Int J Oral-Med Sci 9(3):241-251,2011 Original Article

A Comparative Histopathological and Immunohistochemically Study of Capillary

Hemangioma,Pyogenic Granuloma and Cavernous Hemangioma in the Oral Region: with Special Reference to Vascular Proliferation Factors

Naoko Kawachi

Nihon University Graduate School of Dentistry at Matsudo,Oral Surgery,Matsudo,Chiba 271-8587,Japan

Correspondence to: Naoko Kawachi,DDS Capillary hemangioma, pyogenic granuloma and cavernous heman-

E-mail: wakatakenao＠yahoo.co.jp gioma,benign vascular lesions affect in the oral regions.There have

been some studies of them,but their pathological status is still contro- versial.The aim of the present study was to reveal the characteristic

histopathological and immunohistochemical features such as cell pro- liferation activity, vascular proliferation factors and mesenchymal

marker of these lesions in order to understand the pathological status

of them.In histopathological findings of the present study,capillary

hemangioma consisted of proliferating capillaries having endothelial

cells and ovoid or spindle cells and associated with mast cells and

lobular structures circumscribed with PAS-positive matrices. Pyogenic granuloma exhibited proliferation of the capillaries having

endothelial cells and a few perivascular mesenchymal ovoid or spindle

cells beneath erosive and ulcerative lesions and inflammatory changes. Cavernous hemangioma was composed of remarkably dilated and

hyperplasic blood vessels. Immunohistochemically, Ki-67 labeling

index of capillary hemangioma and pyogenic granuloma was higher

than that of cavernous hemangioma. Positive immunoreactivity for

CD34,CD105 and Tie2 was observed in some perivascular ovoid cells

supported to be endothelial precursor cells. Capillary hemangioma

exhibited that positive immunoreactivity for VEGF was found in the

perivascular cells,mast cells and/or macrophage,whereas pyogenic

granuloma showed that the positive reactivity was also seen mainly in

the endothelial cells.Positive immunoreactivity for α-smooth muscle

actin was identical to perivascular spindle cells,and was supposed to

Keywords: be pericytes.Conclusively,the present study indicated that capillary capillary hemangioma, pyogenic hemangioma and pyogenic granuloma showed different histopathology granuroma, cavernous hemangioma, and immune-profiles of vascular proliferation factors,suggesting they vascular proliferation factors,VEGF would have different pathological status.

the lesions have been unclear(3-5).Thus the subclas- Hemangioma, a relatively frequent benign soft sification of hemangioma is a little controversial. tissue tumor,is also found in the oral region(1-8).It Recently,various vascular proliferation factors,cell is subdivided into capillary hemangioma, pyogenic proliferation factors and mesenchymal markers have granuloma and cavernous hemangioma. Although been found and used for the diseases(3-8),however,

World Health Organization (WHO)classification of the histopathological and immunohistochemical the soft tissue tumors (2) has been widely used, study using these antibodies of these tumors has not pyogenic granuloma is not listed in the classification. been performed comprehensively and conclusively, There have been some reports concerning about as yet. comparative study of these tumors but the detail of The aim of the present study was to reveal the Int J Oral-Med Sci 9(3):241-251,2011 characteristic histopathological feature and to exam- KP-1). Details of primary antibodies used in the ine the pathological status of capillary hemangioma, present study (CD31, CD34, KP-1, SMA, Ki-67, pyogenic granuloma and cavernous hemangioma by VEGF, Tie2),dilution, clone,and antigen retrieval histopathological and immunohistochemical tech- methods, manufacture are shown in Table 1. And niques in order to understand the pathological status then sections were incubated with Histofine Simple of the disease. Stain MAXPO (MULTI)(Nichirei Co, Ltd, Tokyo, Japan),(MAXPO (G)for Tie2)for 1 hr at room tem- perature.The immunoreaction was visualized using

Materials simple stain DAB solution (Nichirei Co,Ltd,Tokyo,

The author retrieved the files on ten cases each of Japan)for 5 min at room temperature. capillary hemangioma,pyogenic granuloma and cav- Double immunohistochemical stain method for ernous hemangioma kept at the Department of Oral colocalization of CD105 and Ki-67 was applied.

