Ⅰ. INTRODUCTION

Oral verruciform xanthoma (OVX) is a rare benign lesion of the oral mucosa, first described by Shafer in 1971 [1]. Clinically, it presents as a papillary or verrucous growth and may resemble squamous papilloma, verruca vulgaris, or even verrucous carcinoma (VC), leading to diagnostic difficulty [2]. Despite this clinical overlap, OVX exhibits distinctive histopathologic features characterized by papillary or verrucous epithelial hyperplasia and the accumulation of lipid-laden foamy macrophages within the connective tissue papillae [2-4].

Although the exact pathogenesis of OVX remains unclear, the lesion is widely regarded as a reactive process associated with chronic irritation, inflammation, or trauma rather than a true neoplasm [5]. Most OVXs are completely cured by local excision, and recurrence is considered rare [2,3].

Here, we describe an unusually large OVX arising from the mandibular gingiva and exhibiting destructive intraosseous extension, a highly uncommon clinical presentation. In addition, we reviewed 28 OVX cases diagnosed at our institution to delineate their clinicopathologic features and broaden the current understanding of this uncommon reactive lesion.

Ⅱ. MATERIALS and METHODS

A total of 40 cases diagnosed as OVX were retrieved from the electronic pathology database of the Department of Oral Pathology, Yonsei University Dental Hospital, between 2005 and 2023. In all cases, the diagnosis was confirmed by histopathological examination of completely excised surgical specimens. After excluding 12 outsourced consultation cases which lacked complete clinical data, the remaining cases (n=28) were included for detailed analysis.

For each case, clinical information – including patient age, sex, lesion location, relevant medical and dental history, and follow-up period – was retrospectively collected. All available slides were reviewed by two oral pathologists (blinded to the original diagnosis) and classified into histologic architectural type – verrucous, papillary and flat – according to the criteria proposed by Nowparast et al. [6]. The degree of inflammatory cell infiltration and the predominant inflammatory cell type (lymphocytes, plasma cells, or neutrophils) were also recorded.

This study was approved by the Institutional Review Board of Yonsei University Dental Hospital (IRB No. 2-2023-0062) and was conducted in accordance with the principles of the Declaration of Helsinki.

Ⅲ. CASE SERIES

Clinicopatholgic characteristics of oral verruciform xanthoma

1. Clinical characteristics

This study included 28 patients (18 males and 10 females; male-to female ratio 1.8:1) with a mean age of 49.2 ± 15.1 years (range, 22-80 years) (Table 1). The gingiva was the most commonly affected site (25 cases, 89%), followed by the tongue (3 cases, 11%); no cases involved the palate. Among gingival lesions, lesions on the maxilla were approximately 2.5 times more frequent than those on the mandible. Most OVXs were solitary and asymptomatic.

An autoimmune disease was identified in two patients (7%): one with oral lichen planus and another with Sjögren’s syndrome. Malignancy was identified in two patients (7%): one with a previous history of oral squamous cell carcinoma (OSCC) and another with concurrent OSCC. An association with prosthetic restorations was noted in four patients (14%).

The mean clinical follow-up period was 10.0 months (available for 12 patients). Reappearance of OVX was noted in four cases with a mean interval of 20.5 months after first excision, although at least two of these were regarded as residual lesion due to incomplete excision rather than true biological recurrence.

2. Histopathological characteristics

Histopathologic review classified the OVXs into verrucous (17 cases, 61%) and papillary (11 cases, 39%) types; the flat type was not observed. The degree of inflammation was graded as mild in 10 cases (36%), moderate in 16 (57%), and severe in 2 (7%). Lymphocytes were the predominant inflammatory cells in most cases (75%), whereas plasma cells (21%) and neutrophils (4%) were occasionally admixed. No cytologic atypia or dysplasia was identified in any specimen.

