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Int. J. Oral Maxillofac. Surg. 2015; xxx: xxx–xxx http://dx.doi.org/10.1016/j.ijom.2015.01.025, available online at http://www.sciencedirect.com

Clinical Paper Clinical Pathology

Intraosseous haemangioma: semantic and medical confusion N. Kadlub L. Dainese, A. Coulomb-L’Hermine, L. Galmiche, V. Soupre, H. Ducou Lepointe, M. -P. Vazquez, A. Picard : Intraosseous haemangioma: semantic and medical confusion. Int. J. Oral Maxillofac. Surg. 2015; xxx: xxx–xxx. # 2015 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Abstract. The literature is rich in case reports of intraosseous haemangioma, although most of these are actually cases of venous or capillary malformations. To illustrate this confusion in terminology, we present three cases of slow-flow vascular malformations misnamed as intraosseous haemangioma. A retrospective study of children diagnosed with intraosseous haemangioma was conducted. Clinical and radiological data were evaluated. Histopathological examinations and immunohistochemical studies were redone by three independent pathologists to classify the lesions according to the International Society for the Study of Vascular Anomalies (ISSVA) and World Health Organization (WHO) classifications. Three children who had presented with jaw haemangiomas were identified. Computed tomography scan patterns were not specific. All tumours were GLUT-1-negative and D2-40-negative. The lesions were classified as central haemangiomas according to the WHO, and as slow-flow malformations according to the ISSVA. The classification of vascular anomalies is based on clinical, radiological, and histological differences between vascular tumours and malformations. Based on this classification, the evolution of the lesion can be predicted and adequate treatment applied. The binary ISSVA classification is widely accepted and should be applied for all vascular lesions.

In 1982, Mulliken and Glowacki published a classification for vascular birthmarks, grouping them into two categories: haemangiomas and malformations.1 Vascular malformation was differentiated from haemangioma by clinical, radiological, and histological features (Table 1). Haemangioma is a common tumour of infancy, with a female predisposition. This 0901-5027/000001+07

lesion appears in infancy, grows rapidly until the age of 8 months to 1 year, and then slowly involutes by adolescence. According to Boyd et al.2 and Kaban and Mulliken,3 haemangiomas do not involve the bone, although they can deform the adjacent bone or create minor osseous overgrowth. Histologically, haemangiomas have endothelial hyperplasia and a

N. Kadlub 1,2,3,8, L. Dainese4,5, A. Coulomb-L’Hermine4,5, L. Galmiche2,6, V. Soupre1,8, H. Ducou Lepointe5,7, M.-P. Vazquez1,2,3,8, A. Picard1,2,3,8 1 APHP, Hoˆpital Necker Enfants Malades, Service de Chirurgie Maxillo-faciale et Plastique Pe´diatrique, Paris, France; 2Universite´ Paris Descartes, Paris, France; 3INSERM, UMRS 1138, Oral and Molecular Pathology, Centre de Recherche des Cordeliers, 75006 Paris, France; 4 APHP, Hoˆpital d’Enfants Armand Trousseau, Service de Cytologie et Pathologie, Paris, France; 5Universite´ Paris 6, Faculte´ de Me´decine Pierre et Marie Curie, Paris, France; 6APHP, Hoˆpital Necker Enfants Malades, Service de Cytologie et Pathologie, Paris, France; 7APHP, Hoˆpital d’Enfants Armand Trousseau, Service d’Imagerie Me´dicale, Paris, France; 8APHP, CRMR des Malformations Rares de la Face et de la Cavite´ Buccale, 75015 Paris, France

Keywords: ISSVA; WHO; haemangioma; angioma; intraosseous haemangioma; central haemangioma; venous malformation; capillary malformation; jaw tumours. Accepted for publication 29 January 2015

large number of mast cells. Moreover, endothelial cells within the infantile haemangioma will stain positive for glucose transporter 1 (GLUT-1).4,5 Vascular malformations are present at birth, and have an equal sex distribution. They grow with the child and may become more prominent, especially at puberty.1 Histologically, vascular malformations do

# 2015 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Kadlub N, et al. Intraosseous haemangioma: semantic and medical confusion, Int J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.ijom.2015.01.025

YIJOM-3094; No of Pages 7

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Kadlub et al.

