HEAD
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NECK SURGERY
Recurrence of Infantile Hemangioma After Termination of Propranolol Treatment Lei Chang, MD, Gang Ma, MD, Yunbo Jin, MD, PhD, Xiaoxiao Ye, MD, Yajing Qiu, MD, Hui Chen, MD, PhD, Wenxin Yu, MD, Xi Yang, MD, Xiaojie Hu, MD, PhD, and Xiaoxi Lin, MD, PhD Abstract: Propranolol has been the first-line treatment for problematic infantile hemangioma (IH) since 2008. The recurrence of IHs after stopping treatment with propranolol was reported in several studies. Mechanisms underlying this phenomenon have not been elucidated so far. Our study is the first to show the general pathology of recurrence of IH after stopping treatment with propranolol. It can provide help for the clinical treatment of IHs. Key Words: recurrence, infantile hemangioma, propranolol, pathology (Ann Plast Surg 2014;72: 173Y175)
S
ince the report of Le´aute´-Labre`ze et al1 in 2008, propranolol has been the first-line treatment for problematic infantile hemangioma (IH). However, the recurrences of IHs after stopping treatment with propranolol were observed in several reports.2Y4 Mechanisms underlying this phenomenon have not been elucidated so far. In this study, we reported the general pathology of 2 cases of recurrences and tried to infer the mechanism underlying this phenomenon.
CASE REPORTS Two patients shared the similar medical history and clinical manifestation. Erythema was observed several days after birth. Then both the superficial and deep part of the lesion expanded rapidly in the following month. We took magnetic resonance imaging examinations for each patient before propranolol treatment. The results accorded with the diagnosis of IH.5,6
Case 1 A 2-month-old infant girl presented with a huge, ulcerated, mixed hemangioma on her right parotid area and neck. Oral propranolol was applied at a dose of 1.0 mg/kg of body weight, twice a day. The whole treatment lasted for 43 weeks. No adverse effects were observed during the treatment. Propranolol was tapered at the age of 12 months. Eight months later, the marked progressive regrowth of both superficial and deep component of the hemangioma was observed (Fig. 1). A specimen was obtained before her second propranolol treatment. The specimen was stained by hematoxylin and eosin, and localized with glut-1, CD31, and factor VIII antigen. Histological evaluation of the specimen exhibited lobules and sheets of capillaries within the dermis and subcutis. There were some Received June 12, 2013, and accepted for publication, after revision, September 25, 2013. From the Department of Plastic and Reconstructive Surgery, School of Medicine, Shanghai Jiao-tong University, Shanghai Ninth People’s Hospital, Shanghai, China. Conflicts of interest and sources of funding: none declared. This study was supported by a grant of the National Natural Science Foundation of China (81272127). Reprints: Xiaoxi Lin, MD, PhD, Department of Plastic and Reconstructive Surgery, School of Medicine, Shanghai Jiao-tong University, Shanghai Ninth People’s Hospital, Zhizaoju Road, Shanghai 200011, China. E-mail: [email protected]. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0148-7043/14/7202-0173 DOI: 10.1097/SAP.0000000000000032
Annals of Plastic Surgery
& Volume 72, Number 2, February 2014
fibrofatty infiltration and increased endothelial cell activity with the formation of syncytial masses with and without lumens. Immunohistochemical stainings with glut-1 and CD31 antigens were positive (Fig. 2). Immunof luorescence staining with factor VIII antigen was positive (Fig. 3).
Case 2 A 1.8-month-old infant girl presented with a huge, superficial, and deep hemangioma on the right shoulder. Oral propranolol was applied at a dose of 1.0 mg/kg of body weight, twice a day. No adverse effects were observed during 45 weeks of therapy. Propranolol was tapered at the age of 12 months. Two months after the treatment was stopped, evident progressive regrowth of deep component of the hemangioma was observed, whereas the superficial component did not show any regrowth or change in color (Fig. 4). Histological evaluation of this patient was very similar to that of case 1.
