The British Journal of Radiology, 75 (2002), 180184

2002 The British Institute of Radiology

Case report

KasabachMerritt syndrome: a review of the therapeutic options and a case report of successful treatment with radiotherapy and interferon alpha
1

S HESSELMANN, MD, 1O MICKE, MD, 2T MARQUARDT, MD, 2S BAAS, MD, 2 J H BRAMSWIG, MD, 2E HARMS, MD and 1N WILLICH, MD
Departments of 1Radiotherapy and 2Pediatrics, University Hospital Muenster, Albert-Schweitzer-Strae 33, D-48149 Muenster, Germany

Abstract. We describe the successful treatment of a neonate with KasabachMerritt syndrome who received local irradiation and interferon alpha therapy after failure of corticosteroid treatment. A male neonate, born after an uneventful pregnancy, had a huge haemangioma involving the upper right cervical region as well as severe thrombocytopenia. He was treated with corticosteroids, interferon alpha and radiotherapy. Prednisolone therapy (5 mg kg21 day21) was started at 41 days of age. No therapeutic effect was observed after 2 weeks. At this time the tumour size had increased dramatically, platelet counts had decreased progressively and coagulation abnormalities had developed. Because corticosteroid therapy had been ineffective and the child was in a life-threatening condition, irradiation was delivered up to a total dose of 9.5 Gy in ve fractions. Simultaneously, prednisolone therapy was slowly decreased and interferon alpha therapy (3 million U m22 day21) was started and continued for 6 weeks. After irradiation with 9.5 Gy and beginning interferon alpha therapy, the tumour decreased in size and coagulation parameters normalized within 4 weeks. 6 months later, platelet counts and coagulation parameters were still normal. The tumour had further decreased in size. No acute severe side effects were observed. Radiation therapy combined with interferon alpha treatment is an alternative treatment modality when high dose corticoid steroid therapy has been ineffective in patients with KasabachMerritt syndrome, despite the risks of growth delay and secondary malignancy. In children showing no response to corticosteroids, radiotherapy and/or interferon alpha should be considered in KasabachMerritt syndrome.

KasabachMerritt syndrome (KMS) is dened by a huge haemangioma with thrombocytopenia and consumption coagulopathy [1] due to endothelial defects within the haemangioma causing platelet activation, plateletbrin thrombosis formation, consumption of clotting and coagulation factors, and increased brinolysis [25]. Almost 200 cases have been reported in the literature since Kasabach and Merritt described the rst case in 1940. More than 80% of cases occur within the rst year of life [6]. Most cases of KMS appear to occur in kaposiform haemangioendotheliomas (46%) and tufted angiomas (31%); 23% showed an infantile (juvenile) haemangioma [7]. With an overall mortality rate of 12%, the mortality rate for patients with diffuse cavernous haemangiomas when a major haemorrhage occurs is 30% [2, 8]. Various treatment regimens have been published, with inconsistent
Received 5 February 2001 and in revised form 8 August 2001, accepted 20 August 2001. 180

results. There are two major treatment objectives, the control of the coagulopathy and thrombocytopenia as well as eradication of the haemangioma. Consequently, different treatment regimens are performed, including systemic corticosteroids [9, 10], irradiation [1115], compression [16], embolisation [17, 18], antibrinolytic agents [5, 19], platelet aggregation inhibitors [20], interferon [2123] as well as other strategies [2426]. Haemangiomas in childhood have been treated successfully with radiotherapy. In recent years this practice has been abandoned for a number of reasons. First, some of these lesions regress spontaneously and require no therapy. Second, radiotherapy can disrupt the growth pattern of the irradiated tissue and cause structural anomalies in paediatric patients. Third, irradiation is associated with a small but denite risk of inducing malignancies. However, in certain situations, e.g. after failure of corticosteroid treatment, radiation therapy is indicated [27]. This report describes a male neonate with KMS involving the
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Case report: KasabachMerritt syndrome and radiotherapy

upper right cervical region for whom radiation therapy combined with interferon alpha was benecial after failure of corticosteroids.