Table 1. Summary of the clinical and pathological differences between haemangioma and vascular malformation. Gender distribution Presence at birth Natural history Histology Immunohistochemistry

Haemangioma

Vascular malformation

Female > male No Rapid proliferation for the first several months of life and spontaneous regression Endothelial hyperplasia Large numbers of mast cells GLUT-1-positive cells

Equal Yes Growth proportionately with the child. May become more prominent, especially at puberty Mature vascular elements Normal numbers of mast cells GLUT-1-negative cells

Table 2. Binary classification of vascular anomalies, accepted in 1996 by the International Society for the Study of Vascular Anomalies (ISSVA). Tumours

Malformations

Haemangioma Haemangioendotheliomas Angiosarcoma Miscellaneous

Slow-flow Capillary Lymphatic Venous Fast-flow Arterial Combined

GLUT-1, glucose transporter 1.

not show endothelial hyperplasia and demonstrate a normal number of mast cells. They consist of mature vascular elements. Vascular malformations can be subdivided according to their vascular components into slow-flow (capillary, venous, and lymphatic) and fast-flow (arteriovenous) malformations. The classification of Mulliken and Glowacki was adopted widely and became the accepted classification of the International Society for the Study of Vascular Anomalies (ISSVA) in 1996.6

Despite this classification, the oral and maxillofacial and orthopaedic literature persists in classifying lesions according to the World Health Organization (WHO). In the WHO classification, haemangioma is defined as ‘‘a benign vasoformative neoplasm or developmental condition of endothelial origin’’,7 which may relate to either haemangioma or vascular malformations. In most of the reported cases, intraosseous haemangiomas (also called cavernous or central hae-

mangiomas) appear to be slow-flow malformations.8–19 The WHO classification is no longer appropriate to describe vascular tumours or malformations and should be replaced by the ISSVA classification. To illustrate this confusion, we reviewed all clinical, radiological, and pathological characteristics of some of the so-designated intraosseous haemangiomas.

Table 3. Summary of the clinical, radiological, and pathological characteristics of the cases of ‘intraosseous haemangioma’ included in this study. Patient 1

Patient 2

Patient 3

Demographic data

Age Gender

2 months Female

12 years Male

12 years Male

Clinical data

Presence at birth Localization Symptoms Skin/mucosal aspects

No Maxilla Rapidly growing swelling Bluish

No Maxilla Asymptomatic Normal

No Mandible Rapidly growing swelling Normal

Radiological data

Lytic/condensing Radiological characteristics Soft tissue involvement Cortical bone expansion

Condensing and lytic Sunburst pattern No Yes

Lytic Honeycomb pattern No Yes

Lytic Soap bubble pattern No Yes

Pathological examination

HES

Thin-walled cavernous vessels Single-layered endothelial cells Fibrous stroma

Small and medium tortuous vessels Flat endothelium

Solid sheets and cords of endothelial cells Distended vessels

Loosely collagenous stroma Normal number of mast cells No endothelial hyperplasia

Fibrous stroma

Normal number of mast cells No endothelial hyperplasia

Normal number of mast cells No endothelial hyperplasia

GLUT-1 CD34 D2-40 SMA

Negative Positive (endothelial cells) Negative Positive: capillary vessels and pericytes

Initial pathological diagnosis

Intraosseous haemangioma

Intraosseous haemangioma

Intraosseous haemangioma

WHO classification

Central haemangioma with cavernous components

Central haemangioma with capillary components

Central haemangioma with mixed cavernous and capillary components

ISSVA classification

Venous malformations

Capillary malformations

Mixed (venous–capillary malformations)

Negative Positive (endothelial cells) Negative Positive: large vessels and pericytes

Negative Positive (endothelial cells) Negative Positive: endothelial aggregates and channels

HES, haematoxylin–eosin–safranin; GLUT-1, glucose transporter 1; SMA, smooth muscle actin; WHO, World Health Organization; ISSVA, International Society for the Study of Vascular Anomalies.

