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Kaposiform haemangioendothelioma (KHE): Not just a bruise
JPRAS Open 1-2 (2014) 1e5
Contents lists available at ScienceDirect
JPRAS Open journal homepage: http://www.journals.elsevier.com/ jpras-open
Case report
Kaposiform haemangioendothelioma (KHE): Not just a bruise J. May a, *, A. Sadri a, L. Shanks a, S.H. Liew a, B. Pizer b a b
Department of Plastic Surgery, Alder Hey Children's Hospital, Liverpool, UK Department of Oncology, Alder Hey Children's Hospital, Liverpool, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 November 2014 Accepted 20 November 2014 Available online 29 November 2014
Kaposiform haemangioendothelioma is a rare, but potentially fatal vascular tumour of childhood. We present a case that highlights the diagnostic and management challenges of this condition, particularly when associated with KasabacheMerritt phenomenon, and supports the use of sirolimus in its treatment. © 2014 The Authors. Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons. This is an open access article under the CC BY-NC-SA license (http:// creativecommons.org/licenses/by-nc-sa/4.0/).
Keywords: Kaposiform haemangioendothelioma KasabacheMerritt phenomenon Consumptive coagulopathy Sirolimus
Introduction Kaposiform haemangioendothelioma (KHE) is a complicated and rare form of locally aggressive vascular tumour with distinctive pathological features.1 It typically appears in infancy and childhood with an estimated incidence of 0.7/100,000 children per year.2 When patients with KHE develop the associated KasabacheMerritt phenomenon (KMP), characterised by platelet trapping and a consumptive coagulopathy, the mortality is as high as 30%.2 KHE and KMP invariably present diagnostic and therapeutic challenges, which, if not rapidly addressed, can result in the death of the child. Hence, early recognition and prompt management is of importance to health professionals. We present a case of KHE with associated KMP that demonstrates the medical and surgical challenges of this condition, highlighting the need for nationally and internationally accepted guidelines and the need for prospective clinical trials.
* Corresponding author. Department of Plastic Surgery, Alder Hey Children's NHS Foundation Trust, Eaton Road, West Derby, Liverpool L12 2AP, UK. E-mail address: [email protected] (J. May). http://dx.doi.org/10.1016/j.jpra.2014.11.003 2352-5878/© 2014 The Authors. Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/4.0/).
2
J. May et al. / JPRAS Open 1-2 (2014) 1e5
Case report A four-week-old female presented with a 12-h history of apparent bruising to the right chest and flank. There was no history of trauma. The child was normally fit and well and was born by induction of labour at 38 weeks. Examination revealed a well child with ecchymosis involving 6% total body surface area (Figure 1). There were no palpable masses to suggest haematoma and the overlying skin was intact. Initial investigations revealed mild anaemia but profound thrombocytopaenia (platelets 14 109/L). A chest radiograph showed extensive soft tissue oedema in the area of interest. Severe thrombocytopaenia continued to worsen and the child was given blood and platelet transfusions. The D-dimer level was highly elevated at 94,768 ng/ml. The Oncology and Plastic Surgery teams suggested a diagnosis of KHE with associated KMP, and treatment with dexamethasone was commenced. A biopsy was performed, confirming the diagnosis of KHE, a Broviac catheter was inserted, and the child was commenced on aspirin and weekly vincristine (0.05 mg/kg). The dexamethasone was changed to oral prednisolone. After 5 days, the child was showing a good clinical and haematological response and was discharged for daily outpatient follow-up. The lesion continued to regress with normalisation of both platelet counts and D-Dimer levels. 4 weeks after diagnosis, the dose of prednisolone was gradually reduced with continuing aspirin and weekly vincristine. Despite continuing vincristine therapy, 8 weeks from presentation, there was a rebound growth of the KHE and a rapidly worsening coagulopathy was evidenced by a D-dimer of 12,264 ng/ml and platelets of 41 109/L. Steroid therapy was recommenced. MRI showed the lesion extending from the mid lateral right abdominal wall into the right axilla (Figure 2). On discussion with an interventional radiologist, it was felt that embolisation would be technically difficult and so sclerotherapy was performed. The procedure was uncomplicated, but had limited effect. 10 weeks after initial diagnosis, the lesion was successfully embolised through the right intercostal arteries, internal thoracic artery, and subscapular artery. The next day, the KHE was excised down to muscle, leaving a significant defect in the right lateral trunk (Figure 3). Four days post-operatively, the child was recommenced on aspirin and vincristine because of worsening coagulopathy, with platelets of 24 109/L and a D-dimer of 23,173 ng/ml. Histopathology showed the KHE was present at the deep margin and repeat MRI showed a significant residual tumour. Further excision of the lesion was felt to carry too great a morbidity because it would involve resection of the musculature of the right lateral trunk.