3. Rare case of giant oral verruciform xanthoma

A 61-year-old male with no significant medical history was referred to our hospital for evaluation of recurrent papillary lesion in the left mandibular molar region. Approximately three years earlier, a papillary lesion on the adjacent gingiva had been clinically diagnosed as squamous papilloma at the time of tooth extraction (Fig. 2A). After extraction, the lesion failed to heal properly and recurred repeatedly at the same site. Although multiple subsequent biopsies performed at the other institution revealed only pseudoepitheliomatous hyperplasia, the patient continued to complain of persistent swelling, bleeding, and pain. Radiographic evaluation demonstrated a massive, expansile lesion causing severe bone destruction, prompting referral to our institution for definitive surgical management.

At presentation to our institution, the extraction site on the left posterior mandible showed a non-healing ulcerative lesion with fibrin exudate and granulation tissue filling the socket (Fig. 2B). Panoramic and contrast-enhanced CT images demonstrated a well-demarcated, encapsulated mass with heterogeneous enhancement, extending from the alveolar ridge to the ascending ramus to the coronoid process (Fig. 2C, D). The lesion appeared as a benign tumor of indeterminate origin; however, given its unusually large size and extensive bone destruction, complete excision was planned to rule out possible malignant transformation.

Under general anesthesia, complete excision of the mass was performed, followed by reconstruction using an anterolateral thigh (ALT) free flap. Grossly, the mass was encapsulated by fibrous tissue but had ruptured during surgery, revealing papillary projections extending into a lumen-like cavity with a whitish-to-tan surface (Fig. 3A). Microscopically, the lesion showed papillary epithelial hyperplasia overlying numerous xanthomatous histiocytes aggregated within the connective tissue papillae (Fig. 3B, C). The overlying epithelium exhibited focal basal cell hyperplasia, yet no invasive growth, epithelial dysplasia, or cellular atypia was identified, consistent with benign proliferative process. The underlying stroma was densely infiltrated with chronic inflammatory cells and surrounded by thick fibrous tissue. At the periphery, the lesion caused pushing-type bone resorption without infiltrative margins. Immunohistochemically, the foamy histiocytes showed strong cytoplasmic positivity for CD68, confirming their macrophage origin (Fig. 3D).

Based on these features, the lesion was diagnosed as an oral verruciform xanthoma. The postoperative course was uneventful, and the patient remained free of recurrence for 2 years of follow-up.

Ⅳ. DISCUSSION

OVX is an uncommon benign lesion of the oral mucosa, first described by Shafer in 1971 [1]. Clinically, OVX usually appears as small, well-circumscribed, papillary or verrucous plaque, most frequently involving the gingiva and alveolar mucosa. The vast majority of OVXs are less than 1cm in diameter, are cured by simple excision, and rarely recurred. Histologically, OVX is characterized by papillary epithelial hyperplasia and the accumulation of lipid-laden foamy macrophages in the connective tissue papillae-features that are considered pathognomonic [2,3]. In this study, we reviewed 28 cases of OVX diagnosed at our institution including an unusual giant variant associated with extensive bone destruction.

OVX is relatively common in middle-aged male patients, but it can occur at any age, with a male-to-female ratio of approximately 1:1 [2,3,7]. Although it can arise at cutaneous sites, often involving the genital region, the majority of cases develop within the oral cavity [2,8]. The gingiva is the most frequently affected site, followed by the palate, tongue, buccal mucosa, vestibule, lip, and floor of mouth [2,3,7]. Multiple lesions have been reported [7], but most cases are solitary. Similar results were found in this study.

