X . , and associates n
7 Wk.
Cortisone (50 mg. daily)
1 Mo.
None. Irradiation also ineffective. ? Malignancy
4. Paletta, F . X . , and associates 11
5 Days Cortisone (5 mg. daily)
5. Meeks, E. A., and associates 12
1 Mo.
Cortisone (25 rag. daily)
6. Scherz, R. G., and associates 13
1 Yr.
Meticorten (10 mg. daily)
l l Days Then radiation added ?
Radiation after 2 wk.
Good response Tumor grew; regressed 3 too., later after splenectomy
7 Days Radiation added after 2 days
Improved, relapsed, improved again on combined drug without relapse after discontinuation
7. James, D. H., and 16 Days MethylprednisoTuttle, A. H. 14 lone (12 mg. daily)
7 Wk.
G~od response
8. Hill, G. J., and Longino, L. 15
2 Wk.
Meticorten (5 mg. daily)
2 Mo.
9. Sutherland, D. A., and Clark H. a6
3 Mo.
Prednisone (10 mg. daily)
1 Mo.
8 Mo.
Prednisone (15 rag. daily)
5 Days Radiation added after 9 days
10. Atkins, H. L., and associates a7 11. Katz, H. PA s
l0 Yr.
12. Valentine, G. H. 19 13. Levine, R., and associates 2~
Radiation added after 1 wk.
None. Later did well after irradiation and excision A C T H * ; radiation added after 9 days
Gradual improvement
Improved
Prednisone (40 rag. daily)
ly.~ Yr.
hnproved. Relapsed when tapered, regressed again with therapy. No permanent regression off prednisone
2 Mo.
Prednisone (5-20 mg. daily)
10 Days A C T H ; radiation
Regressed after irradiation
2 Mo.
Hydrocortisone (60 mg. daily)
4 Days Radiation added after 4 days
Regressed in 1-3 wk.
Prednisone (8 mg. 53 Days daily) ~ACTH = adrenecorticotroplc hormone. ticularly susceptible to alterations in the level of c i r c u l a t i n g corticosteroids. W e w o u l d propose, then, t h a t infants w i t h severe or progressive disease be t r e a t e d w i t h a trial course of p r e d n i s o n e a f t e r a t h o r o u g h m e d i c a l e v a l u a t i o n to e x c l u d e c o n -
ditions w h i c h c o n t r a i n d i c a t e steroid t h e r a p y . L i t t l e t i m e is lost by this brief trial p e r i o d a n d side effects are a l m o s t n e v e r a problem. I f no response is e v i d e n t a f t e r a 2 w e e k period, o t h e r m e a n s of t h e r a p y m a y t h e n be e m p l o y e d .
Volume 72 Number 3
SUMMARY Six patients with extensive hemangiomas were treated with systemic corticosteroid therapy. None of the patients had thrombocytopenia. W h e n therapy was started, three were less than 6 months of age a n d the rem a i n i n g three were 11, 13, a n d 16 months respectively. All except the 16-month-old infant showed dramatic regression of the t u m o r within two weeks after institution of therapy; the unresponsive patient had had extensive resection of his h e m a n g i o m a prior to the trial of steroids. T h r e e patients relapsed after t e r m i n a t i o n of therapy a n d were controlled by a second course; one of these had a second exacerbation after reduction of the dosage to a low level. Mild retardation of growth of the latter infant has been the only complication. It is suggested that in hemangiomas requiring intervention, a short course of systemic steroids may resuIt in a favorable outcome with fewer complications a n d long-term sequelae. We gratefully acknowledge the advice and encouragement of Dr. Mary Ellen Avery in the management of these patients and the preparation of the paper. We also thank Dr. Robert Brodell, Dr. Wilson Grubb, and Dr. Robert Haslam for allowing us to use their patients in this report.
