G U E ST ED I T O R I A L
BJD
British Journal of Dermatology
Paediatric vascular tumours other than infantile haemangioma
DOI: 10.1111/bjd.12917 Although infantile haemangiomas (IHs) represent, by far, the most common vascular proliferations in paediatric patients, other less common and little-known infantile vascular neoplasms do also exist. The review by Hoeger and Colmenero in this edition of BJD nicely covers the clinical, histopathological and rational approaches to treatment of these proliferations, including the most recent advances in our knowledge of their histogenesis.1 The reactive or neoplastic nature of some vascular proliferations is still a matter of debate, and good examples of this are pyogenic granulomas and eruptive pseudoangiomatosis, which are included by Hoeger and Colmenero in their review. These are vascular tumours that we consider to be hyperplastic processes secondary to excessive production of granulation tissue in the former case and reactive capillary proliferation in the latter. But beyond some mostly academic and nosological considerations, there are important recent advances in the immunohistochemical panel of available antibodies for endothelial cells, which have notably contributed to clarifying the true nature of some infantile vascular proliferations. For example, immunohistochemical investigation for Wilms tumour antigen 1 (WT1) is nowadays widely accepted as the most helpful tool to distinguish histopathologically vascular malformations from vascular neoplasms, because they are expressed only in endothelial cells with proliferative capacity. The exception to the rule, represented by proliferating arteriovenous malformations expressing WT1 immunoreactivity in their lesional endothelial cells, does not diminish the usefulness of this marker. However, controversy still persists about the results for this marker in some infantile vascular proliferations, because WT1 immunoreactivity has supported the neoplastic nature of some vascular lesions with the histopathological appearance of vascular malformations, such as benign lymphangioendothelioma.2 In verrucous haemangioma, it is possible for WT1 expression to be found in the pericytic component of vascular structures instead of in endothelial cells, and WT1 cross-reactivity with pericytes and other myoid vessel wall cells is a well-known phenomenon in vascular tumours.3 Glucose transporter (GLUT)1, the most specific marker for IH, is frequently expressed by endothelial cells of verrucous haemangioma,4–7 and because, as far as we know, no link has been established between IHs and verrucous haemangioma, the GLUT1 positivity in verrucous haemangioma is difficult to explain. Thus, further investigations of larger series of several paediatric vascular tumours with these markers are still required.
464
British Journal of Dermatology (2014) 171, pp464–465
To our eyes, histopathological differential diagnosis between rapidly involuting congenital haemangiomas (RICHs), noninvoluting congenital haemangiomas (NICHs) and conventional IHs is not so easy. All of the histopathological features that have been described in RICHs and NICHs may also be seen in conventional IHs in some of their evolution stages. In some cases, a rapid but incomplete involution of a congenital haemangioma can give way to a persistent lesion indistinguishable from NICH; the term PICH (partially involuting congenital haemangioma) has been coined,8 and some authors think that NICH is actually RICH in a state of arrested regression (if partially completed involution occurs in utero, classic NICH may appear).9 Currently, GLUT1 immunostaining is the most reliable method to differentiate congenital haemangiomas from IHs, but future additional histochemical and cytogenetic studies exploring the rapidly involuting nature of RICHs and the complete lack of regression of NICHs should be based on the cell cycle of lesional endothelial cells. Unfortunately, the biological differences between the blood endothelial cells of these two congenital haemangiomas and the proliferating cells of conventional IHs are still unknown. No consensus has yet been reached on the histogenesis of spindle cell haemangioma, and it is still a matter of discussion whether this lesion is a genuine neoplasm, a reactive vascular process or a vascular