Pathology,Nihon University School of Dentistry at Deparaffinized sections were pretreated, and en-

Matsudo. Control specimen comprised ten cases of dogenous peroxidase blocking with 3% hydrogen normal oral mucosa including non-neoplastic ves- peroxidase for 5 minutes was performed,followed by sels. Consideration was given to patient privacy, pretreatment with proteinase K (DakoCytomation diagnosis,and the management and prognosis of the Glostrup,Denmark)for 15 min at room temperature. lesions (Ethics committee recognition number: EC Incubation with primary CD105 antibody for 1 hr was

08-021). done, and then sections were incubated with His- tofine Simple Stain MAXAP (MULTI)(Nichirei Co, Methods Ltd, Tokyo, Japan) for 1 hr at room temperature.

For light microscopical observation, following The immunoreaction was visualized using BCIP/ fixation with 10% neutral formalin solution, speci- NBT Substrate System (DakoCytomation Glostrup, mens were cut into several pieces and routine paraf- Denmark)for 5 min at room temperature.Secondary fin sections(4μm)were prepared.They were stained staining was pretreated with microwave irradiation with hematoxylin and eosin (HE),toluidine blue pH in citrate buffer(10 mM,pH 6.0,5 min×3)to unmask

4.1(TB)and periodic acid schiff reaction (PAS). the Ki-67 epitope.After 30 min incubation with Ki-67

For immunohistochemical observation,deparaffin- antibody,they were incubate with Histofine Simple ized sections were pretreated, and performed en- Stain MAXAP (MULTI)for 30 min at room tempera- dogenous peroxidase blocking with 3% hydrogen ture the immunoreaction was visualized using New peroxidase for 5 min.Next they were pretreated with Fuchsin Substrate Kit (Nichirei Co, Ltd, Tokyo, microwave irradiation in citrate buffer(10 mM, pH Japan)for 5 min at room temperature.It was also

6.0,5 min×3)to unmask primary antibodies(exclude applied double stain method for co-localization of

Table 1. Summary of primary antibodies used in the present study Antigen Primary antibodies Dilution Manufacturer Clonality Clone retrival

Ki-67 1: 100 Autoclave DakoCytomation Monoclonal MIB-1 CD31 1: 100 Autoclave DakoCytomation Monoclonal JC70A

CD34 1: 100 Autoclave DakoCytomation Monoclonal QBEnd 10 CD105 1: 50 Proteinase K DakoCytomation Monoclonal SN6h α-Smoth actin(SMA) 1: 100 Autoclave DakoCytomation Monoclonal 1A4 VEGF 1: 100 Autoclave Thermo Polyclonal

Tie-2 1: 100 Autoclave R&D System Polyclonal

CD68 1: 100 Proteinase K DakoCytomation Monoclonal KP-1 Int J Oral-Med Sci 9(3):241-251,2011

SMA and PAS stains on the same section. or spindled ones with plump nucleus,and the mast

On analysis of proliferative activity,areas show- cells showing metachromasia with TB (Fig.1c)were ing high positivity hot spots were chosen, and the found in the matrix surrounding the lobular area average rates of positive cells (Labeling Index, LI) revealing positive reaction to PAS (Fig.1b). The was calculated after analyzing about 500 cells in five average number of the mast cells was 10.8(Fig.1c). fields at ×400 magnification.The average number of These findings are summarized in Table 2. mast cells revealing metachromasia to TB stain was 2)Pyogenic granuloma also calculated in five fields at ×400. Statistical Ulcer formation was recognized at the surface of significance was determined by Welch T test.Differ- the lesion. In the ulcer area, a layer of fibrin and ences at p＜0.05 were considered statistically signifi- entrapped neutrophil were found. Proliferation of cant. plump endothelial cells forming small canalized cap- illaries and various-sized blood vessels lined with

flatten endothelial cells were observed beneath the

Histopathological findings ulcer (Fig.1d). The proliferating capillaries were

1)Capillary hemangioma also circumscribed with flatten pericyte-like cells.