REFERENCES 1. Bowers, R. E., Graham, E. A., and Tomlinson, K. A.: The natural history of the strawberry nevus, Arch. Dermat. 82: 667, 1960. 2. Simpson, J. R.: Natural history of cavernous hemangiomata, Lancet 2: 1057, 1959. 3. Wallace, H. J.: The conservative treatment of hemangiomatous nevi, Brit. J. Plast. Surg. 6: 78, 1954. 4. Margileth, A. M., and Museles, M.: Cutaneous hemangiomas in children, J. A. M. A. 191: 523, 1965. 5. McElfresh, A. E., and Robbins, R. R.: Radiation therapy of hemangiomas, J. PEDIAT. 59: 311, 1961. 6. Moynahan, E. J.: Natural history of cavernous hemangiomata, Lancet 1: 227, 1960. 7. Bek, V., and Zahn, K.: Cataract as a late sequel of contact roentgen therapy of angiomas in children, Acta radiol. 54: 443, 1960. 8. Wilson, G. M., Kilpatrick, R., Eckert, H., Curran~ R. C., Jepson, R. P., and Blomfield, G. W.: Thyroid neoplasms following irradiation, Brit. M. J. 2: 929, 1958.
Prednisone and hemangiomas
357
9. Walter, J.: Treatment of cavernous hemangioma with special reference to spontaneous regression, J. Faculty Radiol. 5: 135, 1953. 10. Dargeon, H. W., Adio, A. C., and Pack, G. T.: Hemangioma with thrombocytopenia, J. PEDIAT. 54: 285, 1959. 11. Paletta, F. X., Walker, J., and King, J.: Hemangiomathrombocytopenia s y n d r o m e, Plast. & Reconstruct. Surg. 23: 615, 1959, 12. Meeks, E. A., Jay, J. B., and Heaton, L. O.: Thrombocytopenic purpura occurring with large hemangioma, Am. J. Dis. Child. 90: 349, 1955. 13. Scherz, R. G., Louro, J. M., and Geppert, L. J.: Giant hemangioendothelioma with associated thrombocytopenia, J. P~mAT. 52: 212, 1958. 14. James, D. H., and Tuttle, A. H.: Congenital hemangioma with thrombocytopenia, J. PEDIAT. 59: 234, 1961. 15. Hill, G. J., and Longino, L.: Giant hemangioma with thrombocytopenia, Surg. Gynec. & Obst. 114: 304, 1962. 16. Sutherland, D. A., and Clark, H.: Hemangioma associated with thrombocytopenia, Am. J. Med. 33: 150, 1962. 17. Atkins, H. L., Wolff, J. A., and Sitarz, A.: Giant hemangioma in infancy with secondary thrombocytopenia purpura, Am. J. Roentgenol. 89: 1062, 1963. 18. Katz, H. P.: Thrombocytopenia associated with hemangiomata: Critical analysis of steroid therapy, XI International Congress of Pediatrics, Tokyo, 1965, pp. 336-337. 19. Valentine, G. H.: Hemangioma with thrombocytopenia, Canad. M. A. J. 84: 791, 1961. 20. Levine, R., Holcomb, T. M., and Lutzner, M. A.: Hemangioma associated with thrombocytopenia, Arch. Dermat. 82: 94, 1960. 21. Zarem, H. A., and Edgerton, M. T.: Induced resolution of cavernous hemangiomas following prednlsolone therapy, Plast. & Reconstruct. Surg. 39: 76, 1967. 22. Zweifach, B. W., Shorr, E., and Black, M. M.: The influence of the adrenal cortex on behavior of terminal vascular bed, Ann. New York Acad. Sc. 56: 626, 1953. 23. Wyman, L. C., Fulton, G. P., and Shulman, M. H.: Direct observations on the circulation in the hamster cheek pouch in adrenal insufficiency and experimental hypercorticalism, Ann. New York Acad. Sc. 56: 643, 1953. 24. Taubenhaus, M.: The influence of cortisone upon granulation tissue and its synergism and antagonism to other hormones, Ann. New York Acad. So. 56: 666, I953. 25. Smith, A. T., and Allison, D. J.: Skin and femur collagens and urinary hydroxyprollne of cortisone-treated rats, Endocrinology 77: 785, 1965. 26. Houck, J. C., and Patel, Y. M.: Proposed mode of action of corticosteroids on the connective tissue, Nature 206: 158, 1965.
351
Successful treatment of juvenile bemangiomas witb predn isone Six children with extensive hemangiomas were treated with oral prednisone. All except one showed dramatic regression within two weeks after starting therapy; the failure was in the oldest patient, 16 months of age, who had scarring due to extensive resection prior to administration of corticosteroids. Three patients relapsed after termination of therapy but were controlled by a second course; one of these had a second exacerbation after reduction of the dose. The advantages of a short course of systemic corticosteroids over other modes of therapy in hemangiomas requiring intervention are discussed.