The pathogenesis of OVX is considered reactive rather than neoplastic. OVX frequently arises in sites subjected to chronic irritation or trauma, and its characteristic foamy cells represent CD68-positive macrophages that have phagocytosed lipid debris from degenerating keratinocytes. Although direct clonality studies are lacking, OVX consistently shows a very low proliferative index and no evidence of autonomous epithelial growth, supporting the concept of reactive epithelial hyperplasia with secondary xanthomatous change [4]. Earlier hypotheses linking OVX to systemic lipid disorder have been refuted, as accumulated lipid is derived locally from epithelial breakdown rather than circulating lipids [2]. In line with these assumptions, associations with autoimmune diseases, including lichen planus [9,10], as well as malignancy [11,12] have been reported. Similar findings were noted in this study.

OVX often mimics other papillary or verrucous lesions clinically, but its pathogenesis is distinct from human papilloma virus (HPV)-related benign epithelial proliferation such as squamous papilloma or verruca vulgaris. Multiple studies using in situ hybridization and polymerase chain reaction (PCR) have demonstrated no detectable HPV DNA in OVX [13,14], and the giant OVX case also showed negative p16 immunoreactivity (data not shown), arguing against a HPV-driven neoplastic process. OVX is best interpreted as a localized mucosal injury response rather than a true clonal neoplasm, similar to genital verruciform xanthoma [2].

Recurrence of OVX is extremely rare, with recent large series reporting only a few recurrent cases [2,15-17]. In contrast, this study demonstrated a higher reappearance rate (4 cases), prompting reconsideration of the factors contributing to repeated lesions. However, slide re-evaluation revealed that two of these cases showed presence of OVX at the resection margins, indicating incomplete excision. Among the remaining two cases, one occurred adjacent to a fixed dental prosthesis, suggesting that persistent mechanical irritation may have promoted new reactive epithelial proliferation. The other lacked identifiable predisposing factors, however, its marked subepithelial inflammation with plasma cell infiltrate suggests that even subtle or unrecognized mucosal stress may allow OVX to re-emerge. Collectively, these findings indicate that the reappearance of OVX in this study was largely attributable to residual lesion or ongoing local irritation, rather than the intrinsic biological behavior of OVX.

In this study, OVX lesions demonstrated variable but predominantly mild to moderate subepithelial inflammation. Lymphocytes were the predominant inflammatory cells in mild inflamed cases, whereas plasma cells became more apparent with increasing inflammatory severity. As plasma cells arise only after sustained antigenic stimulation and B-cell activation, their presence is generally interpreted as a marker of longer-standing or repetitive mucosal injury [18], consistent with the prevailing view of OVX as a lesion associated with chronic epithelial stress.

In the giant OVX case, due to the papillary and verrucous architecture and significant bone destruction, it was necessary to carefully exclude verrucous carcinoma (VC) or other papillary epithelial neoplasms. However, the absence of invasive growth or epithelial dysplasia, with the characteristic accumulation of CD68-positive foam cells, supported a diagnosis of OVX rather than epithelial tumors. To our knowledge, xanthomatous change is not a recognized feature of VC of the oral cavity [19,20]. Although some reports describe verruciform xanthoma occurring adjacent to carcinoma in situ or conventional carcinoma [11,12], this xanthomatous change is not involved in these epithelial malignancies. Therefore, it was established as OVX rather than an epithelial neoplasm.

The unusual large size of the giant OVX case raises important considerations about the behavior of OVX. Although OVX is generally regarded as a benign and superficial reactive lesion, this case suggests that persistent irritation combined with incomplete removal of a pre-existing lesion may allow itself to undergo slow but continuous expansile growth. The clinical history – initial papillary proliferation at the time of tooth extraction, repeated postoperative inflammation, and progressive enlargement within an unhealed socket – supports a model in which residual epithelial components became entrapped in an inflamed environment, resulting in prolonged epithelial turnover and macrophage-mediated lipid scavenging.

Clinically, this case, together with the reappearance pattern observed in the case series, highlights an important practical message. Even though OVX is typically small and cured by simple excision, residual epithelial components in a persistently inflamed site can generate a slowly expanding reactive lesion capable of adjacent tissue destruction, as seen here. Therefore, complete removal and histopathologic evaluation are essential.