Capillary hemangioma was composed of nodular Table 2. The mean number of mast cells(Mean±SD) - proliferation of capillary sized vessels lined by en- Mast cell(Mean±SD) dothelial cells having plump nucleus(Fig.1a).Eryth- Capillary hemangioma 10.8±1.3⎫ ⎫ ⎫ rocytes were frequently recognized in the lumen ＊ Pyogenic granuloma 1.6±1.0⎭ ＊ ＊ spaces. In many cases, the lobular formation sur- Cavernous hemangioma 1.8±1.5 ⎭ rounded by dense fibrous tissues was observed main- Control 0.5±0.6 ⎭ ly at the lower area of the tumor tissues. Many All p vales are performed by Welch’s t test perivascular mesenchymal cells which were ovoid- ＊ p＜0.01

Fig.1a. Capillary hemangioma is composed of nodular prolifelation of capillary-sized vessels and ovoid,spindle and mast cell -like cells.(HE,original magnification ×400) Fig.1b. In capillary hemangioma the matrix surrounding the lobules shows positive reaction to PAS.(PAS,original magnifica- tion ×100) Fig.1c. In capillary hemangioma of lobular formation,many numbers of the mast cells are found.(TB, original magnifica- tion ×400) Fig.1d. Pyogenic granuloma consists of plump endothelial cells forming poorly canalized capillaries,small and large blood vessels and lymphocyte infiltration.(HE,original magnification ×400) Fig.1e. In pyogenic granuloma, basal lamina of the endothelial cells reveals positive reaction to PAS. (PAS, original magnification ×100) Fig.1f. Cavernous hemangioma shows large,dilated or sinusoidal vessels having irregular lumen. (HE, original magnifica- tion ×200) Int J Oral-Med Sci 9(3):241-251,2011

Some ovoid- or spindle perivascular cells were ob- Table 3. Labeling index of Ki-67(Mean±SD) served between the proliferating capillaries.Moder- Ki-67(Mean±SD) ate inflammatory infiltration with neutrophils and Capillary hemangioma Endothelial cell 17.4±2.8 lymphocytes was present around the proliferating Perivascular cell 23.5±1.8 Pyogenic granuloma Endothelial cell 14.9±2.7 blood vessels and formed the granulation tissue.The Perivascular cell 19.0±2.3 blood vessels showed a clustered or medullar pattern Cavernous hemangioma Endothelial cell 0 separated by less vascular fibrotic matrix. Basal Perivascular cell 0 lamina of the endothelial cells revealed positive Control Endothelial cell 0 reaction to PAS (Fig.1e).A few mast cells showing Perivascular cell 0 metachromasia with TB were recognized and the average number was 1.6.These findings are shown in

Table 2. 3)Cavernous hemangioma

Cavernous hemangioma was composed of large, dilated or sinusoidal vessels having irregular lumen with thin wall lined with flattened endothelial cells (Fig.1f).Flatten,pericytes-like cells around the en- dothelial cells were frequently observed.The luminal spaces were filled with blood, and thrombus or Fig.2a.b. Some endothelial (blue) and perivascular mesen- phlebolith was also seen in some cases.Basal lamina chymal cells(red)reveal Ki-67 positivity in capillary heman- gioma(a)and pyogenic granuloma(b)in double stain of CD105 around the endothelial cells showed positive reaction (blue)and Ki-67(red).(Original magnification ×600) to PAS. A few mast cells showing metachromasia with TB were found around vessels and the number 3)Cavernous hemangioma was 1.8(Table 2-1). Ki-67-positive endothelial cells and perivascular

4)Control mesenchymal spindled cells a were not observed in

Some blood vessels were recognized in the connec- the tumor (LI,0). tive tissue under the mucosa. Few mast cells were 4)Control recognized and the average number was 0.5(Table 2 The immunoreactivity to Ki-67 was similar to that

-1).The surface of the mucosa was covered with of cavernous hemangioma.The LI was 0. parakeratinezed stratified squamous epithelium. Endothelial cells and mesenchymal cell associated

Histochemical and immunohistochemical findings antibodies

The results are summarized in Table 3 The results are summarized in Table 4

Cell proliferation activity: Ki-67 1)Capillary hemangioma

1)Capillary hemangioma Most of endothelial cells were positive to CD31,

Some endothelial cells and the perivascular mesen- CD34(Fig.3a)and CD105.A few of endothelial cells chymal cells revealed positive reactivity for Ki-67 were positive to VEGF (Fig.3b),but many of them

(Fig.2a),and the LI was 17.4 in the endothelial cells were positive to Tie2 (Fig.3c).Some perivascular and 23.5 in the perivascular cells. mesenchymal ovoid cells were positive to CD31, 2)Pyogenic granuloma CD34,CD105 and Tie2 and many of them were posi-