Norman C. Fost, M.D.,* and Nancy B. Esterly, M.D.** BALTIMORE,
T ~ E
MD.
M A J o R I T Y
0 V
capillary
and
cavernous hemangiomas involute spontaneously with good cosmetic results, 1-a but difficulty arises when intervention is forced by involvement of a vital structure, excessively rapid growth with marked disfigurement and tissue destruction, or associated symptomatic thrombocytopenia. Several modes of therapy have been employed in these complicated cases, and each has disadvantages. Surgical excision may result in unsightly scarring or recurrence of tumor in the wound, and entails the risks of anesthesia and postoperative wound infection. 4 Injection of sclerosing solutions is From the Department of Pediatrics, The Children's Medical and Surgical Center, The Johns Hopkins University School of Medicine. *Department of Pediatrics, The lohns Hopkins Hospital. Present address, United States Army Hospital, Fort Jackson, S. C. ***Fellow, Division of Dermatology, Department of Medicine, The ]ohns Hookins University School o] Medicine.
undependable and painful, and the use of refrigerants may cause severe atrophy. 2 Irradiation has been associated with damage to the epiphyses, 5 breasts, gonads, skin, 6 lensf and thyroid, 8 and, in a large series, yielded no better results than in untreated controlsY Not only are these methods ineffective in some cases, but the incidence of complications in treated patients has been reported to be more than ten times that in untreated individuals? Systemic corticosteroids have been used in an attempt to control the bleeding diathesis in patients with giant hemangioma and thrombocytopenia (Kassabach-Merritt syndrome). In a few of these patients regression of the hemangiomas as welI as control of the thrombocytopenia has been noted, 1~176 but the effect of steroids is difficult to assess because it has been combined with other forms of therapy, particularly irradiation. Vol. 72, No. 3, pp. 351-357
352
Fost and Esterly
A
The Journal o[ Pediatrics March 1968
B
Fig. 1. Patient T. M. (in Case 1). (A) at 12 months of age, one month prior to initiation of prednisone therapy; and (B) at age 14 months after one month of prednisone therapy.
I n addition, the capricious n a t u r a l history of these tumors dictates caution in overinterpreting the response to therapy. T h e purpose of this paper is to report 6 patients with mixed capillary a n d cavernous hemangiomas who were treated with prednisone alone, 5 of whom showed p r o m p t a n d dramatic regression of their lesions shortly after initiation of therapy. T w o of the cases have been included in a previous report3 a CASE R E P O R T S Case 1. Patient T. M. (JHH 114-77-36), a full-term Caucasian boy, was noted at birth to have a small nodule on the right anterior frontal area and a pinhead-sized mark on the right pinna. During the first months of life there was gradual growth of these lesions as well as development and coalescence of satellite hemangiomas throughout the right temporal area. At 5 months of age extensive ulceration of the superficial lesions and compression of the external auditory canal by enlargement of the cavernous component prompted intervention. An unknown dose of irradiation was given; however, no change was noted in the size of the lesion. At 12 months of age the patient was referred to this hospital because of increasing prominence and distortion of the right ear. An elevated reddish-purple, confluent, roughened hemangioma involving the right ear and tempo-
ral area measured 9 by 14 cm. (Fig. 1, A). Gray-white sclerotic areas were scattered throughout the lesion and no ulceration was seen. The right tympanic membrane was not visible. The patient was observed for a month and no change in the hemangioma was noted. Prednisone, 30 mg. every day, was started and a decrease in the size of the lesion was noted within a few days. After two weeks of therapy, the cavernous component had been reduced significantly (Fig. 1, B) and the ear canal was patent. The dosage of prednisone was gradually reduced, and discontinued after three months of therapy. Two years later there has been no recurrence of ttimor. Case 2. Patient C. Co. (JHH 113-02-19) was noted at birth to have a left facial bruise which became raised and red during the subsequent several days. She was first seen at this hospital at age 1 month with an extensive capillary and cavernous hemangioma of the left face and head. By 2!/2 months of age extension and swelling of the tumor resulted in proptosis of the left eye and marked enlargement of the upper lip. The upper lip was partially excised because constant contact with the nose had produced ulceration of the nasal tip. At 6 months of age continued progression (Fig. 2, A) prompted institution of prednisone, 20 rag. every day, for 1 month. At 1 week there was slight but definite improvement, and at 1 month, dramatic regression. Prednisone was discontinued after 4 months, at which time the lesion was still re-
Volume 72 Number 3
Prednisone and hemangiomas
353
A
Fig. 2. Patient C. Co. (in Case 2), (A) at age 6 months at initiation of prednisone therapy; and (B) at 11 months, one month after termination of therapy.
