angiokeratoma is a rare cutaneous vascular disorder of the papillary dermis that is characterized by one or more dilated vessels in the upper part of the dermis . in the majority of cases , it is also associated with epidermal reactions such as acanthosis and/or hyperkeratosis1 .
this disorder can be classified into five types : ( 1 ) a generalized systemic form ( angiokeratoma corporis diffusum of fabry ) ; ( 2 ) a bilateral form occurring on the dorsal surfaces of the fingers and toes ( angiokeratoma of mibelli ) ; ( 3 ) a localized scrotal form ( angiokeratoma of fordyce ) ; ( 4 ) a solitary papular angiokeratoma ; and ( 5 ) a multiple papular and plaque - like form ( angiokeratoma circumscriptum)2,3 .
although the clinical characteristics are different , common histological features include hyperkeratosis of the epidermis and dilated vascular spaces with or without organizing thrombi in the papillary dermis of cutaneous lesions4,5 . among the five types of angiokeratomas ,
most of the cases of angiokeratoma in the oral cavity have presented in conjunction with generalized systemic conditions ( fabry disease and fucosidosis ) .
isolated oral angiokeratoma unrelated to any systemic disease or cutaneous lesion has been rarely reported . to the best of our knowledge ,
only ten cases of isolated angiokeratoma in the oral cavity have been reported in the literature3,4,5,6,7,8,9,10,11,12.(table 1 ) the majority of reported oral angiokeratoma cases occurred on the tongue , but one case involved the buccal mucosa . in this report , we describe an additional case of angiokeratoma circumscriptum in the oral cavity that involved the buccal mucosa without accompanying systemic disease or skin lesion . to characterize this unusual oral lesion ,
the surgical specimen was analyzed by immunohistochemistry for the expression of vascular endothelial growth factor ( vegf ) and its two receptors , vegfr-1 and vegfr-2 .
an 18-year - old female patient was referred for an evaluation of a dark - colored , painless , elevated lesion in the oral cavity .
clinically , a 52-cm - sized , multi - lobular , irregular , raised lesion was observed on the right side of the buccal mucosa.(fig .
a ) the lesion was firm , did not bleed on manipulation , and was not accompanied by mucosal ulceration .
she had first recognized a small lesion on her cheek mucosa about three years prior , which had gradually increased in size .
magnetic resonance imaging showed an ill - defined , heterogeneously enhanced lesion on the right side of the buccal mucosa.(fig .
c ) a punch biopsy of the lesion showed epithelial hyperkeratosis , acanthosis , papillomatosis , and large dilated cystic lesions containing erythrocytes under the epithelial tissue.(fig .
b ) these characteristics were consistent with angiokeratoma . under general anesthesia , the cheek lesion
was completely excised , and the surgical defect was primarily closed with a cheek advancement flap.(fig .
b ) the patient was followed for more than three years without any evidence of recurrence . to confirm the angiogenic characteristics of the tumor , the specimen was immunostained for vegf and two of its receptors ( vegfr-1 and vegfr-2 ) . for immunohistochemical analysis ,
the tumor specimen was embedded in a paraffin block , cut into 4-m sections , and mounted on glass slides .
after hydration , immunohistochemical staining was performed using an automated immunostainer ( benchmark xt ; ventana medical systems inc . ,
tucson , az , usa ) , and detection was performed using the ultraview universal dab kit ( ventana medical systems inc . ) according to the manufacturer 's protocol .
briefly , sections were deparaffinized using an ez prep solution ( ventana medical systems inc . ) and then treated with cc1 standard ( ethylenediaminetetraacetic acid [ edta ] , ph 8.4 ) for 60 minutes at 100 for antigen retrieval . next ,
the slides were treated at 37 for 4 minutes with ultraview universal dab inhibitor ( 3% h2o2 ) to block endogenous peroxidase activity .
slides were then incubated at 37 first with each primary antibody for 32 minutes and then with the secondary antibody ( universal hrp multimer ; ventana medical systems inc . ) for 8 minutes .
finally slides were treated with dab+h2o2 substrate for 8 minutes , and nuclei were counterstained in hematoxylin ii and bluing reagent at 37. immunostained sections were photographed under a nikon eclipse ti - u microscope ( nikon instruments inc . , tokyo , japan ) , and the proportion of positive staining was calculated for both endothelial and stromal cells in the lesion .
the primary antibodies used and the results of the immunohistochemical staining are summarized in table 2 . immunostaining revealed that the stromal cells in the lesion and endothelial cells lining the pathologically dilated vessels expressed vegf and its two receptors ( vegfr-1 and vegfr-2).(fig .