Some endothelial cells and the perivascular mesen- tive to VEGF.Some perivascular mesenchymal spin- chymal cells revealed positivity for Ki-67(Fig.2b), dle cells were positive to VEGF.Mast cells revealed and the LI of the former was 14.9 and the latter was are positive reactivity to VEGF.Perivascular mesen-

19.0. chymal spindle cells were positive to SMA (Fig.3d). Int J Oral-Med Sci 9(3):241-251,2011

Fig.3a. Endothelial cells and ovoid cells are positive to CD34 in capillary hemangioma of lobular formation. (Original magnification ×600) Fig.3b. Some endothelial cells and many perivascular mesenchymal ovoid cells are positive to VEGF in capillary hemangioma of lobular formation.(Original magnification ×600) Fig.3c. Most of endothelial and ovoid cells are positive to Tie2 in capillary hemangioma of lobular formation. (Original magnification ×600) Fig.3d. Perivascular mesenchymal cells are positive to SMA in capillary hemangioma of lobular formation. (Original magnification ×600) Fig.3e. In pyogenic granuloma PAS-positive lines(pink)are irregularly recognized between and around these SMA-positive (brown)cells in double staining of SMA and PAS.(Original magnification ×400) Fig.3f. Some perivascular mesenchymal ovoid cells show positive reaction to KP-1 in capillary hemangioma of lobular formation.(Original magnification ×600) Fig.3g. Some endothelial cells and many perivascular mesenchymal ovoid cells are positive to VEGF in pyogenic granuloma. (Original magnification ×600) Fig.3h. Most endothelial cells are positive to CD34 in pyogenic granuloma.(Original magnification ×400) Fig.3i. Vascular surrounding cells reveal immunopositivity to SMA,but other perivascular mesenchymal cells are negative in pyogenic granuloma.(Original magnification ×400) Fig.3j. PAS-positive lines (pink) are regularly observed around the SMA positive cells (brown)in pyogenic granuloma in double staining of SMA and PAS.(Original magnification ×200) Fig.3k. Many perivascular mesenchymal ovoid cells show positive reaction to KP1 in pyogenic granuloma.(Original magnifica- tion ×400) Fig.3l. In pyogenic granuloma PAS-positivity (pink) is observed both at the inside and outside of the SMA positive cells (brown)in double staining of SMA and PAS.(Original magnification ×200) Int J Oral-Med Sci 9(3):241-251,2011

Tabel 4. The result of immunohistochemistry

CD31 CD34 CD105 VEGF Tie2 SMA

Capillary hemangioma Endothelial cell ＋ ＋＋ ＋＋ －～＋ ＋＋ － Perivascular ovoid cell ＋ ＋ ＋ ＋ ＋ － Perivascular spindle cell － － － －～＋ － ＋＋ Pyogenic granuloma Endothelial cell ＋＋ ＋＋ ＋＋ ＋＋～＋ ＋＋ － Perivascular ovoid cell －～＋ －～＋ －～＋ ＋＋ －～＋ － Perivascular spindle cell － － － －～＋ － ＋＋～－ Cavernous hemangioma Endothelial cell ＋ ＋＋ － ＋ ＋＋ － Perivascular spindle cell － － － － － ＋＋ Normal Endothelial cell ＋＋ ＋＋ － －～＋ ＋＋ － Perivascular spindle cell － － － － － ＋＋ － : negative,＋ : moderate positive,＋＋ : strong positive

PAS-positive lines were irregularly recognized gioma. between and around these SMA-positive cells in the double staining of SMA and PAS (Fig.3e).KP-1- positive macrophages were seen around the capil- Hemangioma is the representative benign lesion laries(Fig.3f). among the vascular-related tumors in the head and

2)Pyogenic granuloma neck region (1-13).Some authors consider that cav-

The immunoreactivity of endothelial cells was ernous hemangioma is vascular malformation (9-11) almost same as that of capillary hemangioma but and capillary hemangioma is a neoplastic lesion(3,6, many endothelial cells were positive to VEGF (Fig. 12,13).On the other hand,pyogenic granuloma is not

3g). The perivascular mesenchymal ovoid were listed in WHO of the soft tissue tumors(2).The term almost negative for CD31,CD34(Fig.3h),CD105 and pyogenic granuloma was introduced by Hartzell in

