Ⅰ. INTRODUCTION

Verruciform xanthoma (VX) is a rare benign lesion of oral mucosa with unclear etiology.^1-5) It mainly occurs in the oral cavity, but can also be found on the penis,⁶⁾ vulva,⁷⁾ and skin.⁸⁾ Oral VX usually appears as an asymptomatic, small, and solitary mass with flat or pedunculated surface.^1-4) Lesion color ranges from pinkish red to gray. It is often clinically confused with papilloma, leukoplakia, condyloma, verruca vulgaris, verrucous carcinoma, or squamous cell carcinoma.^1-4) Histopathologically, VX is characterized by papillary or verrucous proliferation of squamous epithelium with varying degrees of parakeratosis and abundant foamy cells, also called xanthoma cells, confined in the submucosal stroma.^1-4) Here we report 4 cases of oral VX with different clinical features with similar histopathological characteristics to emphasize the importance of differential diagnosis.

Ⅱ. CASE REPORTS

Four cases of oral VX were retrieved from medical records at the department of oral and maxillofacial surgery, Kyungpook National University Dental Hospital. The clinical features of the patients are described in Table 1.

Case 1

A man aged 39 years presented at our institution in 2016 with sore pain on the right maxillary hard palate. At first, he was referred to the department of periodontics because he was a heavy smoker and his diagnosis was considered to be periodontitis. The periodontics practitioner referred him to the department of oral and maxillofacial surgery for biopsy. On intraoral examination, a reddish plaque-like lesion approximately 1.4 × 1.9 cm² was found on the hard palate adjacent to #16-17 palatal gingiva (Fig. 1A). The surface was granular with mild ulceration. The patient complained of sore pain on palpation and chewing food on the right side. Excisional biopsy was performed with a provisional diagnosis of squamous cell carcinoma. Microscopy showed polyps overlaid by flat and hyperkeratinized stratified squamous epithelium covering a core containing accumulation of xanthomatous histiocytes (Fig. 2A, B). The diagnosis was oral VX. Healing was favorable after total excision, but whitish lesions appeared on the site of operation after 6 months. The patient made an appointment for a rebiopsy but did not show up.

Case 2

A 73-year-old female patient reported with a painless, hyperplastic lesion located in the anterior part of the Mn. alveolar ridge. She used full dentures for both upper and lower dentitions and discovered this lesion only 10 days before. On examination, a reddish-pink verrucous lesion was found with an approximate size of 0.5 × 1.0 cm². This lesion was pedunculated and a clinical diagnosis was squamous papilloma or irritation fibroma (Fig. 1B). Histopathological features showed verrucous proliferation of the stratified squamous surface epithelium with acanthosis and hyperkeratosis overlying the surface. Also, lipid-laden foamy cells, also called xanthoma cells, were gathered in the submucosal connective tissue (Fig. 2C, D). The final diagnosis was oral VX. The healing was good and there has been no recurrence.

Case 3

A 67-year-old man who had undergone liver transplantation had a surgical excision of a granular, plaque-like lesion on the lingual side of gingiva nearby the #34-35 area. The lesion was a reddish-pink color and approximately 0.6 × 2.0 cm² in size. There was no pain, bleeding, or ulceration associated with this gingival lesion (Fig. 1C). On histopathological examination, hematoxylin and eosin staining showed verrucous proliferation of the stratified squamous epithelial cell layer, covered with a hyperkeratotic layer. Lots of xanthoma cells were seen in the connective tissue papillae between epithelial ridges, showing the classic features of oral VX (Fig. 2E, F). After the excision, the operation site required secondary healing and there was no recurrence.

Case 4

An 83-year-old man reported with a chief complaint of gingival growth of the anterior part of the Mn. alveolar ridge. He had planned to have a partial denture remade for lower dentition, but a dentist from a local dental clinic recommended removal of the lesion before prosthodontic treatment. Intraoral examination revealed a solitary, pedunculated, and cauliflower-like growth, measuring about 0.5 × 0.6 cm² (Fig. 1D). This lesion was suspected to be a squamous papilloma at first, but histopathology revealed foamy cells with clear cytoplasm and pyknotic nuclei in the connective tissue (Fig. 2G, H). The final diagnosis was oral VX. He also mentioned a similar lesion on his genital area. After excision, there was no relapse.