Case report
A male neonate, born following an uneventful pregnancy and delivery, was referred to the Department of Pediatrics of the University of Muenster, Germany for management of a large mass in the right upper cervical region. He was born at 38 weeks gestation. His weight was 3000 g, his length 49 cm and his Activity Pulse Grimace Appearance Respiration (APGAR) score was 10/10. The tumour had been present at birth and had subsequently enlarged. Ultrasound revealed a 2 cm62 cm63 cm mass at 4 days of age, which had increased to 3 cm63 cm63.5 cm 3 weeks later. A haemangioma (5.5 cm63.5 cm axial) was diagnosed on MRI at 6 weeks of age, extending from the right basilar cranium to the deep cervical area with contact to the internal carotid artery. Nuchal muscles were inltrated. The haemangioma extended to the dura mater at the C1/C2 level and encased the right vertebral artery. Platelet counts were decreased to 47 000 ml21 (normal 150 000450 000 ml21), prothrombin time (Quick) was normal (93%; normal . 70%) and activated partial thromboplastin time (APTT) was slightly increased (45.5 s; normal , 36 s). Fibrinogen was low (41 mg dl21; normal 180450 mg dl21) and brin degradation products (D-dimers) were 2 mg ml21 (normal , 2 mg ml21). 2 days later platelet counts were 16 000 ml21, prothrombin time was 91% and APTT was 45 s. Fibrinogen was 37 mg dl21 and D-dimers were 8 mg ml21. A consumption coagulopathy was diagnosed. Oral prednisolone therapy (5 mg kg21 day21) and heparin therapy (300 U kg21 day21) were started at 41 days of age. No therapeutic effect was observed. 2 weeks after the beginning of

prednisolone therapy, laboratory data were as follows: platelet count 10 000 ml21, prothrombin time , 20%, APTT . 200 s, brinogen , 20 mg dl21 and D-dimers 4 mg ml21, indicating disseminated intravascular coagulation (DIC). Owing to tumour progression and DIC, emergency radiation therapy was performed using electron beam therapy (14 MeV) at a single dose of 1.5 Gy (eld size 10 cm610 cm). 2 days later the haemangioma had enlarged further (7.5 cm67 cm65 cm) and an inspiratory stridor had developed. Irradiation was continued by 60Co c-ray (eld size 7.5 cm610 cm) with 2 Gy per day to a total dose of 9.5 Gy. Prednisolone therapy was slowly decreased. At the fth day of radiotherapy, the laboratory data had improved (platelet count 28 000 ml21, prothrombin time 90%, APTT . 200 s, brinogen , 40 mg dl21, D-dimers 4 mg ml21) (Figure 1). Following irradiation, subcutaneous interferon alpha therapy was performed for 6 weeks with gradually increasing doses up to 3 million U m22 day21. Platelet counts increased to normal and the tumour regressed during the 8 weeks following irradiation treatment. 6 weeks later laboratory data were nearly normal (platelet count 200 000 ml21, prothrombin time . 100%, APTT 38.7 s, brinogen 204 mg dl21, D-dimers 21 4 mg ml ) (Figure 1). An MRI 1 month later showed a decrease of the tumour volume to 3 cm63 cm64 cm, no contact to the dura mater and no compression of the larynx or pharynx. 6 months after therapy, platelet counts and the coagulation prole were still normal and the tumour was hardly visible. Until now, no severe acute side effects have been observed.

Discussion
After steroid failure, this patient was treated successfully by radiotherapy and interferon alpha,

Figure 1. Platelet (m) and brinogen () levels in relation to treatment. The British Journal of Radiology, February 2002 181

S Hesselmann, O Micke, T Marquardt et al

without severe complications. The management of KMS has been widely discussed in previous reports. There are two major treatment objectives. First, the control of coagulopathy and thrombocytopenia and, second, eradication of the haemangioma. Antiplatelet drugs, heparin or antibrinolytic agents may interrupt the selfperpetuating cycle of coagulationbrinolysis. Complete resection of the haemangioma is extremely difcult even under optimal conditions. Thus, we have used radiotherapy combined with interferon alpha therapy to control the lifethreatening coagulopathy and tumour size.