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YIJOM-3094; No of Pages 7

Intraosseous haemangioma Materials and methods

We conducted a retrospective study from 2006 to 2013, using the clinical records database of our maxillofacial surgery unit. Three children diagnosed histologically with an intraosseous haemangioma were identified. A chart review and computed tomography (CT) scan analysis was conducted independently by two surgeons and one radiologist. A new pathological examination was conducted by three independent pathologists, and the cases were classified according to the WHO and the ISSVA classifications (Table 2).

Demographic information (age, gender), clinical data (clinical history, tumour localization, swelling, symptoms, clinical examination), and radiological characteristics (bone lysis, cortical bone invasion, soft tissue invasion, calcification, medullar bone involvement) were analyzed. Sections 3 mm in thickness were analyzed with haematoxylin–eosin–safranin (HES). Immunohistochemical staining was performed for GLUT-1 (marker for immature haemangioma),5 CD34 (positive in endothelial cells),20 D2-40 (marker for lymphatic endothelium),21 and smooth muscle actin (SMA; marker for mature pericytes).22

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Results

Three patients, two males and one female (mean age 8 years, range 2 months to 12 years), were included in the study. None had a lesion at birth. In one patient, the lesion was discovered during a random panoramic X-ray. The other two presented a rapidly growing swelling, one at the age of 2 months and the other at 12 years. The lesions were located in the maxilla (n = 2) and the mandible (n = 1). One patient had bluish skin and mucosa. A summary of the clinical, radiological, and pathological characteristics of these three patients is given in Table 3.

Fig. 1. A 2-month-old girl with maxillary venous malformations. (A) Axial CT scan showing an intraosseous lesion with sunburst appearance, expanding the cortical bone. (B) Large channels surrounded by a thin layer of endothelial cells interspersed with more solid areas with stromal collagen (HES staining, magnification 200). (C) Vessels are lined with CD34-positive endothelial cells (magnification 200). (D) Endothelial cells are GLUT-1-negative; red blood cells serve as a positive control (magnification 200). (E) Capillary vessels and pericytes expressing SMA (magnification 200).

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CT scans showed one condensing and lytic lesion and two lytic lesions. The pattern of the tumour showed a heterogeneous distribution: sunburst (n = 1), honeycomb (n = 1), and soap bubble (n = 1). There was no involvement of the soft tissues. The cortical bone was expanded in all of these cases (Figs. 1–3). HES staining showed cavernous vessels in one case, capillary vessels in another, and an association of capillary and cavernous vessels in the third. A normal number of mast cells was noted in all cases and there was no endothelial hyperplasia. All endothelial cells stained positive for CD34. The endothelium was negative for GLUT-1

and D2-40. Pericytes were positive for SMA (Figs. 1–3). According to the WHO, all lesions were classified as central haemangiomas and sub-classified as a central haemangioma with capillary components (n = 1), cavernous components (n = 1), or mixed components (n = 1) (Table 3). According to the ISSVA, the lesions should be classified as slow-flow malformations: capillary malformations, venous malformations, and mixed capillary and venous malformations. Discussion

The distinction between vascular tumours and vascular malformations is now well

accepted in paediatrics. However, orthopaedic and maxillofacial surgeons continue to misname intraosseous vascular malformations as haemangioma. In most cases, the WHO classification of vascular bone tumours is incompletely applied. The definition of central haemangioma, according to the WHO, should include an appropriate qualifier such as ‘cavernous’, ‘capillary’, or ‘epithelioid’, etc. The ISSVA published the binary classification in 1996 (Table 2), based on clinical appearance and radiological and pathological characteristics.6,23 This classification highlighted the dichotomy between tumours (haemangioma) and vascular malformations (Tables 1 and 2).

Fig. 2. A 12-year-old boy with a maxillary capillary malformation. (A) Axial CT scan showing an expansible lesion of the maxilla, with a honeycomb appearance. (B) Tortuous capillaries in a fibrous background (HES staining, magnification 200). (C) Vessels are lined with CD34positive endothelial cells (magnification 200). (D) Endothelial cells are D2-40-negative (magnification 200). (E) Endothelial cells are GLUT1-negative; red blood cells serve as a positive control (magnification 200). (F) Large vessels and pericytes expressing SMA (magnification 200).