Figure 1. Infant at initial presentation.
J. May et al. / JPRAS Open 1-2 (2014) 1e5
3
Figure 2. MRI of the lesion pre-operatively.
Figure 3. Defect following surgical excision of KHE.
The child's condition stabilised, but she continued to require platelet transfusions around every three days. The anti-platelet drug, clopidogrel, was added to aspirin and prednisolone therapy, in accordance with Consensus-Derived Practice Standards.3 Steroid therapy was having limited effect. Although not generally effective in KHE, a trial of propranolol was commenced, but this was not successful in improving the coagulopathy. A trial of sirolimus, recently shown to be effective in the treatment of refractory KHE,4,5 was then started. The child's general and haematological condition subsequently improved, with a reduction in the frequency of platelet transfusions. After four weeks there was normalisation of platelet counts and thus no further platelet transfusions required. The D-Dimer levels also showed a marked improvement. Steroids, aspirin and clopidogrel were discontinued between six and eight weeks after the start of sirolimus, the dose of which was adjusted to achieve therapeutic blood levels. The trunk defect healed well by secondary intention (Figure 4). When the child was 15 months old and after 10 months of sirolimus a trial of stopping this treatment was attempted. Two months later this was followed by followed by clear further evidence of KMP with a platelet count of 24 109/L and a D-dimer of 30,915 ng/ml. Sirolimus therapy was rapidly recommenced with a rapid return to normal platelet counts. Now 2 years and 3 months after diagnosis, the KHE is controlled with sirolimus monotherapy that is planned to continue for at least for another two years.
4
J. May et al. / JPRAS Open 1-2 (2014) 1e5
Figure 4. Outcome at 1-year follow-up.
Discussion This case demonstrates the complexity and challenges of KHE complicated by KMP. The authors propose that this condition be treated in tertiary referral centres, with access to the variety of possible therapeutic interventions. KHE usually presents as an indurated purple lesion with nebulous margins. In infancy these lesions typically occur in the skin and soft tissue of the neck, extremities and trunk. However, numerous reports have identified cases involving non-cutaneous areas such as retroperitoneum.2,6 Despite these tumours expressing benign histology, their aggressive behaviour can result in the compression and infiltration of adjacent structures. This significantly increases morbidity and mortality, especially when associated with KMP.7 KMP is the most serious complication associated with KHE. The pathophysiology is commonly accepted as the trapping of platelets via the abnormally proliferating endothelium of the vascular lesion. This intralesional trapping results in secondary ingestion of clotting factors. The consumptive coagulopathy can progress to disseminated intravascular coagulation (DIC) and often death. Early diagnosis is a key in the treatment of KHE. The lesion can often be misdiagnosed as infantile haemangioma,8 which generally responds well to propranolol treatment,9 but this is not the case for KHE. Magnetic resonance imaging is the imaging modality of choice in KHE, but treatment should not delayed by radiological investigations.3 Surgical resection, though offering a potential cure for KHE, is often not a viable option in view of the high morbidity and mortality due to tumour invasion of large neurovascular structures, muscle and fascia. The option of surgical excision requires meticulous preoperative planning and the risk to benefit ratio must be carefully considered. Embolisation, either as a definitive procedure or as an adjunct to resection, has been advocated as a therapeutic intervention, but it can be technically very challenging.10 The aims of pharmacological treatment are to rapidly correct coagulopathy and, thereafter, decrease tumour size. Recent consensus-derived guidelines supported the use of steroids and vincristine as firstline therapy when KHE is associated with KMP.3 A number of other agents were advocated, including sirolimus. This case report adds support to the use of sirolimus, a mammalian target of rapamycin inhibitor, and a drug that is currently being tested in a prospective clinical trial for diagnoses that include complicated KHE. The use of the antiplatelet agents aspirin and clopidogrel is discussed although the evidence base is limited. The consensus-derived guidelines are based on expert opinion, and there is still a paucity of robust literature to support them. Clinical trials are required to advance the management of KHE and KMP, but the rarity of the disease means that patient numbers may limit the power of these studies.