Tie2. The perivascular mesenchymal spindle cells 1904,and firstly reported by Hullihen in 1844(3-5). revealed immunopositivity to SMA (Fig.3i).PAS- Thus, the pathological status of capillary heman- positive lines were regularly observed around the gioma, pyogenic granuloma and cavernous heman-

SMA-positive cells in the double staining of SMA gioma are still controversial. and PAS (Fig.3j).KP-1-positive macrophages were There have been some histopathological and im- seen around the capillaries(Fig.3k). munohistochemical studies about capillary heman- 3)Cavernous hemangioma gioma or pyogenic granuloma (1-6).They reported

Some endothelial cells were positive to CD31,and that capillary hemangioma was an underlying lesion many of them were positive to CD34,but negative to of pyogenic granuloma which was frequently as-

CD105.Some endothelial cells were positive to VEGF sociated with marked ulcerative change, although and many of them were positive to Tie2.Most of the term capillary hemangioma is recognized today perivascular mesenchymal spindle cells were posi- to be synonymous with pyogenic granuloma.On the tive to SMA in the double staining of SMA and PAS. other report,pyogenic granuloma is considered to be

PAS-positive reactivity was observed both at the non-neoplastic in nature. inside and outside of the SMA-positive cells(Fig.3l). In the present study,there were some differences in

There was no positive reaction to KP1. the morphological features of the vascular element

4)Control between capillary hemangioma and pyogenic

Immunoreactivity of the endothelial cells and per- granuloma.At first,thick PAS-positive membranous ivascular cells were similar to cavernous heman- matrices and lobular appearance were observed in Int J Oral-Med Sci 9(3):241-251,2011 capillary hemangioma but in pyogenic granuloma hemangioma and pyogenic granuloma,because cav- blood vessels showed a clustered or medullar pattern ernous hemangioma was non neoplastic. separated by less vascular fibrotic septa and PAS- Several properties of VEGF make it universally positive membranous matrices. accepted an important regulator of angiogenesis and

Ki-67,a marker of cell proliferation activity,is tumor genesis of the vascular tumors; induction and useful to define the proliferation status of both en- promotion of endothelial cells, and inhibition of dothelial cells and perivascular mesenchymal cells apoptosis.(22-26).Yuan et al.(12)reported that the

(5,14).In the present study,the LI of endothelial cells positive immunoreactivity for VEGF was mostly in the capillary hemangioma was 17.4 and perivas- localized in macrophages and fibroblasts in pyogenic cular mesenchymal was 23.5. That of endothelial granuloma. In the present study, the positive im- cells in the pyogenic granuloma was 14.9 and perivas- munoreactivities for VEGF were recognized in the cular mesenchymal was 19.In each lesion,LI tended many endothelial cells of pyogenic granuloma, but to be higher in the perivascular mesenchymal ovoid the positivity was unremarkable in capillary heman- cells than the endothelial cells.No significant differ- gioma.Meanwhile,the degree of VEGF was appar- ence was recognized between capillary hemangioma ently more abundant in the perivascular cells of and pyogenic granuloma. But no Ki-67 immunor- capillary hemangioma, and many mast cells and eactivity was identified in endothelial cells of cavern- some KP-1-positive macrophages regarding as ma- ous hemangioma and control blood vessels. These crophages were positive to VEGF. In pyogenic results suggested that capillary hemangioma and granuloma, some inflammatory cells and macro- pyogenic granuloma had a possibility of true neo- phage were also positive to VEGF. plastic character, whereas cavernous hemangioma Mast cells originate from hemopoietic stem cell was hamartomatous lesion.Further,the results sug- around the blood vessels complete their maturation gested that the tumors consisted of both endothelial in vascularized peripheral tissues. On activation, and perivascular mesenchymal cells proliferation. mast cells can rapidly release VEGF, apparently

It is well known that CD31 and CD34 are so repre- from a preformed pool in the cytoplasm(27-30).The sentative specific markers for endothelial cells that histopathological behavior of mast cells in heman- many studies use them to detect endothelial cells(15 gioma is indefinite(31-34).In the present study,mast