malformation. Its biological behaviour and its slow growth, as well as the absence of metastases, have led some authors to suggest that spindle cell haemangioma is not a genuine neoplasm but a reactive hyperplastic vascular process occurring as a consequence of recurrent episodes of intravascular thrombosis with subsequent thrombus recanalization.10–14 This point of view is not shared by other authors,15 who consider spindle cell haemangioma to be a benign vascular neoplasm or a vascular malformation in which thrombosis may develop. In our opinion, a strong argument in favour of the malformation hypothesis is the presence of larger, dilated and malformative vascular structures, such as thick-walled veins and vascular lacunae, which always occur in conjunction with spindle cell haemangioma. Additionally, spindle cell haemangioma may show areas with blood endothelial differentiation next to areas with lymphatic endothelial differentiation, another hallmark of malformative vascular growth. Recently, it has been reported that 20/28 (71%) spindle cell haemangiomas harboured mutations in exon 4 of the isocitrate dehydrogenase genes IDH1 or IDH2. Given that mutations were absent in 154 other vascular lesions, IDH1 or IDH2 mutations seem to be highly specific for spindle cell haemangioma. As a consequence of the mutation, expression of hypoxia-inducible
© 2014 British Association of Dermatologists
Guest Editorial
factor-1a is not induced, and therefore the exact mechanism by which mutations in IDH1 or IDH2 lead to vascular tumorigenesis remains to be established.16 Malignant cutaneous vascular tumours are extremely uncommon in children. Only a multidisciplinary analysis of large series would adequately address all the issues that should be covered by guidelines for diagnosis and treatment of these malignancies at paediatric age, but these guidelines are still lacking and most studies are based on a few case reports. Hoeger and Colmenero included tufted haemangioma–kaposiform haemangioendothelioma among the malignant vascular neoplasms. According to the classic pathology concept of malignancy this interpretation may be inaccurate, because these neoplasms lack metastatic potential, but their frequent association with Kasabach–Merritt syndrome supports their inclusion within the group of low-grade malignant vascular tumours. These vascular lesions share a common podoplanin-positive lymphatic endothelial immunophenotype, and podoplanin is the only known endogenous ligand for C-type leptin-like receptor (CLEC)2. The binding of podoplanin to CLEC2 appears to be the predominant initiator of the blood-clotting phenomena observed in Kasabach–Merritt syndrome, and this finding addresses CLEC2 as the ideal target for new drug therapies in children with this syndrome. The recent finding of MYC amplifications in a subset of angiosarcomas also opens new therapeutic possibilities for the management of this aggressive neoplasm.17 1
Department of Dermatology, Fundacion Jimenez Dıaz, Universidad Autonoma, Avda. Reyes Catolicos 2, 28040 Madrid, Spain 2 Department of Dermatology, Hospital del Ni~no Jesus, Universidad Autonoma, Madrid, Spain E-mail: [email protected]
L. REQUENA1 A. TORRELO2
References
465
2 Revelles JM, Dıaz JL, Angulo J et al. Giant benign lymphangioendothelioma. J Cutan Pathol 2012; 39:950–6. 3 Requena L, Kutzner H. Cutaneous Soft Tissue Tumors. Philadelphia, PA: Lippincott Williams & Wilkins, 2014; in press. 4 Clairwood MQ, Bruckner AL, Dadras SS. Verrucous hemangioma: a report of two cases and review of the literature. J Cutan Pathol 2011; 38:740–6. 5 Tennant LB, Mulliken JB, Perez-Atayde AR, Kozakewich HP. Verrucous hemangioma revisited. Pediatr Dermatol 2006; 23:208–15. 6 Laing EL, Brasch HD, Steel R et al. Verrucous hemangioma expresses primitive markers. J Cutan Pathol 2013; 40:391–6. 7 Trindade F, Torrelo A, Requena L et al. An immunohistochemical study of verrucous hemangiomas. J Cutan Pathol 2013; 40:472–6. 8 Nasseri E, Piram M, McCuaig CC et al. Partially involuting congenital hemangiomas: a report of 8 cases and review of the literature. J Am Acad Dermatol 2014; 70:75–9. 9 Mulliken JB, Enjolras O. Congenital hemangiomas and infantile hemangioma: missing links. J Am Acad Dermatol 2004; 50:875–82. 