J. May et al. / JPRAS Open 1-2 (2014) 1e5
5
Ethical approval N/A. Funding None. Conflict of interest None. References 1. Zukerberg L, Nickoloff B, Weiss S. Kaposiform hemangioendothelioma of infancy and childhood e an aggressive neoplasm associated with KasabacheMerritt syndrome and lymphangiomatosis. Am J Surg Pathol. 1993 Apr;17:321e328. 2. Croteau SE, Liang MG, Kozakewich HP, et al. Kaposiform hemangioendothelioma: atypical features and risks of KasabacheMerritt phenomenon in 107 referrals. J Pediatr. 2013 Jan;162:142e147. 3. Drolet BA, Trenor CC, Brandao LR, et al. Consensus-derived practice standards plan for complicated Kaposiform hemangioendothelioma. J Pediatr. 2013 Jul;163:285e291. 4. Hammill AM, Wentzel M, Gupta A, et al. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer. 2011;57:1018e1024. 5. Blatt J, Stavas J, Moats-Staats B, Woosley J, Morrell DS. Treatment of childhood Kaposiform hemangioendothelioma with sirolimus. Pediatr Blood Cancer. 2010;55:1396e1398. 6. Tsang W, Chan J. Kaposi-like infantile hemangioendothelioma e a distinctive vascular neoplasm of the retroperitoneum. Am J Surg Pathol. 1991 Oct;15:982e989. 7. Enjolras O, Mulliken J, Wassef M, et al. Residual lesions after KasabacheMerritt phenomenon in 41 patients. J Am Acad Dermatol. 2000 Feb;42:225e235. 8. Sarkar M, Mulliken J, Kozakewich P, Robertson R, Burrows P. Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg. 1997 Nov;100:1377e1386. 9. May JE, Liew SH. A new treatment pathway for propranolol use in infantile haemangiomas. J Plast Reconstr Aesthet Surg. 2014 Mar;67:e91ee92. 10. Garcia-Monaco R, Giachetti A, Peralta O, et al. Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon: successful treatment with embolization and vincristine in two newborns. J Vasc Interv Radiol. 2012 Mar;23:417e422.
Contents lists available at ScienceDirect
JPRAS Open journal homepage: http://www.journals.elsevier.com/ jpras-open
Case report
Kaposiform haemangioendothelioma (KHE): Not just a bruise J. May a, *, A. Sadri a, L. Shanks a, S.H. Liew a, B. Pizer b a b
Department of Plastic Surgery, Alder Hey Children's Hospital, Liverpool, UK Department of Oncology, Alder Hey Children's Hospital, Liverpool, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 November 2014 Accepted 20 November 2014 Available online 29 November 2014
Kaposiform haemangioendothelioma is a rare, but potentially fatal vascular tumour of childhood. We present a case that highlights the diagnostic and management challenges of this condition, particularly when associated with KasabacheMerritt phenomenon, and supports the use of sirolimus in its treatment. © 2014 The Authors. Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons. This is an open access article under the CC BY-NC-SA license (http:// creativecommons.org/licenses/by-nc-sa/4.0/).
Keywords: Kaposiform haemangioendothelioma KasabacheMerritt phenomenon Consumptive coagulopathy Sirolimus
Introduction Kaposiform haemangioendothelioma (KHE) is a complicated and rare form of locally aggressive vascular tumour with distinctive pathological features.1 It typically appears in infancy and childhood with an estimated incidence of 0.7/100,000 children per year.2 When patients with KHE develop the associated KasabacheMerritt phenomenon (KMP), characterised by platelet trapping and a consumptive coagulopathy, the mortality is as high as 30%.2 KHE and KMP invariably present diagnostic and therapeutic challenges, which, if not rapidly addressed, can result in the death of the child. Hence, early recognition and prompt management is of importance to health professionals. We present a case of KHE with associated KMP that demonstrates the medical and surgical challenges of this condition, highlighting the need for nationally and internationally accepted guidelines and the need for prospective clinical trials.
* Corresponding author. Department of Plastic Surgery, Alder Hey Children's NHS Foundation Trust, Eaton Road, West Derby, Liverpool L12 2AP, UK. E-mail address: [email protected] (J. May). http://dx.doi.org/10.1016/j.jpra.2014.11.003 2352-5878/© 2014 The Authors. Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/4.0/).