Ⅲ. DISCUSSION

Oral VX is an uncommon benign lesion, accounting for 0.025-0.05% of all pathology cases.¹⁾ It was first described by Shafer et al.¹⁾ in 1971, and several cases have been presented in the literature, showing that the lesion can also appear on other sites, such as the penis, vulva, and skin.^6-8) Most commonly, oral lesions occur in middle-aged persons, with the mean age of 40-50 years, and there is no obvious sex preponderance.¹⁾

The mean age of the 4 patients in this study with oral VX was 65.5 years, and a male predominance was shown, with 3 male patients out of 4 people. Oral VX is most often found in gingiva, followed by buccal mucosa, hard palate, and tongue.^1-4) In the present study, 3 cases appeared on gingiva and 1 case was found on hard palate. The common treatment for oral VX is conservative surgical excision and recurrence is seldom reported.^1-4) The patients of this study received surgical excision and no recurrence was reported.

The etiopathogenesis of oral VX is unclear but it seems to be associated with inflammation and conditions other than epithelial trauma.¹²⁾ Viral infection has been considered as another possible etiologic agent, but in situ hybridization for common types of human papillomavirus (HPV) is negative for oral VX.¹²⁾ Therefore, viral etiology is not likely.^10,13) The most prevailing theory for oral VX is that epithelial tissue damage leads to the breakdown of cell membranes, which consist of phospholipids, allowing macrophages to take it up in connective tissue. In VX, these macrophages become foamy cells.^2,3,12)

Clinically, oral VX appears as a solitary papule or plaque showing verrucous or papillomatous mucosal growth with color ranging from pinkish red to gray.^5,9) However, there are a few case reports about multiple oral VX¹⁰⁾ and accompanying lesions on other sites.¹¹⁾ One of our patients mentioned a similar lesion on his genital area. Due to its clinical morphology, oral VX is usually misdiagnosed as a viral wart, as either a premalignant or malignant condition.^5,9) Making a differential diagnosis, including squamous papilloma, verruca vulgaris, verrucous carcinoma, or squamous cell carcinoma, is not easy with the naked eye.^1-4,12,13) Only the known histopathologic feature, the existence of abundant foamy cells confined within lamina propria papillae and not extending below rete pegs, is a distinctive factor for differential diagnosis.^1-4) Microscopically, oral VX was classified into 3 categories by Nowparast et al.,⁵⁾ including: 1) a warty or verrucous appearance, 2) a papillary or cauliflower architecture, and 3) a slightly raised or flat lesion.^5,9)

This classification system was used in the present study. One case showed a flat-type morphology while the others appeared as verrucous-type. Most presented cases can be categorized according to Nowparast et al.’s system,⁵⁾ but there are a few cases not included in these categories. Atypical oral VXs show florid epithelial or pseudocarcinomatous hyperplasia.¹³⁾ In those cases, the diagnosis is dependent on immunohistochemistry. The positivity of CD68 and negativity of S100 are marker patterns for xanthomatous histocytes in the lamia propria.^2,3,12,13) Nontypical lesions also make differential diagnosis difficult.¹³⁾

There have been some cases of oral VX occurring with systemic disease, such as lupus erythematosus¹⁴⁾ and lichen planus¹⁵⁾ or local lesions including carcinoma in situ.¹⁶⁾ One hypothesis is that there are no particular associations between oral VX and the concomitant lesions of oral mucosa, and the disturbance of epithelium, caused by systemic disease or other local lesions, makes patients susceptible to oral VX.^15,16)

In conclusion, practitioners may easily misdiagnose oral VX as a papilloma or malignant tumor because of its clinical features, and therefore biopsy is required to accurately diagnose this lesion. Furthermore, because oral VX may occur other than on gingiva, such as lip, and even concomitant lesions sometimes exist on the skin or genital areas, lesions on other sites should also be carefully examined.