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YIJOM-3094; No of Pages 7

Intraosseous haemangioma

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Fig. 3. A 12-year-old boy with a mandible capillary and venous malformation. (A) Axial CT scan showing an expansible lesion of the mandible, with a soap bubble appearance. The initial radiological diagnosis was ameloblastoma. (B) Solid sheets and cords of endothelial cells. The small and inconspicuous lumens are lined with large and epithelioid cells. The nuclei are small, without significant pleomorphism, and nucleoli are inconspicuous. The vessels are focally distended and surrounded by a fibrous stroma, conferring a cavernous appearance (HES staining, magnification 200). (C) Endothelial cells are positive for CD34 on immunohistochemical staining (magnification 200). (D) Endothelial cells are GLUT-1-negative; red blood cells serve as a positive control (magnification 200). (E) Endothelial cells are D2-40-negative (magnification 200). (F) Endothelial aggregates and channels are surrounded by SMA-positive cells (magnification 200).

Infantile haemangioma is a common vascular tumour involving the soft tissue. Appearing in early infancy, its life-cycle is characterized by two phases: the proliferating phase and the involuting phase. Juvenile (or infantile) haemangioma is a specific entity, characterized by endothelial cells proliferating and expressing GLUT-1 as a specific marker.4,5 The cases reported herein did not exhibit pathological or clinical features of infantile haemangioma.

In the first case (patient 1, Table 3), the clinical evolution of the tumour may have displayed characteristics of infantile haemangioma, but the pathological examination was consistent with a venous malformation: the presence of normal venous vessels, GLUT-1-negative endothelial cells, and a normal number of mast cells eliminated infantile immature haemangioma.5 On the other hand, the clinical features of the other two cases were not consistent with haemangioma, and patho-

logical examination confirmed the diagnosis of vascular malformations. Maxillofacial or craniofacial intraosseous slow-flow malformations are uncommon. There are a few well-documented cases in the international literature. All of these were designated as haemangioma, central haemangioma, or cavernous or capillary haemangioma according to the WHO classification, which was often incompletely applied. In the present study, these published cases were reviewed and

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ISSVA diagnosis

WHO classification

Treatment

Venous vessels

Cavernous haemangioma

Venous malformation

Surgical resection

Maxilla

Venous vessels

Cavernous haemangioma

Venous malformation

F

Maxilla

Lytic lesion

Venous vessels

Central haemangioma

Venous malformation

41 years

F

Zygoma

Venous vessels

Haemangioma

Venous malformation

30 years

F

Calvaria

Capillary vessels

Capillary haemangioma

Capillary malformation

51 years

M

Calvaria

Venous vessels

Cavernous haemangioma

Venous malformation

Panagos and Hirsch (2009)13 Alves et al. (2006)14

77 years

M

Maxilla

Venous vessels

Central haemangioma

Venous malformation

22 years

M

Venous vessels

Haemangioma

Venous malformation

Garcia-Marin et al. (2001)15 Arribas-Garcia et al. (2009)16 Ozdemir et al. (2002)17 Gomez Oliveira et al. (2008)18 Marcinow et al. (2012)19

20 years

M

Venous vessels

Cavernous haemangioma

Venous malformation

42 years

F

Mandibular condyle Occipital condyle Zygoma

Sun ray appearance Osteocondensing tumour Soap bubble appearance Soap bubble appearance Lytic lesion

Venous vessels

Cavernous haemangioma

Venous malformation

7 years

M

51 years

F

Venous and capillary vessels Capillary vessels

Capillary–venous haemangioma Cavernous haemangioma

Capillary–venous malformation Venous malformation

47 years

M

Venous vessels

Cavernous haemangioma

Venous malformation

Haemangioma with a venous component Haemangioma with a venous component Haemangioma with a venous component Haemangioma with a venous component Haemangioma with a capillary component Haemangioma with a venous component Haemangioma with a venous component Haemangioma with a venous component Haemangioma with a venous component Haemangioma with a venous component Haemangioma with a capillary component Haemangioma with a venous component Haemangioma with a venous component

Localization

Ramchandani et al. (2004)8 Werle et al. (2003)9

38 years

F

Zygoma

1 month

F

Jen et al. (2004)10

74 years

Savastano et al. (1997)11 Khanam et al. (2001)12

Mandibular symphysis Mandibular body Zygoma

Honeycomb appearance Soap bubble appearance Lytic lesion Honeycomb appearance Ground-glass appearance

Steroid therapy Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Embolization Surgical resection Surgical resection Surgical resection Surgical resection

ISSVA, International Society for the Study of Vascular Anomalies; WHO, World Health Organization; F, female; M, male.