2
J. May et al. / JPRAS Open 1-2 (2014) 1e5
Case report A four-week-old female presented with a 12-h history of apparent bruising to the right chest and flank. There was no history of trauma. The child was normally fit and well and was born by induction of labour at 38 weeks. Examination revealed a well child with ecchymosis involving 6% total body surface area (Figure 1). There were no palpable masses to suggest haematoma and the overlying skin was intact. Initial investigations revealed mild anaemia but profound thrombocytopaenia (platelets 14 109/L). A chest radiograph showed extensive soft tissue oedema in the area of interest. Severe thrombocytopaenia continued to worsen and the child was given blood and platelet transfusions. The D-dimer level was highly elevated at 94,768 ng/ml. The Oncology and Plastic Surgery teams suggested a diagnosis of KHE with associated KMP, and treatment with dexamethasone was commenced. A biopsy was performed, confirming the diagnosis of KHE, a Broviac catheter was inserted, and the child was commenced on aspirin and weekly vincristine (0.05 mg/kg). The dexamethasone was changed to oral prednisolone. After 5 days, the child was showing a good clinical and haematological response and was discharged for daily outpatient follow-up. The lesion continued to regress with normalisation of both platelet counts and D-Dimer levels. 4 weeks after diagnosis, the dose of prednisolone was gradually reduced with continuing aspirin and weekly vincristine. Despite continuing vincristine therapy, 8 weeks from presentation, there was a rebound growth of the KHE and a rapidly worsening coagulopathy was evidenced by a D-dimer of 12,264 ng/ml and platelets of 41 109/L. Steroid therapy was recommenced. MRI showed the lesion extending from the mid lateral right abdominal wall into the right axilla (Figure 2). On discussion with an interventional radiologist, it was felt that embolisation would be technically difficult and so sclerotherapy was performed. The procedure was uncomplicated, but had limited effect. 10 weeks after initial diagnosis, the lesion was successfully embolised through the right intercostal arteries, internal thoracic artery, and subscapular artery. The next day, the KHE was excised down to muscle, leaving a significant defect in the right lateral trunk (Figure 3). Four days post-operatively, the child was recommenced on aspirin and vincristine because of worsening coagulopathy, with platelets of 24 109/L and a D-dimer of 23,173 ng/ml. Histopathology showed the KHE was present at the deep margin and repeat MRI showed a significant residual tumour. Further excision of the lesion was felt to carry too great a morbidity because it would involve resection of the musculature of the right lateral trunk.
Figure 1. Infant at initial presentation.
J. May et al. / JPRAS Open 1-2 (2014) 1e5
3
Figure 2. MRI of the lesion pre-operatively.
Figure 3. Defect following surgical excision of KHE.
The child's condition stabilised, but she continued to require platelet transfusions around every three days. The anti-platelet drug, clopidogrel, was added to aspirin and prednisolone therapy, in accordance with Consensus-Derived Practice Standards.3 Steroid therapy was having limited effect. Although not generally effective in KHE, a trial of propranolol was commenced, but this was not successful in improving the coagulopathy. A trial of sirolimus, recently shown to be effective in the treatment of refractory KHE,4,5 was then started. The child's general and haematological condition subsequently improved, with a reduction in the frequency of platelet transfusions. After four weeks there was normalisation of platelet counts and thus no further platelet transfusions required. The D-Dimer levels also showed a marked improvement. Steroids, aspirin and clopidogrel were discontinued between six and eight weeks after the start of sirolimus, the dose of which was adjusted to achieve therapeutic blood levels. The trunk defect healed well by secondary intention (Figure 4). When the child was 15 months old and after 10 months of sirolimus a trial of stopping this treatment was attempted. Two months later this was followed by followed by clear further evidence of KMP with a platelet count of 24 109/L and a D-dimer of 30,915 ng/ml. Sirolimus therapy was rapidly recommenced with a rapid return to normal platelet counts. Now 2 years and 3 months after diagnosis, the KHE is controlled with sirolimus monotherapy that is planned to continue for at least for another two years.
4
J. May et al. / JPRAS Open 1-2 (2014) 1e5
Figure 4. Outcome at 1-year follow-up.