-19).The target of CD31 is platelet endothelial cell cells showing metachromasia with TB were recog- adhesion molecule-1 (PECAM-1)and the expression nized in all lesions,but they were abundant in lobules of CD31 is recognized in endothelial cells and inflam- with PAS-positive matrices of capillary heman- matory cells (17).CD34 is known to express in the gioma (Table 2).These results suggested that the maturation of the endothelial cells and is also in- mast cells might be associated with proliferation of dicated in immature mesenchymal cells (18, 19). the blood vessels of these tumors especially in capil- CD105,a kind of glycoprotein, is predominantly in lary hemangioma. the endothelial cells of the neoformed blood vessels Tie2 is an endothelium-specific receptor tyrosine

(20,21).In the present study,CD31,CD34 and CD105 kinase consisting of extracellular domain, a trans- were recognized in the almost endothelial cells in the membrane domain and a split intracellular kinase tumors and some perivascular mesenchymal ovoid domain (35-38).The tyrosine kinase receptor Tie2 cells in capillary hemangioma suggesting to be en- accelerates the development of the embryonic vas- dothelial precursor cells.Negative reaction of CD105 culature and persists in adult endothelial cells during was found in the perivascular cells of cavernous wound healing. Unlike the VEGF receptor system, hemangioma and control. These results suggested Tie2 receptors are not required for angiogenesis but that CD105 had advantage as a marker of an- appear essential to support functions of the more giogenesis during the tumor growth of capillary mature endothelium. Tie2 is unregulated in capil- Int J Oral-Med Sci 9(3):241-251,2011 laries during neovascularization processes and col- nism: Endothelial progenitor cells,primary deliver- laborates with VEGF in regulating angiogenesis and ed from bone marrow, mobilize to the blood by vascular maturation (35).Sato et al. (13) reported stimulation such as VEGF ; they migrate to a that in capillary hemangioma, positive immunor- neovascularization site and differentiate into endoth- eactivity for Tie2 was recognized only in the perivas- elial cells,and assist angiogenesis. cular ovoid cells and suggested that the Tie2-posi- Angiogenesis and vasculogenesis are due to the tive ovoid cells played an important role in the activations of in situ endothelial progenitor cells and development and progression of tumor. bone marrow-derived or in situ endothelial progeni- In the present study,positive immunoreactivity for tor cells, respectively. In the present study, the

Tie2 in pyogenic granuloma was observed only in growth of many endothelial precursor cells,pericytes endothelial cells,whereas in capillary hemangioma and few inflammatory cells were found in capillary

Tie2 positivity was recognized both in endothelial hemangioma, but whereas in pyogenic granuloma cells and perivascular mesencymal ovoid cells there are many inflammatory cells but a few endoth- around the capillaries.Since the perivascular mesen- elial precursor cells. As the result, in pyogenic cymal ovoid cells which did not forming the lumen granuloma an angiogenetic process suggests to simi- revealed positive reactivity for CD34 or CD105,in the lar to former processes and in capillary hemangioma present study,Tie2 would be endothelial precursor the process similar to the latter. cells. Conclusively,the present study indicated that cap- Generally,fibroblastic mesenchymal cells are pres- illary hemangioma and pyogenic granuloma showed ent in the outside of the endothelial cells.The base- different histopathology and immune-profiles of ment membrane and the fibroblastic mesencymal vascular proliferation factors,suggesting they would spindled cells are supposed to be pericytes,and capil- have identical pathological status. lary is restricted to vessels consisting of one layer only of endothelial cells and basal lamina,in which a few pericytes may be embedded(39). To examine and compare the histopathological

In the present study,the perivascular mesenchymal status of the present study performed capillary spindled cells were found in the outside of the endoth- hemangioma, pyogenic granuloma and cavernous elial cells and basement membrane,exhibited posi- hemangioma, histopathological and immunohisto- tive immunoreactivity for growth factors and also chemical analyzed and review of the literature,and

SMA.In these perivascular mesenchymal cells,SMA the following results were obtained. -positive cells suggested pericytes. 1. Histopathologically,capillary hemangioma con- Post-natal neovascularization in the physiological sisted of proliferating capillaries having many or pathological events is consistent with neovessel endothelial cells and perivascular ovoid cells and formation contributed by angiogenesis and vas- associated with mast cells and lobular structures culogenesis at various rates between their two mech- circumscribed with PAS-positive matrices,espe- anisms (40-42). cially in lower area of the tumor tissues.Pyogenic