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Authors’ diagnosis

Soap bubble appearance Lytic lesion

Gender

Kadlub et al.

Histological characteristics

Age

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Radiological characteristics

Reference

classified according to the ISSVA and the WHO and are presented in Table 4; the clinical, radiological, and pathological aspects of these cases are also summarized in Table 4. In the literature cases, intraosseous slow-flow malformations (named haemangioma) were encountered in all ages and in both sexes. Pathological sections demonstrated the diagnosis of a vascular malformation in all cases. Surgical resection was opted for in most of the cases (Table 4). This classification issue has so far been addressed only by Boyd et al. in 19842 and Kaban and Mulliken in 1986.3 Boyd et al.2 described 580 vascular lesions and showed that bone was principally involved in vascular malformations (34%), whereas haemangioma only involved bone in 1% of cases, in which it displaced the structure but without invading the bone. Kaban and Mulliken described nine vascular maxillofacial anomalies.3 Among these anomalies, four lesions had an intraosseous origin, and all of them appeared to be intraosseous vascular malformations. For a better understanding of the disease, the ISSVA classification should be applied to intraosseous vascular malformations instead of the WHO classification. The distinction between a malformation and a tumour is not only semantic – their evolution and treatment are different.

Funding

The authors declare no funding source for this research.

Competing interests

The authors declare no competing interests.

Ethical approval

Under French law, retrospective studies do not require examination by the ethics committee or ethics committee approval.

Patient consent

Not applicable.

References

1. Mulliken JB, Glowacki J. Hemangioma and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 1982; 69:412–22. 2. Boyd JB, Mulliken JB, Kaban LB, Upton 3rd J, Murray JE. Skeletal changes associated

Please cite this article in press as: Kadlub N, et al. Intraosseous haemangioma: semantic and medical confusion, Int J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.ijom.2015.01.025

Table 4. Summary of the principal characteristics of maxillofacial intraosseous vascular malformations, mislabelled as haemangioma. Review of the international literature from 1996 to 2013.

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19. Marcinow AM, Provenzano MJ, Gurgel RK, Chang KE. Primary intraosseous cavernous hemangioma of the zygoma: a case report and literature review. Ear Nose Throat J 2012;91. 210, 212, 214–5. 20. Lin G, Finger E, Gutierrez-Ramos JC. Expression of CD34 in endothelial cells, hematopoietic progenitors and nervous cells in fetal and adult mouse tissues. Eur J Immunol 1995;25:1508–16. 21. Niakosari F, Kahn HJ, Marks A, From L. Detection of lymphatic invasion in primary melanoma with monoclonal antibody D2-40: a new selective immunohistochemical marker of lymphatic endothelium. Arch Dermatol 2005;141:440–4. 22. Smoller BR, Apfelberg DB. Infantile (juvenile) capillary hemangioma: a tumor of heterogeneous cellular elements. J Cutan Pathol 1993;20:330–6. 23. Enjolras O, Mulliken JB. Vascular tumors and vascular malformations (new issues). Adv Dermatol 1997;13:375–423.

Address: Natacha Kadlub Service de Chirurgie Maxillo-faciale et Plastique Hoˆpital Necker Enfants Malades 149 rue de Se`vres 75015 Paris France Tel: +33 1 71 39 67 76 E-mail: [email protected]

Please cite this article in press as: Kadlub N, et al. Intraosseous haemangioma: semantic and medical confusion, Int J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.ijom.2015.01.025

Intraosseous haemangioma: semantic and medical confusion.

The literature is rich in case reports of intraosseous haemangioma, although most of these are actually cases of venous or capillary malformations. To...
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