10 Fletcher CDM, Beham A, Schmid C. Spindle cell haemangioendothelioma: a clinicopathological and immunohistochemical study indicative of a non-neoplastic lesion. Histopathology 1991; 18:291– 301. 11 Imayama S, Murakamai Y, Hashimoto H, Hori Y. Spindle cell hemangioendothelioma exhibits the ultrastructural features of reactive vascular proliferation rather than of angiosarcoma. Am J Clin Pathol 1992; 97:279–87. 12 Battocchio S, Facchetti F, Brisigotti M. Spindle cell hemangioendothelioma: further evidence against its proposed neoplastic nature. Histopathology 1993; 22:296–8. 13 Fukunaga M, Ushigome S, Nikaido T et al. Spindle cell hemangioendothelioma: an immunohistochemical and flow cytometric study of six cases. Pathol Int 1995; 45:589–95. 14 Fletcher CDM. The non-neoplastic nature of spindle cell hemangioendothelioma. Am J Clin Pathol 1992; 98:545–6. 15 Perkins P, Weiss SW. Spindle cell hemangioendothelioma. An analysis of 78 cases with reassessment of its pathogenesis and biologic behavior. Am J Surg Pathol 1996; 20:1196–204. 16 Kurek KC, Pansuriya TC, van Ruler MA et al. R132C IDH1 mutations are found in spindle cell hemangiomas and not in other vascular tumors or malformations. Am J Pathol 2013; 182:1494–500. 17 Manner J, Radlwimmer B, Hohenberger P et al. MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema. Am J Pathol 2010; 176:34–9.
1 Hoeger PH, Colmenero I. Vascular tumours in infants. Part I: benign vascular tumours other than infantile haemangioma. Br J Dermatol 2014; 171:466–73.
© 2014 British Association of Dermatologists
British Journal of Dermatology (2014) 171, pp464–465
BJD
British Journal of Dermatology
Paediatric vascular tumours other than infantile haemangioma
DOI: 10.1111/bjd.12917 Although infantile haemangiomas (IHs) represent, by far, the most common vascular proliferations in paediatric patients, other less common and little-known infantile vascular neoplasms do also exist. The review by Hoeger and Colmenero in this edition of BJD nicely covers the clinical, histopathological and rational approaches to treatment of these proliferations, including the most recent advances in our knowledge of their histogenesis.1 The reactive or neoplastic nature of some vascular proliferations is still a matter of debate, and good examples of this are pyogenic granulomas and eruptive pseudoangiomatosis, which are included by Hoeger and Colmenero in their review. These are vascular tumours that we consider to be hyperplastic processes secondary to excessive production of granulation tissue in the former case and reactive capillary proliferation in the latter. But beyond some mostly academic and nosological considerations, there are important recent advances in the immunohistochemical panel of available antibodies for endothelial cells, which have notably contributed to clarifying the true nature of some infantile vascular proliferations. For example, immunohistochemical investigation for Wilms tumour antigen 1 (WT1) is nowadays widely accepted as the most helpful tool to distinguish histopathologically vascular malformations from vascular neoplasms, because they are expressed only in endothelial cells with proliferative capacity. The exception to the rule, represented by proliferating arteriovenous malformations expressing WT1 immunoreactivity in their lesional endothelial cells, does not diminish the usefulness of this marker. However, controversy still persists about the results for this marker in some infantile vascular proliferations, because WT1 immunoreactivity has supported the neoplastic nature of some vascular lesions with the histopathological appearance of vascular malformations, such as benign lymphangioendothelioma.2 In verrucous haemangioma, it is possible for WT1 expression to be found in the pericytic component of vascular structures instead of in endothelial cells, and WT1 cross-reactivity with pericytes and other myoid vessel wall cells is a well-known phenomenon in vascular tumours.3 Glucose transporter (GLUT)1, the most specific marker for IH, is frequently expressed by endothelial cells of verrucous haemangioma,4–7 and because, as far as we know, no link has been established between IHs and verrucous haemangioma, the GLUT1 positivity in verrucous haemangioma is difficult to explain. Thus, further investigations of larger series of several paediatric vascular tumours with these markers are still required.
