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Verruciform xanthoma of the oral mucosa -cases report CHIUNG-FANG HUANG1 JING-MING HUNG2 CHENG-YUE SUNG1 YI-JUNG LU1 KUANG-HSUN LIN3 YUN-HO LIN4 1 Department of Dentistry, Taipei Medical University Hospital, Taipei, Taiwan, ROC. School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan, ROC. 3 Department of Dentistry, Taipei Medical University – Municipal Wan Fang Hospital, Taipei, Taiwan, ROC. 4 Department of Pathology, Taipei Medical University, Taipei, Taiwan, ROC. 2 A verruciform xanthoma (VX) is an uncommon lesion confined mainly to the oral mucosa. The diagnosis is almost always made during a histologic examination. Histologically, it is characterized by papillomatosis, parakeratosis, and aggregates of foam cells in the connective tissue papillae. The histogenetic origin of the lipid-laden foam cells is controversial. Three cases of oral mucosal VX are reported. The immunohistochemical study showed that the foam cells were positive for CD68 and vimentin and negative for S-100. Based on our findings, we suggest that foam cells, as a histological hallmark of the lesion, are most likely derived from the monocyte-macrophage lineage. We failed to detect human papillomavirus in all 3 cases. Differentiating a verrucous carcinoma from VX is important, especially in small superficial lesions, which could lead to an inappropriate and excessive surgical intervention. Treatment of VX consists of a simple surgical excision and the prognosis is excellent. (J Dent Sci, 2(4):226-229 , 2007) Key words: verruciform xanthoma, monocyte-macrophage. A verruciform xanthoma (VX) is an uncommon lesion confined mainly to the oral mucosa1. The most common site of involvement is the gingival margin, followed by the palate and floor of the mouth2,3. Lesions that may occur elsewhere usually arise on the perineum or skin. Clinically, a VX is a single lesion with a verruciform appearance, but it may appear as polypoid, papillomatous, or sessile. A few authors have reported the rare occurrence of multiple lesions4-6. The color of such lesions may be red or pink, but may occasionally be yellowish-red or grayish. The clinical appearance of a VX is not diagnostic; the diagnosis is almost always made during histologic examination. Histologically, it is characterized by papillomatosis, parakeratosis, and aggregates of foam cells in the submucosal stroma without epidermal atypia1,2,7. It was reported that the most often affected sites were in epithelia subjected to trauma or irritation. Most patients with a VX do not have hyperlipidemia. The histogenetic origin of the lipid-laden foam cells is controversial, but they are known to be cells of the monocyte / macrophage lineage 8-12 . The pathogenesis of VX remains unknown, although an inflammatory, immuneassociated response and possibly human papillomavirus (HPV) infection have been proposed. We present 3 cases of oral mucosal VX and results of the immunohistochemical studies. CASE PRESENTATION Received: October 2, 2007 Accepted: November 27, 2007 Reprint requests to: Dr. Yun-Ho Lin, Department of Pathology, Taipei Medical University, No.250, Wu-Hsing Street, Taipei, Taiwan 11042, ROC. 226 The 3 cases diagnosed with a VX were taken from the pathology files of the Dental Department of Taipei Medical University Hospital in 2004~2006. J Dent Sci 2007‧Vol 2‧No 4 Verruciform xanthoma of the oral mucosa Case 1 Histopathology A 66-year-old Asian female requested for a routine oral examination, and a pink soft mass in the area of the right mandibular buccal gingivae of the central and lateral incisor was found. The patient said that the mass had existed for a long time and was painless. The patient has cardiomegaly and hypertension which is well controlled by medications. On physical examination, we observed a 0.3 × 0.2 cm, pink, well-demarcated papillomatous mass. There was no other lymphadenopathy. Under the impression of a papilloma as a clinical diagnosis, it was excised. Histopathologically, these 3 sections were similar on microscopic examination. The lesions showed papillomatosis with parakeratotic squamous epithelium and a hyperplastic epidermis without atypia. Exocytosis of leukocytes of the epidermis was seen. Simultaneously, there was abundance of pale foamy histiocytes in the elongated dermal papillae (Figures 1, 2). Below the benign epithelium, a focal interface and interstitial infiltrate of lymphocytes, plasma cells, and neutrophils were observed. Serial 5-µm-thick, formalin-fixed, paraffinembedded specimens were immunohistochemically stained with monoclonal antibodies against CD68, Case 2 A 33-year-old Asian male was referred to our hospital from a local dentist on account of a mass over the right mandibular buccal gingivae of the first and second premolars for 1 year. The lesion was neither painful nor ulcerated. The patient had a social history of smoking, alcohol consumption, and betel nut chewing for over 10 years, but denied any systemic disease. On physical examination, a 1.5 × 1.0 cm, sessile, pink, exophytic papilloma-like mass distinctly delineated from the adjacent tissue was found. In the bilateral buccal areas, submucosal fibrosis and leukoplakia were also noted. Our impression was a papilloma and the mass was excised under local anesthesia. Case 3 A 76-year-old Asian male was referred to our hospital from a local dentist on account of an inconspicuous mass growing in the area of the left mandibular lingual gingivae between the first and second premolars. The lesion was painless and moderately inflamed. On physical examination, a 0.5 × 0.5 cm, pink to red, non-tender verruciform projection was found. The patient had periodontitis with poor oral hygiene. There was no other lymphadenopathy. Laboratory results revealed mildly elevated levels of creatinine (2.3 mg/dl), uric acid (8.7 mg/dl), cholesterol (249 mg/dl), and blood urea nitrogen (26 mg/dl). Under local anesthesia, the verrucous hyperplastic mass was excised. J Dent Sci 2007‧Vol 2‧No 