DISCUSSION As far as we know, our study is the first to show the general pathology of recurrence of IH after stopping treatment with propranolol. The prominent effect of propranolol on growing IH can be attributed to 3 molecular mechanisms, namely, vasoconstriction, inhibition of angiogenesis, and induction of apoptosis. Its long-term effects are believed to be due to induction of apoptosis in proliferating endothelial cells.7 Razon et al8 demonstrated that the involutive phase involves both high apoptosis and proliferation, and concluded that increased apoptosis during the second year of life can offset cellular proliferation and may be involved in initiating regression of hemangioma. Schupp et al3 reported 6 relapses in 55 infants with IH after termination of propranolol treatment. They conjectured that relapses may be more likely in patients in whose therapy is initiated at a younger age, while still in the proliferating phase. And after a second treatment course by using propranolol, no significant relapse was observed. Bagazgoitia et al2 reported that recurrence was present in 5 of 26 cases. They conferred that propranolol has been proven to induce apoptosis of endothelial cells; some cells may remain proliferative after treatment is stopped. However, their findings were based on clinical experience, not pathological biopsy. Khan et al9 isolated CD133+ hemangioma stem cells from proliferating phase IH using antiYCD133-coated magnetic beads, and their findings provide evidence for a stem cell origin of IH, which is in contrast to the long-held view that IH arises from endothelial cells. In recent years, the important role of hemangioma stem cells in proliferation and involution of IH has been widely accepted. Wong et al10 assumed that hemangioma stem cells continue to proliferateV albeit at a slow rate in IH and can explain the phenomenon of rebound growth after propranolol therapy has been tapered. Proliferating phase of IH is identified with increased endothelial cell activity with the formation of syncytial masses with and without lumens. Meanwhile, glut-1, CD31, and factor VIII antigen are present in endothelial cells of the hemangioma and in cells of normal adjacent vessels.7 However, there have been no reports of www.annalsplasticsurgery.com
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
173
Annals of Plastic Surgery
Chang et al
& Volume 72, Number 2, February 2014
FIGURE 1. Before treatment (A), at the termination of treatment (B), and 8 months after propranolol was stopped (C).
FIGURE 2. Histologic analysis of case 1. A, There were some fibrofatty infiltration and increased endothelial cell activity with the formation of syncytial masses with and without lumens. B, Immunohistochemical staining with glut-1 antigen was positive. C, Immunohistochemical staining with CD31 antigen was positive (magnification, 100). Size bar, 20 Km.
FIGURE 3. Immunof luorescence staining with factor VIII antigen was positive. A, Staining with factor VIII antigen. B, Staining with DAPI. C, Synthetic picture (magnification, 100). Size bar, 20 Km. 174
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* 2013 Lippincott Williams & Wilkins
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Plastic Surgery
& Volume 72, Number 2, February 2014
IH After Termination of Propranolol Treatment
FIGURE 4. Before treatment (A), at the termination of treatment (B), and 2 months after propranolol was stopped (C).
general pathology of recurrence of IH after stopping treatment with propranolol so far. In our 2 cases, although involuted fatty tissue could be observed in pathological sections, there were still a large number of proliferative endothelial cells remaining. This characteristic was very similar to that of proliferating IH. Therefore, it can be explained why a second propranolol treatment is effective. However, where did proliferative endothelial cells come from? Did they differentiate from hemangioma stem cells or remained endothelial cells? We still cannot answer these questions. Due to ethical concerns, we failed to collect specimens at the first termination of propranolol treatment. Therefore, we can only describe the pathology of recurrence and infer the mechanism underlying this phenomenon. Further researches are necessary. REFERENCES 1. Le´aute´-Labre`ze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649Y2651. 2. Bagazgoitia L, Herna´ndez-Martin A, Torrelo A. Recurrence of infantile hemangiomas treated with propranolol. Pediatr Dermatol. 2011;28:658Y662.
* 2013 Lippincott Williams & Wilkins
3. Schupp CJ, Kleber JB, Gunther P, et al. Propranolol therapy in 55 infants with IH: dosage, duration, adverse effects and outcome. Pediatr Dermatol. 2011;28: 640Y644. 4. Georgountzou A, Karavitakis E, Klimentopoulou A, et al. Propranolol treatment for severe infantile hemangiomas: a single-centre 3-year experience. Acta Paediatr. 2012;101:e469Ye474. 5. Greene AK, Rogers GF, Mulliken JB. Management of parotid hemangioma in 100 children. Plast Reconstr Surg. 2004;113:53Y60. 6. Khan SN, Sepahdari AR. Orbital masses: CT and MRI of common vascular lesions, benign tumors, and malignancies. Saudi J Ophthalmol. 2012;26: 373Y383. 7. Thuy L, Hochman M. Pathogenesis of infantile hemangioma. Facial Plast Surg. 2012;28:554Y562. 8. Razon MJ, Kraling BM, Mulliken JB, et al. Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation 1998;5: 189Y195. 9. Khan ZA, Boscolo E, Picard A, et al. Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J Clin Invest. 2008; 118:2592Y2599. 10. Wong A, Hardy KL, Kitajewski AM, et al. Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells. Plast Reconstr Surg. 2012;130:1012Y1021.