4 ) among both stromal and endothelial cells in the lesion , the percentage of positive - staining cells was higher for vegfr-2 than that for vegfr-1 . interestingly ,
some endothelial cells showed co - expression of vegf and both of its receptors ( arrows ) , whereas others co - expressed only vegf and vegf-2 ( arrowhead ) . proportions of the cells staining positive for each of vegf , vegfr-1 , and vegfr-2 are shown in table 2 .
the first case of angiokeratoma was reported by mibelli in 1890 , and the manifestation of the disorder found on fingers and toes is now known as angiokeratoma of mibelli13 .
angiokeratoma circumscriptum was first described in 1915 by fabry as a localized lesion on a lower extremity13,14 .
it typically occurs unilaterally on the lower legs or feet , but it has also been observed on the thighs , buttocks , or elsewhere .
the lesions are deep red to blue - black in color and are usually elevated , warty , purplish and compressible papules13 . in most cases ,
angiokeratoma circumscriptum is present at birth , but in some cases , it develops during childhood or adulthood4,7 .
oral mucosal involvement is most commonly detected as a component of angiokeratoma corporis diffusum ( fabry disease and fucosidosis ) .
in addition to the present case , a review of the literature revealed ten cases of isolated angiokeratoma that occurred in the oral cavity.(table 1 ) of those , four cases were solitary angiokeratoma and six were angiokeratoma circumscriptum .
except for one case of solitary angiokeratoma that involved the buccal mucosa6 , the remaining nine occurred on the tongue ( pathologically , six were angiokeratoma circumscriptum and three were solitary angiokeratoma)3,4,5,7,8,9,10,11,12 . to our knowledge , the present report is the second case published on isolated oral angiokeratoma confined to the buccal mucosa and the first case report on angiokeratoma circumscriptum involving the buccal mucosa .
the histopathological features of angiokeratoma in the oral cavity are similar to those in skin lesions , which are hyperkeratosis , acanthosis , papillomatosis of the squamous epithelium , and dilated subepithelial blood vessels with thrombosis5 .
it has been thought that altered hemodynamics , such as local injury to papillary capillaries , cause telangiectatic lesions in the papillary dermis with overlying reactive hyperkeratosis and acanthosis of the epidermis3,4 .
interestingly , matrix metalloproteinase-9 ( mmp-9 ) has been identified in the epidermis , particularly in hyperkeratotic lesions of angiokeratoma circumscriptum , by immunohistochemistry15 .
the expression of mmp-9 may be related to the hyperkeratotic changes in angiokeratoma3,15 . in the surgical specimen analyzed in the present study , vegf and
its two receptors ( vegfr-1 and vegfr-2 ) were expressed in the endothelial cells of dilated vessels .
vegf has been characterized as a heparin - binding angiogenic growth factor that plays a critical role in angiogenesis and vasculogenesis during tumor growth and tissue regeneration16,17 . of the several vegf receptors ,
vegfr-1 is primarily involved in cell migration and vascular maintenance rather than cell proliferation , whereas vegfr-2 participates directly in regulating cell mitosis and proliferation ; however , their precise roles have not been completely elucidated16 . in the specimen analyzed in the present study ,
immunostaining intensity was stronger and the proportion of positive cells was higher for vegfr-2 than for vegfr-1 , indicating enhanced cell proliferation of endothelial cells .
additionally , the coexpression of vegf and both of its receptors or only vegf-2 was detected in some of the endothelial cells lining the pathologically dilated vessels .
the coexpression of vegf and vegfrs by the endothelial cells in the lesion indicates that vegf is an autocrine growth factor for these cells17 .
these results suggest that endothelial cells in the pathologically dilated vessels possess vegf autocrine growth activity involved in vasculogenesis and maintenance in the angiokeratoma lesion .
 angiokeratoma is a benign cutaneous lesion of the capillaries , presenting as dilated vessels in the upper part of the dermis . 
 although this disorder is classified into various types and has been occasionally reported in the skin of the scrotum or extremities , the involvement of the oral cavity mucosa has been rarely reported . 
 the present study reports a case of angiokeratoma circumscriptum in the buccal mucosa . 
 the expression of vascular endothelial growth factor ( vegf ) and both of its receptors ( vegfr-1 and vegfr-2 ) was demonstrated by immunohistochemistry in the endothelial cells lining the dilated vessels . 
 the expression of vegfr-2 was higher than that of vegfr-1 in the endothelial cells in the lesion , indicating an increased rate of endothelial cell proliferation within the lesion . 
 interestingly , some of the endothelial cells co - expressed vegf and its two receptors . 
 these results suggest that endothelial cells in the pathologically dilated vessels possess vegf autocrine growth activity involved in vasculogenesis and maintenance in angiokeratoma lesions . to our knowledge , this is the second report published on isolated oral angiokeratoma confined to the buccal mucosa and the first case report on angiokeratoma circumscriptum involving the buccal mucosa . 
I. Introduction
II. Cases Report
III. Discussion