464
British Journal of Dermatology (2014) 171, pp464–465
To our eyes, histopathological differential diagnosis between rapidly involuting congenital haemangiomas (RICHs), noninvoluting congenital haemangiomas (NICHs) and conventional IHs is not so easy. All of the histopathological features that have been described in RICHs and NICHs may also be seen in conventional IHs in some of their evolution stages. In some cases, a rapid but incomplete involution of a congenital haemangioma can give way to a persistent lesion indistinguishable from NICH; the term PICH (partially involuting congenital haemangioma) has been coined,8 and some authors think that NICH is actually RICH in a state of arrested regression (if partially completed involution occurs in utero, classic NICH may appear).9 Currently, GLUT1 immunostaining is the most reliable method to differentiate congenital haemangiomas from IHs, but future additional histochemical and cytogenetic studies exploring the rapidly involuting nature of RICHs and the complete lack of regression of NICHs should be based on the cell cycle of lesional endothelial cells. Unfortunately, the biological differences between the blood endothelial cells of these two congenital haemangiomas and the proliferating cells of conventional IHs are still unknown. No consensus has yet been reached on the histogenesis of spindle cell haemangioma, and it is still a matter of discussion whether this lesion is a genuine neoplasm, a reactive vascular process or a vascular malformation. Its biological behaviour and its slow growth, as well as the absence of metastases, have led some authors to suggest that spindle cell haemangioma is not a genuine neoplasm but a reactive hyperplastic vascular process occurring as a consequence of recurrent episodes of intravascular thrombosis with subsequent thrombus recanalization.10–14 This point of view is not shared by other authors,15 who consider spindle cell haemangioma to be a benign vascular neoplasm or a vascular malformation in which thrombosis may develop. In our opinion, a strong argument in favour of the malformation hypothesis is the presence of larger, dilated and malformative vascular structures, such as thick-walled veins and vascular lacunae, which always occur in conjunction with spindle cell haemangioma. Additionally, spindle cell haemangioma may show areas with blood endothelial differentiation next to areas with lymphatic endothelial differentiation, another hallmark of malformative vascular growth. Recently, it has been reported that 20/28 (71%) spindle cell haemangiomas harboured mutations in exon 4 of the isocitrate dehydrogenase genes IDH1 or IDH2. Given that mutations were absent in 154 other vascular lesions, IDH1 or IDH2 mutations seem to be highly specific for spindle cell haemangioma. As a consequence of the mutation, expression of hypoxia-inducible
© 2014 British Association of Dermatologists
Guest Editorial
factor-1a is not induced, and therefore the exact mechanism by which mutations in IDH1 or IDH2 lead to vascular tumorigenesis remains to be established.16 Malignant cutaneous vascular tumours are extremely uncommon in children. Only a multidisciplinary analysis of large series would adequately address all the issues that should be covered by guidelines for diagnosis and treatment of these malignancies at paediatric age, but these guidelines are still lacking and most studies are based on a few case reports. Hoeger and Colmenero included tufted haemangioma–kaposiform haemangioendothelioma among the malignant vascular neoplasms. According to the classic pathology concept of malignancy this interpretation may be inaccurate, because these neoplasms lack