One mechanism: By angiogenetic stimulation granuloma exhibited proliferation of the capil- (hypoxia,inflammation),pericytes leave endothelial laries having some endothelial cells and some cells and a basal membrane is digested by vascular perivascular ovoid cells with ulcerative lesions endothelial cells protease and a vascular cavity is and inflammatory changes. Cavernous heman- expanded. The extended blood vessel increases gioma was composed of remarkable dilated and neovascularity by sprouting, bridging, intussuscep- hyperplasic blood vessels. tions.Finally pericytes build a mature blood vessel 2. Mast cells showing metachromasia with TB were around neovascular circumference. Other mecha- more frequent in capillary hemangioma than in Int J Oral-Med Sci 9(3):241-251,2011

the other lesions. H, Fujitsuka H, Kato Y, Miyamoto K, Shibata T, Shimokawa K : Lobular capillary hemangioma of oral 3. Immunohistochemically, Ki-67 LI of capillary mucosa: Clinicopathological study of 43 cases with a hemangioma and pyogenic granuloma was higher special refrence to immunohistochemical characteri- than that of cavernous hemangioma. zation of the vascular elements.Pathol Int, 53: 1-7, 4. Positive immunoreactivity for CD34,CD105 and 2003. 2. Weiss SW : Histological Typing of Soft Tissue Tie2 was observed in some perivascular ovoid Tumours(WHO.World Health Organization.Interna- cells supported to be endothelial precursor cells. tional Histological Classification of Tumours),Vol.2, 5. Capillary hemangioma exhibited that positive 1994,Springer-Verlag, New York Berlin Heidelberg, immunoreactivity for VEGF was found in some USA.

perivascular mesenchymal ovoid cells,mast cells 3. Freitas TM, Miguel MC, Silveira EJ, Freitas RA, Galvao HC : Assessment of angiogenic markers in and/or macrophage; whereas in pyogenic oral hemangiomas and pyogenic granulomas.Exp Mol

granuloma, many endothelial cells and perivas- Pathol,79 : 79-85,2005. cular mesenchymal ovoid cells and macrophages 4. Jafarzddeh H, Santkhani M, Mohtasham N : Oral

were positive to VEGF. pyogenic granuloma: a review.J Oral Sci,48: 167- 6. Positive immunoreactivity for SMA was identical 175,2006. 5. Rezvani G, Azarpira N, Bita G, Zeynab R: Prolifer- to perivascular spindle cells,supposed to be per- ative activity in oral pyogenic granuloma: a compara- icytes,with irregular avaragements of PAS-posi- tive immonohistochemical study. Indian J Pathol

tive matrices. Microbiol,403: 403-407,2010. These results indicated that capillary hemangioma 6. Epivatianos A, Antoniads D, Zaraboukas T, Zairi E, Poulopoulos A, Kiziridou A, Iordanidis S : Pyogenic showed proliferating activity of the unit of capil- granuloma of oral cavity: comparative study of its laries such as endothelial cells and pericytes-like clinicopathological and immunohistochemical fea- perivascular cells with appearance of the mast cells tures.Pathol Int,55: 391-397,2005. and lobules of PAS-positive matrices, whereas 7. Dhaybi AR,Powell J,McCuaig C,Kokta V : Differen- tiation of vascular tumors from vascular malforma- pyogenic granuloma exhibited remarkable prolifer- tions by expression of Wilms tumor 1 gene: evalua- ative activity mainly of the endothelial cells and also tion of 126 cases.J Am Acad Dermal,63: 1052-1057, identified with inflammatory changes, suggestively 2010. different pathological status in these tumors. 8. Aguirre RL, Nishioka M, Esguerra RL, Wang LH, Arai N,Okada N,Amagasa T : Histopathological and

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vascular lesions.Oral Med Pathol,97: 97-103,2006. The authors are grateful to Professor Y.Akimoto 9. Weiss SW,Goldblum JR,Enzinger FM : Enzinger and

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School of Dentistry at Matsudo)for his direction and Louis,USA. 10.Sure U, Freman S, Bozinov O,Benes L, Siegel AM, helpful advice, and appreciate Professor H. Bertalanffy H : Biological activity of adult cavernous Yamamoto (Department of Oral Pathology,Nihon malformations: a study of 56 patients.J Neurosurg, University School of Dentistry at Matsudo) and 102: 342-347,2005.

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