Discussion This case demonstrates the complexity and challenges of KHE complicated by KMP. The authors propose that this condition be treated in tertiary referral centres, with access to the variety of possible therapeutic interventions. KHE usually presents as an indurated purple lesion with nebulous margins. In infancy these lesions typically occur in the skin and soft tissue of the neck, extremities and trunk. However, numerous reports have identified cases involving non-cutaneous areas such as retroperitoneum.2,6 Despite these tumours expressing benign histology, their aggressive behaviour can result in the compression and infiltration of adjacent structures. This significantly increases morbidity and mortality, especially when associated with KMP.7 KMP is the most serious complication associated with KHE. The pathophysiology is commonly accepted as the trapping of platelets via the abnormally proliferating endothelium of the vascular lesion. This intralesional trapping results in secondary ingestion of clotting factors. The consumptive coagulopathy can progress to disseminated intravascular coagulation (DIC) and often death. Early diagnosis is a key in the treatment of KHE. The lesion can often be misdiagnosed as infantile haemangioma,8 which generally responds well to propranolol treatment,9 but this is not the case for KHE. Magnetic resonance imaging is the imaging modality of choice in KHE, but treatment should not delayed by radiological investigations.3 Surgical resection, though offering a potential cure for KHE, is often not a viable option in view of the high morbidity and mortality due to tumour invasion of large neurovascular structures, muscle and fascia. The option of surgical excision requires meticulous preoperative planning and the risk to benefit ratio must be carefully considered. Embolisation, either as a definitive procedure or as an adjunct to resection, has been advocated as a therapeutic intervention, but it can be technically very challenging.10 The aims of pharmacological treatment are to rapidly correct coagulopathy and, thereafter, decrease tumour size. Recent consensus-derived guidelines supported the use of steroids and vincristine as firstline therapy when KHE is associated with KMP.3 A number of other agents were advocated, including sirolimus. This case report adds support to the use of sirolimus, a mammalian target of rapamycin inhibitor, and a drug that is currently being tested in a prospective clinical trial for diagnoses that include complicated KHE. The use of the antiplatelet agents aspirin and clopidogrel is discussed although the evidence base is limited. The consensus-derived guidelines are based on expert opinion, and there is still a paucity of robust literature to support them. Clinical trials are required to advance the management of KHE and KMP, but the rarity of the disease means that patient numbers may limit the power of these studies.
J. May et al. / JPRAS Open 1-2 (2014) 1e5
5
Ethical approval N/A. Funding None. Conflict of interest None. References 1. Zukerberg L, Nickoloff B, Weiss S. Kaposiform hemangioendothelioma of infancy and childhood e an aggressive neoplasm associated with KasabacheMerritt syndrome and lymphangiomatosis. Am J Surg Pathol. 1993 Apr;17:321e328. 2. Croteau SE, Liang MG, Kozakewich HP, et al. Kaposiform hemangioendothelioma: atypical features and risks of KasabacheMerritt phenomenon in 107 referrals. J Pediatr. 2013 Jan;162:142e147. 3. Drolet BA, Trenor CC, Brandao LR, et al. Consensus-derived practice standards plan for complicated Kaposiform hemangioendothelioma. J Pediatr. 2013 Jul;163:285e291. 4. Hammill AM, Wentzel M, Gupta A, et al. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer. 2011;57:1018e1024. 5. Blatt J, Stavas J, Moats-Staats B, Woosley J, Morrell DS. Treatment of childhood Kaposiform hemangioendothelioma with sirolimus. Pediatr Blood Cancer. 2010;55:1396e1398. 6. Tsang W, Chan J. Kaposi-like infantile hemangioendothelioma e a distinctive vascular neoplasm of the retroperitoneum. Am J Surg Pathol. 1991 Oct;15:982e989. 7. Enjolras O, Mulliken J, Wassef M, et al. Residual lesions after KasabacheMerritt phenomenon in 41 patients. J Am Acad Dermatol. 2000 Feb;42:225e235. 8. Sarkar M, Mulliken J, Kozakewich P, Robertson R, Burrows P. Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg. 1997 Nov;100:1377e1386. 9. May JE, Liew SH. A new treatment pathway for propranolol use in infantile haemangiomas. J Plast Reconstr Aesthet Surg. 2014 Mar;67:e91ee92. 10. Garcia-Monaco R, Giachetti A, Peralta O, et al. Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon: successful treatment with embolization and vincristine in two newborns. J Vasc Interv Radiol. 2012 Mar;23:417e422.