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Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
175
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NECK SURGERY
Recurrence of Infantile Hemangioma After Termination of Propranolol Treatment Lei Chang, MD, Gang Ma, MD, Yunbo Jin, MD, PhD, Xiaoxiao Ye, MD, Yajing Qiu, MD, Hui Chen, MD, PhD, Wenxin Yu, MD, Xi Yang, MD, Xiaojie Hu, MD, PhD, and Xiaoxi Lin, MD, PhD Abstract: Propranolol has been the first-line treatment for problematic infantile hemangioma (IH) since 2008. The recurrence of IHs after stopping treatment with propranolol was reported in several studies. Mechanisms underlying this phenomenon have not been elucidated so far. Our study is the first to show the general pathology of recurrence of IH after stopping treatment with propranolol. It can provide help for the clinical treatment of IHs. Key Words: recurrence, infantile hemangioma, propranolol, pathology (Ann Plast Surg 2014;72: 173Y175)
S
ince the report of Le´aute´-Labre`ze et al1 in 2008, propranolol has been the first-line treatment for problematic infantile hemangioma (IH). However, the recurrences of IHs after stopping treatment with propranolol were observed in several reports.2Y4 Mechanisms underlying this phenomenon have not been elucidated so far. In this study, we reported the general pathology of 2 cases of recurrences and tried to infer the mechanism underlying this phenomenon.
CASE REPORTS Two patients shared the similar medical history and clinical manifestation. Erythema was observed several days after birth. Then both the superficial and deep part of the lesion expanded rapidly in the following month. We took magnetic resonance imaging examinations for each patient before propranolol treatment. The results accorded with the diagnosis of IH.5,6
Case 1 A 2-month-old infant girl presented with a huge, ulcerated, mixed hemangioma on her right parotid area and neck. Oral propranolol was applied at a dose of 1.0 mg/kg of body weight, twice a day. The whole treatment lasted for 43 weeks. No adverse effects were observed during the treatment. Propranolol was tapered at the age of 12 months. Eight months later, the marked progressive regrowth of both superficial and deep component of the hemangioma was observed (Fig. 1). A specimen was obtained before her second propranolol treatment. The specimen was stained by hematoxylin and eosin, and localized with glut-1, CD31, and factor VIII antigen. Histological evaluation of the specimen exhibited lobules and sheets of capillaries within the dermis and subcutis. There were some Received June 12, 2013, and accepted for publication, after revision, September 25, 2013. From the Department of Plastic and Reconstructive Surgery, School of Medicine, Shanghai Jiao-tong University, Shanghai Ninth People’s Hospital, Shanghai, China. Conflicts of interest and sources of funding: none declared. This study was supported by a grant of the National Natural Science Foundation of China (81272127). Reprints: Xiaoxi Lin, MD, PhD, Department of Plastic and Reconstructive Surgery, School of Medicine, Shanghai Jiao-tong University, Shanghai Ninth People’s Hospital, Zhizaoju Road, Shanghai 200011, China. E-mail: [email protected]. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0148-7043/14/7202-0173 DOI: 10.1097/SAP.0000000000000032
Annals of Plastic Surgery
& Volume 72, Number 2, February 2014
fibrofatty infiltration and increased endothelial cell activity with the formation of syncytial masses with and without lumens. Immunohistochemical stainings with glut-1 and CD31 antigens were positive (Fig. 2). Immunof luorescence staining with factor VIII antigen was positive (Fig. 3).
Case 2 A 1.8-month-old infant girl presented with a huge, superficial, and deep hemangioma on the right shoulder. Oral propranolol was applied at a dose of 1.0 mg/kg of body weight, twice a day. No adverse effects were observed during 45 weeks of therapy. Propranolol was tapered at the age of 12 months. Two months after the treatment was stopped, evident progressive regrowth of deep component of the hemangioma was observed, whereas the superficial component did not show any regrowth or change in color (Fig. 4). Histological evaluation of this patient was very similar to that of case 1.
