Dermatology Online Journal

Flat type verruciform xanthoma of the tongue and its differential diagnosis
Ozgur Mete¹, Esma Kurklu², Bilge Bilgic¹, Hayati Beka³, Meral Unur²
Dermatology Online Journal 15 (9): 5

1. Istanbul University, Istanbul Faculty of Medicine, Department of Pathology
2. Istanbul University, Faculty of Dentistry, Department of Oral Medicine and Surgery
3. Istanbul University, Istanbul Faculty of Medicine, Department of Microbiology
Istanbul, Turkey. ozgurmete77@gmail.com

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Abstract

We present herein a case of oral verruciform xanthoma (VX) in order to discuss this relatively rare entity in light of currentinformation. A 38-year-old woman, non-smoker, presented with a lesion at the left ventral surface of the tongue. The lesion is characterized by a mild epithelial proliferation and sub-epithelial accumulation of foam cells, which were positive for CD68, and negative for CD1a and S-100 protein. Human papillomavirus (HPV) DNA typing for low, intermediate, and high-risk groups was also performed and no etiological link between HPV and this lesion was found. The past medical history of the patient was unremarkable and further investigations did not reveal any biochemical abnormalities or systemic disease. Verruciform xanthoma is an uncommon benign lesion of undetermined etiology. It is a superficial normolipemic xanthoma, probably reflecting a multifactorial reactive and dystrophic process unrelated to HPV. It is noteworthy that in a small and superficial biopsy, xanthoma cells may be scanty and can be missed, especially if the pathologist is unfamiliar with the existence of this uncommon lesion. Its clinical and pathological recognition and correct diagnosis is critical because VX can occur in conjunction with other systemic and cutaneous inflammatory diseases; therefore, it necessitates further clinical assessment.

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Introduction

Verruciform xanthoma (VX) is an uncommon benign lesion of adults and was first described by Shafer in 1971 in the oral mucosa [1]. Subsequently, extra-oral cases have been reported in the anogenital mucosa and skin including vulva, penis, and scrotum [2, 3, 4]. Oral VX presents as a demarcated, granular, soft, and asymptomatic lesion exhibiting a flat to papillary or verrucous surface. Verruciform xanthoma can be solitary or multiple and can be found in masticatory mucosal sites with a predilection of involvement in the gingival margin, hard palate, and tongue [5, 6, 7]. Irrespective of the intra- or extra-oral location of the lesion, the accumulation of lipid-laden macrophages or foamy histiocytes (xanthoma cells) in the elongated connective tissue papillae between the acanthotic squamous epithelial ridges of uniform depth is the characteristic microscopic feature of VX [4, 8]. Despite the distinct histological findings, the clinical differential diagnosis of VX encompasses several benign and malignant lesions. We discuss the diagnostic pitfalls and pathogenesis of this rare entity in light of information from the literature.

Case report

Figure 1	Figure 2
Figure 1. Slightly elevated yellowish lesion on the left ventral surface of the tongue Figures 2 & 3. Focal parakeratosis, mild epithelial acanthosis with regularly elongated rete and xanthoma cells within the connective tissue papillae (H&E)

Figure 3	Figure 4
Figure 4. CD68 immunopositivity in xanthoma cells (anti-CD68)

A 38-year-old non-smoking female presented with a lesion at the left ventral surface of the tongue, that exhibited a mild dull pain, that she first noticed 2.5 months prior to seeking medical care. The plaque was about 1 cm in size, yellowish-pink colored, and slightly elevated with an irregular surface consisting of numerous papulesthat resembled fish eggs (Fig. 1). Her past medical history, including her family history was unremarkable. No history of frank trauma to the relevant side of the tongue was declared. Because the clinical features were not suggestive of any specific and usual oral lesion, diagnostic punch biopsy was performed. Histopathological examination revealed focal parakeratosis, mild epithelial acanthosis with regularly elongated rete and subepithelial cellular infiltrates composed uniformly of foamy macrophages, which were positive for CD68, and negative for S-100 protein, CD1a, and epithelial membrane antigen (Figs. 2-4). The morphological features were consistent with a flat-plaque type oral VX. Human papillomavirus DNA was not detected in the lesion using two different kits (digene HPV HC2 DNA test and DNA chip-Papillocheck HPV Screening). Blood studies including glucose, triglycerides, and cholesterol determinations revealed normal ranges. Further clinical assessment of the patient did not reveal any associated disease. The complete excision of the lesion was performed and no recurrence has occurred one year after surgery.