Fig. 3. Patient M. M. (in Case 3) at 8 months, three months after resection of hemangioma.
gressing (Fig. 2, B). Two years later there was no recurrence. Case 3. Patient M. M. ( J H H 111-31-69) was first admitted to this hospital at 4 weeks of age because of increasing respiratory distress. Hoarseness and blue discoloration of the face were noted at birth. At two weeks of age it became apparent that an extensive hemangioma
was present. When admitted at the age of I month there were raised hemangiomas over the tongue, palate, buccal vermilion, and perioral surfaces and scattered lesions elsewhere on the face, neck, and trunk. Tracheostomy was required, at which time redness of the epiglottis and arytenoids was noted. Ulcerated skin lesions with superimposed staphylococcal infection were treated with topical and systemic antibiotics. Three months later he was readmitted because of feeding difficulties secondary to extension of the tumor. Partial removal of hemangioma from the head and neck was accomplished in a 3 stage operative procedure. Transient right facial nerve palsy was a complication, and a feeding gastrostomy tube was required for 3 months. When examined at 1 year of age the hemangioma was static but the patient was severely disfigured (Fig. 3). There was extensive fibrosis and scarring involving the tissue of the lower jaw; the mouth remained open. At 16 months and again at 23 months he received a 2 week course of steroids without noticeable change in the hemangiomas. At 23 months laryngoscopy showed that the airway was obstructed below the vocal cords by hemangioma bulging into the tracheal lumen. At 3 years of age he continues to require a tracheostomy because of occasional stridor associated with vigorous play and with upper respiratory tract infections.
354
Fost and Estcrh,
A
The Journal of Pediatrics March 1968
B
Fig. 4. Patient H. M. (in Case 4), (A) at 6 weeks of age, first course of prednisone started: and (B) 5 ~ months of age, regression on prednisone therapy is apparent.
Redness of the tracheal wall and reduction in the size of the lumen below the vocal cords are still observed on laryngoscopy. Case 4. Patient H. M. ( J H H 120-52-97) was noted to have a small hemangioma on the chest at birth. One week later there were lesions on the lower face and neck; at two weeks of age the lower lip became involved. She was first seen at this hospital at 6 weeks of age, having been hospitalized elsewhere and treated with a topical antibiotic for ulceration of the lip. The face was markedly disfigured by a firm subcutaneous mass in the left preauricular area. There were multiple raised red hemangiomas involving both ears, the face, anterior neck, and thorax. Small lesions were present on the tip of the tongue and the buccal mucosa. The lower lip was eroded and weeping. The hemangiomas on the neck and chest were ulcerated and infected (Fig. 4, A). The patient was started on prednisone, 20 mg. every day, and tapered to 7.5 mg. daily over a 3 week period, at which time there was noticeable regression, particularly of the cavernous component of the lesion. The ulcerated areas healed rapidly with topical therapy. Prednisone was discontinued at 3 months of age because of the excellent response, but one month later she was readmitted for further therapy
because of striking regrowth of the hemangiomas. Once again there was prompt and dramatic flattening of the lesions when prednisone, 20 mg. daily, was given (Fig. 4, B). At 6 months of age enlargement of the lesions in the parotid areas was again observed. Prednisone had been reduced to 5 ms. daily. The dosage was increased to 10 ms. every day for 6 weeks and then reduced to 5 mg. daily. It has been maintained at this dosage since the age of 9 months and there has been no regrowth of the tumor. The parotid areas have become flat and the capillary lesions have faded considerably. Mild growth retardation has been the only untoward effect of therapy. Case 5. Patient J. W., a full-term male infant, was first noted to have a small hemangioma of the lower lip at 8 months of age. Three months later the patient was started on prednisone 20 rag. daily because of continued rapid growth of the lesion. After 2 weeks of therapy there was definite improvement, and the dosage was gradually reduced and discontinued over a 2 week period. At 13 months of age, one month after discontinuation of therapy, the lesion was observed to be enlarging. A 6 week course of prednisone, 10 mg. daily, resulted in a decrease in the size of the hemangioma. Case 6. Patient C. C. developed nmltiple