DISCUSSION As far as we know, our study is the first to show the general pathology of recurrence of IH after stopping treatment with propranolol. The prominent effect of propranolol on growing IH can be attributed to 3 molecular mechanisms, namely, vasoconstriction, inhibition of angiogenesis, and induction of apoptosis. Its long-term effects are believed to be due to induction of apoptosis in proliferating endothelial cells.7 Razon et al8 demonstrated that the involutive phase involves both high apoptosis and proliferation, and concluded that increased apoptosis during the second year of life can offset cellular proliferation and may be involved in initiating regression of hemangioma. Schupp et al3 reported 6 relapses in 55 infants with IH after termination of propranolol treatment. They conjectured that relapses may be more likely in patients in whose therapy is initiated at a younger age, while still in the proliferating phase. And after a second treatment course by using propranolol, no significant relapse was observed. Bagazgoitia et al2 reported that recurrence was present in 5 of 26 cases. They conferred that propranolol has been proven to induce apoptosis of endothelial cells; some cells may remain proliferative after treatment is stopped. However, their findings were based on clinical experience, not pathological biopsy. Khan et al9 isolated CD133+ hemangioma stem cells from proliferating phase IH using antiYCD133-coated magnetic beads, and their findings provide evidence for a stem cell origin of IH, which is in contrast to the long-held view that IH arises from endothelial cells. In recent years, the important role of hemangioma stem cells in proliferation and involution of IH has been widely accepted. Wong et al10 assumed that hemangioma stem cells continue to proliferateV albeit at a slow rate in IH and can explain the phenomenon of rebound growth after propranolol therapy has been tapered. Proliferating phase of IH is identified with increased endothelial cell activity with the formation of syncytial masses with and without lumens. Meanwhile, glut-1, CD31, and factor VIII antigen are present in endothelial cells of the hemangioma and in cells of normal adjacent vessels.7 However, there have been no reports of www.annalsplasticsurgery.com
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
173
Annals of Plastic Surgery
Chang et al
& Volume 72, Number 2, February 2014
FIGURE 1. Before treatment (A), at the termination of treatment (B), and 8 months after propranolol was stopped (C).
FIGURE 2. Histologic analysis of case 1. A, There were some fibrofatty infiltration and increased endothelial cell activity with the formation of syncytial masses with and without lumens. B, Immunohistochemical staining with glut-1 antigen was positive. C, Immunohistochemical staining with CD31 antigen was positive (magnification, 100). Size bar, 20 Km.
FIGURE 3. Immunof luorescence staining with factor VIII antigen was positive. A, Staining with factor VIII antigen. B, Staining with DAPI. C, Synthetic picture (magnification, 100). Size bar, 20 Km. 174
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* 2013 Lippincott Williams & Wilkins
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Plastic Surgery
& Volume 72, Number 2, February 2014
IH After Termination of Propranolol Treatment
FIGURE 4. Before treatment (A), at the termination of treatment (B), and 2 months after propranolol was stopped (C).
general pathology of recurrence of IH after stopping treatment with propranolol so far. In our 2 cases, although involuted fatty tissue could be observed in pathological sections, there were still a large number of proliferative endothelial cells remaining. This characteristic was very similar to that of proliferating IH. Therefore, it can be explained why a second propranolol treatment is effective. However, where did proliferative endothelial cells come from? Did they differentiate from hemangioma stem cells or remained endothelial cells? We still cannot answer these questions. Due to ethical concerns, we failed to collect specimens at the first termination of propranolol treatment. Therefore, we can only describe the pathology of recurrence and infer the mechanism underlying this phenomenon. Further researches are necessary. REFERENCES 1. Le´aute´-Labre`ze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649Y2651. 2. Bagazgoitia L, Herna´ndez-Martin A, Torrelo A. Recurrence of infantile hemangiomas treated with propranolol. Pediatr Dermatol. 2011;28:658Y662.
* 2013 Lippincott Williams & Wilkins
3. Schupp CJ, Kleber JB, Gunther P, et al. Propranolol therapy in 55 infants with IH: dosage, duration, adverse effects and outcome. Pediatr Dermatol. 2011;28: 640Y644. 4. Georgountzou A, Karavitakis E, Klimentopoulou A, et al. Propranolol treatment for severe infantile hemangiomas: a single-centre 3-year experience. Acta Paediatr. 2012;101:e469Ye474. 5. Greene AK, Rogers GF, Mulliken JB. Management of parotid hemangioma in 100 children. Plast Reconstr Surg. 2004;113:53Y60. 6. Khan SN, Sepahdari AR. Orbital masses: CT and MRI of common vascular lesions, benign tumors, and malignancies. Saudi J Ophthalmol. 2012;26: 373Y383. 7. Thuy L, Hochman M. Pathogenesis of infantile hemangioma. Facial Plast Surg. 2012;28:554Y562. 8. Razon MJ, Kraling BM, Mulliken JB, et al. Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation 1998;5: 189Y195. 9. Khan ZA, Boscolo E, Picard A, et al. Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J Clin Invest. 2008; 118:2592Y2599. 10. Wong A, Hardy KL, Kitajewski AM, et al. Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells. Plast Reconstr Surg. 2012;130:1012Y1021.
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Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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