Steroids
Steroid therapy plays a major role in the current treatment of childhood haemangiomas. The mechanism of action of steroids is not yet clearly understood. In addition to their antiangiogenic properties, corticosteroids facilitate intralesional thrombosis by inhibiting brinolysis. Fost and Easterly [28] were the rst to report a dramatic response of cavernous haemangiomas to oral prednisone. Many authors have since conrmed that 25 mg day21 of prednisone induces regression of haemangiomas after 23 weeks. It is not unusual that haemangiomas increase in size after steroids are withdrawn, so that multiple courses of therapy are necessary. In contrast to the excellent steroid response rate for skin haemangiomas (90%), a similar result has not been reported for KMS (3050%) [12, 29]. It has been concluded that in patients not responding to corticosteroids, alternative therapies (e.g. radiotherapy and/or interferon alpha) should be used within 34 weeks [30].

Interferon alpha
Interferon alpha is an important alternative treatment for the treatment of KMS. Interferon alpha inhibits angiogenesis by suppressing overexpression of basic broblast growth factor (bFGF), an angiogenic protein, in infantile haemagiomas. In 1989, White et al [31] reported the successful use of interferon alpha-2a in the treatment of pulmonary haemangiomatosis. Indications for interferon alpha-2a therapy have since expanded to include haemangiomas that are cosmetically or functionally deforming, of massive size or life threatening [3235]. Interferon alpha2a and interferon alpha-2b appear to be equally effective. Greinwald et al [35] described response rates in a prospective non-randomized trial in 24 paediatric patients: complete response was seen in 42%, substantial response in 16%, intermediate response in 26% and no response in 16% of the patients. 5 patients (26%) developed neurological
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abnormalities (gait, ne motor decits). Many reports in the literature have indicated the efciency of interferon alpha. Some authors, such as Blei et al [33], found that some haemangiomas are more resistant to therapy with interferon alpha-2a owing to differences in drug metabolism, caliber of blood vessels and different blood ow. The current literature suggests a minimum response rate to interferon alpha therapy of 60%, with limited reversible side effects [22, 36]. Adverse effects of interferon alpha2a include constitutional symptoms (e.g. fever, malaise and fatigue, elevated liver enzymes, nausea, renal failure, transient neutropenia and anaemia, hypothyroidism, bone marrow suppression, myalgia) and especially neurological symptoms (e.g. gait abnormalities, memory disturbances, ataxia, paresthesia, numbness, oculomotor nerve paralysis, retinopathy, spastic diplegia) [37, 38]. Most neurological symptoms resolve after discontinuation of therapy. Neurological complications in haemangioma patients treated with interferon were rst reported by Chang et al in 1997 [34]. His group described a patient with delayed gross motor skills that were attributed to interferon alpha-2b therapy (3 million U m22 day21). These motor decits resolved completely after treatment was discontinued. In 1998, Barlow et al [39] described ve patients with spastic diplegia among a cohort of 26 infants treated with interferon alpha-2a for haemangiomas. Two patients developed gait, posture and ne motor decits after 46 months of therapy. After discontinuation of therapy, symptoms resolved within 3 months. Three patients had persistent neurological decits, which included abnormalities of gait and speech. In two children the neurological ndings did not appear until they were 17 months old. The third patient with persistent neurological dysfunction had received a prolonged course of therapy over a period of 21 months before symptoms appeared. In his trial Greinwald et al [35] observed that patients who developed neurological abnormalities began interferon alpha-2a therapy at an earlier age (4.7 months) than patients without neurological difculties (11.1 months). The mean time from initiation of therapy to the appearance of neurological symptoms was 4.8 months. Therefore, treatment with interferon alpha should, like radiotherapy, only be considered for lifethreatening haemangiomas that are unresponsive to corticosteroids.