Volume 72 Number 3
capillary hemangiomas on the lower lip and in the parotid areas at the age of 3 weeks. By 8 weeks of age these lesions had coalesced, and enlargement of deep hemangiomas in the parotid areas resulted in compression of the external auditory canals. Prednisone therapy, 20 rag. daily, was initialed and 2 weeks later there was definite decrease in the size of the hemangiomas. The dosage was decreased to 10 mg. every day; however, after 1 month, slight enlargement of the lesions was again noted. The dosage was increased to 15 mg. daily, and there has been no change in the size of the tumor. DISCUSSION The natural history of most juvenile hemangiomas is one of spontaneous but irregular regression. Although spontaneous resolution may be expected in the vast majority of patients, 1-3 certain situations preclude an expectant approach. Rapid growth of an hemangioma, particularly those about the face and neck, is not only cosmetically distressing but may interfere with vital functions. Associated thrombocytopenia may be life-threatening. Ulceration is not usually an indication for intervention, since significant hemorrhage is extremely rare, but scarring is more frequent when ulceration is severe. Our patients were treated with systemic corticosteroids in the hope that the more commonly used therapeutic methods could be avoided. In this series all of the patients except one showed a striking regression of lesions within 2 weeks after therapy was instituted. Furthermore, 3 of these patients (in Cases 4, 5, and 6) had regrowth of hemangioma tissue after reduction in dosage or discontinuation of therapy. These patients were adequately managed with a second course of steroids. Although the follow-up is brief, their lesions are now arrested or involuting. We feel that the course of these patients offers additional evidence that regression of the hemangiomas resulted from steroid therapy rather than to spontaneous resolution. Patient M. M. (in Case 3), the one unresponsive patient, still requires a trache-
Prednlsone and hemangiornas
3 55
ostomy at the age of 3 years and has a cosmetically poor result from surgery. Since there was massive involvement of the head and neck structures some type of intervention was necessary at the time of resection. However, had corticosteroid therapy been instituted prior to the extensive resection of his lesion, some of the sequelae might have been avoided. Because of this experience Patients 4, 5, and 6 were treated earlier in the course of their disease. The series of Zarem and Edgerton 21 from the plastic surgery service of this institution includes two of the patients in this report (in Cases 1 and 2) and describes an additional 5 patients with rapidly growing hemangiomas who responded to systemic corticosteroid therapy. In Table I are listed 13 other patients from the English Literature 1~ who were also treated with systemic corticosteroid therapy alone or in combination with another modality. It is difficult to evaluate the response in some of these cases and to segregate the possible role of steroids in this response. Nevertheless, the over-all findings support the impression that steroids may be an effective means of therapy in certain situations. The mechanism of action of systemic corticosteroids on hemangiomas is unknown. Zweifach, Shorr, and Black 22 have shown that corticosteroids maintain arteriolar tone and heighten vascular sensitivity to vasoconstrictive agents in the adrenalectomized rat. Arteriolar constriction and narrowing of the precapillary sphincters have been demonstrated in the hamster cheek pouch during treatment with intramuscular cortisone acetateY 3 These animals also showed resistance to formation of petechiae and susceptibility to white thromboembolism in the cheek pouch venules (leukocytic coating of the endothelial wall). In addition, steroids may significantly alter fibroblasts, ground substance, and collagen formation. '-'~-26 Although these effects have not been studied in reference to vascular structures, the immature and rapidly proliferating vessels of hemangiomas may well be par-
356
Fost and Esterly
The Journal o[ Pediatrics March 1968
T a b l e I. R e p o r t e d cases of h e m a n g i o m a s t r e a t e d w i t h c o r t i c o s t e r o i d s