4 Figure 1. Microscopically, the lesion showed papillary epithelium with parakeratosis. There was an abundance of xanthoma foam cells which had infiltrated the dermal papillae. Inflammatory infiltrates of lymphocytes and neutrophils were also noted. (H&E stain, 100×) Figure 2. Higher magnification of Figure 1 showing xanthoma cells with small nuclei in the dermal papillae. (H&E stain, 200×) 227 C.F. Huang, J.M. Hung, K.H. Lin, et al. Figure 3. Foam cells showing strong cytoplasmic CD68 immunostaining. The epithelial cells (immunohistochemical staining, 200×) were negative. vimentin, and S-100 protein. The sections were also subjected to detect of HPV using genechips (EasychipHPV Blot, King Car Food Industrial, Ilan, Taiwan). Easychip HPV Blot genechips are capable of identifying the genotypes of HPV via a polymerase chain reaction-based method. The results were as follows: the foam cells showed strong cytoplasmic CD68 immunostaining (Figure 3). The mesodermal and foam cells in the interstitial tissue showed strong immunoreactivity to vimentin. S-100 protein staining highlighted Langerhans' cells, while epithelial cells and xanthoma cells showed almost no immunostaining. The xanthoma foam cells were positive for CD68 and vimentin and negative for S-100. Therefore, the xanthoma foam cells were confirmed to be macrophages. HPV was not detected in any of the specimens. DISCUSSION A VX was first reported by Shafer in 1971, and this rare lesion is mainly confined to the oral cavity1. The gingiva is the most commonly affected site (57.4%) as reported by Philipsen et al.2, which was also found in our 3 cases. Many authors consider it to be a reactive process rather than a true neoplasm. Mild trauma or irritation has been proposed as playing a role in the etiopathogenesis because lesions are often found in the masticatory mucosa yet there is usually no direct evidence of local irritants, including our 3 cases. A VX is characterized by a squamous epithelial surface of varying morphologies covered with parakeratin and a hyperplastic epidermis without 228 atypia1,2,7. The outstanding feature of this lesion is the presence of foam cells, which fill the elongated dermal papillae but the relationship between these features has not been defined. The histogenetic origin of the lipid-laden foam cells is controversial. Foam cells have been regarded as fibroblasts, melanoytes13,14, or macrophages. Most authors believe that foam cells are lipid-laden macrophages8-11. Mostafa et al.12 were the first to demonstrate the origin of VX foam cells as cells of the monocyte/macrophage lineage. In our 3 cases, the foam cells showed strong CD68 immunoreactivity. CD68 is a monocytichistiocytic cell marker, confirming the possible role of macrophages in the formation of typical foam cells. Another proof of their mesodermal origin is that foam cells are strongly stained by vimentin. S-100 proteinpositive dendritic cells (Langerhans' cells) were not observed in previous reports11,12,15 and our results were also in accordance. The etiology and pathogenesis of oral VXs are still far from being clarified. Zegarelli et al. and others2,13,16-18 introduced the concept that lipidcontaining macrophages accumulate due to epithelial degeneration. The products of epithelial breakdown elicit an inflammatory response and a subsequent release of lipid material through epithelial degeneration, which is finally scavenged by macrophages. Travis et al.6 suggested that xanthoma cells are macrophages responsible for removing lipids that accumulate in the submucosal tissues, and that the epithelial hyperplasia is a secondary event. VXs were suggested to be a local immunologic disorder by Mostafa et al.12 Mohsin et al.19 considered that the possible viral infection of the oral cavity and genital skin was similar to an HPV infection. Khaskhely et al.20 reported a case of a VX associated with HPV type 6, but this is not consistent with the research of many other workers or our own3,11,21-23. The HPV is a fairly ubiquitous organism and can be isolated from apparently normal tissue24,25 even in up to 55% of people in Zhang’s report26. Further studies are needed to determine whether HPV plays a role in the pathogenesis of VX or is merely coincidental. The clinical features of VXs are non-specific. The papillary or verrucous outer appearance often leads to a clinical misdiagnosis of a papilloma (cases 1 and 2) or verrucous hyperplasia (case 3). A correct diagnosis is almost always made during the histologic examination. Histopathologically, VXs can be misdiagnosed as verruca vulgaris, a granular cell J Dent Sci 2007‧Vol 2‧No 4 Verruciform xanthoma of the oral mucosa tumor, condyloma accuminatum, or verrucous carcinoma2,20. Differentiating verrucous carcinoma from a VX is important, especially in small superficial lesions, which could lead to an inappropriate and excessive surgical intervention. VXs show papillomatosis with parakeratotic squamous epithelium and a hyperplastic epidermis without atypia. In verrucous carcinoma, the characteristic xanthoma cells are absent; furthermore, the epidermal downgrowth takes the form of bulbous processes rather than relatively narrow ridges2. Treatment of a VX consists of simple surgical excision. The prognosis for VXs is excellent. ACKNOWLEDGEMENTS The authors thank the Yuan-Shan Research Institute, King Car Food Industrial Co., Ilan, Taiwan and Mr. Lee Bor-Heng for the detection of HPV in the study. 11. 12. 13. 14. 15. 16. 17. 18. REFERENCES 1. Shafer W. Verruciform xanthoma. Oral Surg, 31: 784-789, 1971. 2. Philipsen HP, Reichart PA, Takatac T, Ogawac I. Verruciform xanthoma – Biological profile of 282 oral lesions based on a literature survey with nine new cases from Japan. Oral Oncol, 39: 325-336, 2003. 3. DE Rosa G, Barra E, Gentile R, Boscaino A, Diprisco B, Ayala F. Verruciform xanthoma of the vulva: case report. Genitourin Med, 65: 252-241, 1989. 4. Young CHE, High AS. Verruciform xanthomatosis. 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