Radiotherapy
In Kasabach and Merrits original report 60 years ago [1], the treatment modality used was radiation therapy. Initially, radiotherapy was
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Case report: KasabachMerritt syndrome and radiotherapy

the most popular method to treat haemangiomas. Haemangiomas were considered to be very radiosensitive, especially when treated early. Radiotherapy prior to 1960 was administered by radium/radon plaques, moulds or glass capsules applied to the skin, implantation of radioactive seeds or needles, or application of low voltage X-rays (6140 kV). Commonly, a combination of the above mentioned techniques was used to treat a single haemangioma. Approximately 85% of haemangiomas treated with radiotherapy prior to 1960 completely resolved and 15% showed improvement. Occasionally, haemangiomas were resistant to radiotherapy. 615% of patients had scarring of the skin, skin atrophy, increased pigmentation or telangiectasis. Permanent hair loss was also reported. Many children treated for skin haemangiomas prior to 1960 have now reached adulthood, and additional late effects have been reported such as breast hypoplasia, growth retardation and radiation-induced malignancies. Treatment side effects were related to total dose and treatment volume as well as to inadequate radiotherapy technique. A retrospective study of 18 000 patients treated with radiotherapy for haemangiomas in childhood found a signicantly increased dose-dependent risk of breast cancer, brain tumours, papillary thyroid cancer and bone tumours. Furst et al [40, 41] reported a cancer incidence in 234 (1.53%) of 15 336 patients with haemangioma who received radiotherapy, and in 34 (1.26%) of 2694 patients with haemangioma who received no radiation. This difference was not signicant. It is important to recognize the risks involved in using ionizing radiation to treat a benign but potentially life-threatening disease. Today, radiotherapy uses supercial and megavoltage photons, electrons, 60Co and radioactive implants for the treatment of complicated haemangiomas. In view of these severe long-term sequelae, we conclude that radiotherapy is no longer an appropriate treatment for skin haemangiomas without severe life-threatening coagulopathy. A 23 week course of oral prednisone is the initial treatment of choice. Complicated cavernous lesions can be an indication for radiotherapy when alternative therapies, e.g. corticosteroids, have failed. A retrospective analysis of 153 reported cases of KMS supports this conclusion [2]. With the combination of radiation and steroids, mortality rates were 2.5% compared with 30% in patients receiving no treatment. Other treatment modalities did not appear to be as benecial. In the literature, the response to radiotherapy was reported in 60100% [13, 40, 42, 43]. It must be stressed that in a life-threatening condition, emergency radiation therapy should be considered as the rst choice of treatment and
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should not be delayed if rapid steroid response is not forthcoming. Some reports have shown that radiotherapy is ineffective even in high doses [4, 6]. When radiotherapy is used, the lowest dose should be used so that the incidence of possible late effects and secondary malignancies is reduced. Cavernous haemangiomas with thrombocytopenia generally will respond to total radiotherapy doses of 720 Gy [44], although in some cases a dose of 10 Gy by conventional fractionation appears to be sufcient [15]. In this case, a dose of 9.5 Gy was necessary for the control of symptoms. Optimal therapy is only possible when the extent of the tumour is dened by CT or MRI to avoid insufcient radiation therapy.

Conclusion
Radiotherapy and interferon alpha are used in children with life-threatening haemangiomas. In this case of KMS, radiotherapy controlled disseminated intravascular coagulation and improved the coagulation prole. It is difcult to determine whether the documented response was due to radiotherapy, interferon alpha or both treatment regimens. We conclude that radiotherapy, despite possible severe sequelae in some cases, is still indicated in the treatment of childhood haemangioma if the clinical case is complicated and alternative therapies have failed.

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