metastatic potential, but their frequent association with Kasabach–Merritt syndrome supports their inclusion within the group of low-grade malignant vascular tumours. These vascular lesions share a common podoplanin-positive lymphatic endothelial immunophenotype, and podoplanin is the only known endogenous ligand for C-type leptin-like receptor (CLEC)2. The binding of podoplanin to CLEC2 appears to be the predominant initiator of the blood-clotting phenomena observed in Kasabach–Merritt syndrome, and this finding addresses CLEC2 as the ideal target for new drug therapies in children with this syndrome. The recent finding of MYC amplifications in a subset of angiosarcomas also opens new therapeutic possibilities for the management of this aggressive neoplasm.17 1
Department of Dermatology, Fundacion Jimenez Dıaz, Universidad Autonoma, Avda. Reyes Catolicos 2, 28040 Madrid, Spain 2 Department of Dermatology, Hospital del Ni~no Jesus, Universidad Autonoma, Madrid, Spain E-mail: [email protected]
L. REQUENA1 A. TORRELO2
References
465
2 Revelles JM, Dıaz JL, Angulo J et al. Giant benign lymphangioendothelioma. J Cutan Pathol 2012; 39:950–6. 3 Requena L, Kutzner H. Cutaneous Soft Tissue Tumors. Philadelphia, PA: Lippincott Williams & Wilkins, 2014; in press. 4 Clairwood MQ, Bruckner AL, Dadras SS. Verrucous hemangioma: a report of two cases and review of the literature. J Cutan Pathol 2011; 38:740–6. 5 Tennant LB, Mulliken JB, Perez-Atayde AR, Kozakewich HP. Verrucous hemangioma revisited. Pediatr Dermatol 2006; 23:208–15. 6 Laing EL, Brasch HD, Steel R et al. Verrucous hemangioma expresses primitive markers. J Cutan Pathol 2013; 40:391–6. 7 Trindade F, Torrelo A, Requena L et al. An immunohistochemical study of verrucous hemangiomas. J Cutan Pathol 2013; 40:472–6. 8 Nasseri E, Piram M, McCuaig CC et al. Partially involuting congenital hemangiomas: a report of 8 cases and review of the literature. J Am Acad Dermatol 2014; 70:75–9. 9 Mulliken JB, Enjolras O. Congenital hemangiomas and infantile hemangioma: missing links. J Am Acad Dermatol 2004; 50:875–82. 10 Fletcher CDM, Beham A, Schmid C. Spindle cell haemangioendothelioma: a clinicopathological and immunohistochemical study indicative of a non-neoplastic lesion. Histopathology 1991; 18:291– 301. 11 Imayama S, Murakamai Y, Hashimoto H, Hori Y. Spindle cell hemangioendothelioma exhibits the ultrastructural features of reactive vascular proliferation rather than of angiosarcoma. Am J Clin Pathol 1992; 97:279–87. 12 Battocchio S, Facchetti F, Brisigotti M. Spindle cell hemangioendothelioma: further evidence against its proposed neoplastic nature. Histopathology 1993; 22:296–8. 13 Fukunaga M, Ushigome S, Nikaido T et al. Spindle cell hemangioendothelioma: an immunohistochemical and flow cytometric study of six cases. Pathol Int 1995; 45:589–95. 14 Fletcher CDM. The non-neoplastic nature of spindle cell hemangioendothelioma. Am J Clin Pathol 1992; 98:545–6. 15 Perkins P, Weiss SW. Spindle cell hemangioendothelioma. An analysis of 78 cases with reassessment of its pathogenesis and biologic behavior. Am J Surg Pathol 1996; 20:1196–204. 16 Kurek KC, Pansuriya TC, van Ruler MA et al. R132C IDH1 mutations are found in spindle cell hemangiomas and not in other vascular tumors or malformations. Am J Pathol 2013; 182:1494–500. 17 Manner J, Radlwimmer B, Hohenberger P et al. MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema. Am J Pathol 2010; 176:34–9.
1 Hoeger PH, Colmenero I. Vascular tumours in infants. Part I: benign vascular tumours other than infantile haemangioma. Br J Dermatol 2014; 171:466–73.
© 2014 British Association of Dermatologists
British Journal of Dermatology (2014) 171, pp464–465