Dosage
Duration o[ treatment
Other treatment
Effect
--
Regressed slightly in 1 mo,, subsequently continued to regress
Author
Age
1. Dargeon, H . W . , and associates 1~
2 Yr.
Hydrocortisone (25 mg. daily)
2 Wk.
2. Dargeon, H . W . , and associates x~
1 Mo.
Cortisone (75 rag. daily)
1 Mo.
Tumor grew; later regressed with irradiation
3. Paletta, F . X . , and associates n
7 Wk.
Cortisone (50 mg. daily)
1 Mo.
None. Irradiation also ineffective. ? Malignancy
4. Paletta, F . X . , and associates 11
5 Days Cortisone (5 mg. daily)
5. Meeks, E. A., and associates 12
1 Mo.
Cortisone (25 rag. daily)
6. Scherz, R. G., and associates 13
1 Yr.
Meticorten (10 mg. daily)
l l Days Then radiation added ?
Radiation after 2 wk.
Good response Tumor grew; regressed 3 too., later after splenectomy
7 Days Radiation added after 2 days
Improved, relapsed, improved again on combined drug without relapse after discontinuation
7. James, D. H., and 16 Days MethylprednisoTuttle, A. H. 14 lone (12 mg. daily)
7 Wk.
G~od response
8. Hill, G. J., and Longino, L. 15
2 Wk.
Meticorten (5 mg. daily)
2 Mo.
9. Sutherland, D. A., and Clark H. a6
3 Mo.
Prednisone (10 mg. daily)
1 Mo.
8 Mo.
Prednisone (15 rag. daily)
5 Days Radiation added after 9 days
10. Atkins, H. L., and associates a7 11. Katz, H. PA s
l0 Yr.
12. Valentine, G. H. 19 13. Levine, R., and associates 2~
Radiation added after 1 wk.
None. Later did well after irradiation and excision A C T H * ; radiation added after 9 days
Gradual improvement
Improved
Prednisone (40 rag. daily)
ly.~ Yr.
hnproved. Relapsed when tapered, regressed again with therapy. No permanent regression off prednisone
2 Mo.
Prednisone (5-20 mg. daily)
10 Days A C T H ; radiation
Regressed after irradiation
2 Mo.
Hydrocortisone (60 mg. daily)
4 Days Radiation added after 4 days
Regressed in 1-3 wk.
Prednisone (8 mg. 53 Days daily) ~ACTH = adrenecorticotroplc hormone. ticularly susceptible to alterations in the level of c i r c u l a t i n g corticosteroids. W e w o u l d propose, then, t h a t infants w i t h severe or progressive disease be t r e a t e d w i t h a trial course of p r e d n i s o n e a f t e r a t h o r o u g h m e d i c a l e v a l u a t i o n to e x c l u d e c o n -
ditions w h i c h c o n t r a i n d i c a t e steroid t h e r a p y . L i t t l e t i m e is lost by this brief trial p e r i o d a n d side effects are a l m o s t n e v e r a problem. I f no response is e v i d e n t a f t e r a 2 w e e k period, o t h e r m e a n s of t h e r a p y m a y t h e n be e m p l o y e d .
Volume 72 Number 3
SUMMARY Six patients with extensive hemangiomas were treated with systemic corticosteroid therapy. None of the patients had thrombocytopenia. W h e n therapy was started, three were less than 6 months of age a n d the rem a i n i n g three were 11, 13, a n d 16 months respectively. All except the 16-month-old infant showed dramatic regression of the t u m o r within two weeks after institution of therapy; the unresponsive patient had had extensive resection of his h e m a n g i o m a prior to the trial of steroids. T h r e e patients relapsed after t e r m i n a t i o n of therapy a n d were controlled by a second course; one of these had a second exacerbation after reduction of the dosage to a low level. Mild retardation of growth of the latter infant has been the only complication. It is suggested that in hemangiomas requiring intervention, a short course of systemic steroids may resuIt in a favorable outcome with fewer complications a n d long-term sequelae. We gratefully acknowledge the advice and encouragement of Dr. Mary Ellen Avery in the management of these patients and the preparation of the paper. We also thank Dr. Robert Brodell, Dr. Wilson Grubb, and Dr. Robert Haslam for allowing us to use their patients in this report.
REFERENCES 1. Bowers, R. E., Graham, E. A., and Tomlinson, K. A.: The natural history of the strawberry nevus, Arch. Dermat. 82: 667, 1960. 2. Simpson, J. R.: Natural history of cavernous hemangiomata, Lancet 2: 1057, 1959. 3. Wallace, H. J.: The conservative treatment of hemangiomatous nevi, Brit. J. Plast. Surg. 6: 78, 1954. 4. Margileth, A. M., and Museles, M.: Cutaneous hemangiomas in children, J. A. M. A. 191: 523, 1965. 5. McElfresh, A. E., and Robbins, R. R.: Radiation therapy of hemangiomas, J. PEDIAT. 59: 311, 1961. 6. Moynahan, E. J.: Natural history of cavernous hemangiomata, Lancet 1: 227, 1960. 7. Bek, V., and Zahn, K.: Cataract as a late sequel of contact roentgen therapy of angiomas in children, Acta radiol. 54: 443, 1960. 8. Wilson, G. M., Kilpatrick, R., Eckert, H., Curran~ R. C., Jepson, R. P., and Blomfield, G. W.: Thyroid neoplasms following irradiation, Brit. M. J. 2: 929, 1958.
Prednisone and hemangiomas
357
9. Walter, J.: Treatment of cavernous hemangioma with special reference to spontaneous regression, J. Faculty Radiol. 5: 135, 1953. 10. Dargeon, H. W., Adio, A. C., and Pack, G. T.: Hemangioma with thrombocytopenia, J. PEDIAT. 54: 285, 1959. 11. Paletta, F. X., Walker, J., and King, J.: Hemangiomathrombocytopenia s y n d r o m e, Plast. & Reconstruct. Surg. 23: 615, 1959, 12. Meeks, E. A., Jay, J. B., and Heaton, L. O.: Thrombocytopenic purpura occurring with large hemangioma, Am. J. Dis. Child. 90: 349, 1955. 13. Scherz, R. G., Louro, J. M., and Geppert, L. J.: Giant hemangioendothelioma with associated thrombocytopenia, J. P~mAT. 52: 212, 1958. 14. James, D. H., and Tuttle, A. H.: Congenital hemangioma with thrombocytopenia, J. PEDIAT. 59: 234, 1961. 15. Hill, G. J., and Longino, L.: Giant hemangioma with thrombocytopenia, Surg. Gynec. & Obst. 114: 304, 1962. 16. Sutherland, D. A., and Clark, H.: Hemangioma associated with thrombocytopenia, Am. J. Med. 33: 150, 1962. 17. Atkins, H. L., Wolff, J. A., and Sitarz, A.: Giant hemangioma in infancy with secondary thrombocytopenia purpura, Am. J. Roentgenol. 89: 1062, 1963. 18. Katz, H. P.: Thrombocytopenia associated with hemangiomata: Critical analysis of steroid therapy, XI International Congress of Pediatrics, Tokyo, 1965, pp. 336-337. 19. Valentine, G. H.: Hemangioma with thrombocytopenia, Canad. M. A. J. 84: 791, 1961. 20. Levine, R., Holcomb, T. M., and Lutzner, M. A.: Hemangioma associated with thrombocytopenia, Arch. Dermat. 82: 94, 1960. 21. Zarem, H. A., and Edgerton, M. T.: Induced resolution of cavernous hemangiomas following prednlsolone therapy, Plast. & Reconstruct. Surg. 39: 76, 1967. 22. Zweifach, B. W., Shorr, E., and Black, M. M.: The influence of the adrenal cortex on behavior of terminal vascular bed, Ann. New York Acad. Sc. 56: 626, 1953. 23. Wyman, L. C., Fulton, G. P., and Shulman, M. H.: Direct observations on the circulation in the hamster cheek pouch in adrenal insufficiency and experimental hypercorticalism, Ann. New York Acad. Sc. 56: 643, 1953. 24. Taubenhaus, M.: The influence of cortisone upon granulation tissue and its synergism and antagonism to other hormones, Ann. New York Acad. So. 56: 666, I953. 25. Smith, A. T., and Allison, D. J.: Skin and femur collagens and urinary hydroxyprollne of cortisone-treated rats, Endocrinology 77: 785, 1965. 26. Houck, J. C., and Patel, Y. M.: Proposed mode of action of corticosteroids on the connective tissue, Nature 206: 158, 1965.