Discussion

Xanthomas represent the accumulation of lipid-rich histiocytes (macrophages) known as foam cells. The lipids in xanthomas are primarily free and esterified cholesterol, but occasionally other sterols and even triglycerides accumulate [4]. This is usually the result of a high plasma concentration with subsequent permeation of lipoproteins through the walls of capillaries. The lipid is taken up by macrophages, which evolve into foam cells [4]. Xanthomas are usually associated with disorders of lipoprotein metabolism. However, there are subtypes of xanthomas occurring in a normolipemic condition. Although Travis et al. reported a case of multifocal VX in association with an undefined systemic lipid storage disease, the majority of VX patients have normal lipid metabolism [4, 7].

Verruciform xanthoma has been reported in patients with HIV-1 infection and in association with HPV type 6. However, attempts to detect the association between oral VX and HPV-DNA by in situ hybridization have failed in the majority of the case series [2, 4, 9, 10].

Interestingly, several concomitant oral and skin lesions have been described in patients with VX, which are oral discoid lupus erythematosus, lichen planus, dystrophic epidermolysis bullosa, epidermal nevi, leukoplakia, focal acantholytic dyskeratosis, pemphigus vulgaris, and chronic GVHD (graft-versus-host disease) [4, 11-15]. It is noteworthy that most of them are closely associated with basal membrane destruction and epithelial cell damage; therefore the presence of concomitant VX lesions in such patients may be explained hypothetically by a secondary or "dystrophic" phenomenon. Moreover, xanthoma cells have been reported in injury sites, such as scars or bites, and in areas of chronic inflammation, such as atopic dermatitis and contact dermatitis, irrespective to the patient lipid profile [4, 16].

However, Hu et al. have investigated the role of matrix metalloproteinase (MMP-2 and -9) and the accumulation of foam cells in VX lesions and suggested that the latter is mediated partly by an immune mechanism associated with MMPs, which degrade basal membrane of the epithelium and promote a reciprocal induction between the mesenchymal and epithelial cells [17]. Subsequently, Ide et al. have investigated the role of local factors that regulate selective recruitment and persistent accumulation of foamy macrophages in the subepithelial area. They suggested that under synergistic regulation of T cells, macrophage recruitment in the sub-basal mesenchyme and the lysosomal engulfment of epithelial lipids by macrophages are essential in the formation of the VX lesion. Once it is developed, oxidized-LDL induced foam cells and macrophage-dependent debris disposal may clinically perpetuate VX [18].

Because VX can be found in a wide variety of disorders, such as certain inflammatory disorders and some rare syndromes, a reactive phenomenon rather than a neoplastic process is more likely the explanation of this histological finding. In light of previous studies, the formation of xanthoma cells reflects a secondary phenomenon, probably related to the degeneration or damage of cells in the overlying epithelium. Moreover, this event is regulated by local tissue factors and leads to uptake of the keratinocyte lipid by dermal macrophages or fibroblasts to form the foam cells. However, further molecular studies will clarify this issue and will help to identify trigger factors, which interact with the local tissue factors.

Irrespective of the intra- or extraoral location of the lesion, the diagnostic hallmark of VX is the presence of xanthoma cells within the connective tissue papillae. Yet, three histological subtypes (types A, B, and C) have been described based on the texture of the surface epithelium [5, 8, 19]. Lesions of the verrucous type (type A) are usually elevated and do not show a thickened stratum granulosum. There is hyperparakeratosis, verrucous-type acanthosis, and elongation of the rete ridges. The papillary form (type B) has many finger-like projections composed of stratified squamous epithelium containing connective tissue cores and forming crypt-like spaces covered by parakeratosis. In the flat type (type C), mild acanthosis and subtle-thin parakeratosis with variable elongation of rete ridges are commonly observed [5, 8, 19].

It is important to stress that the clinical features of VX are non-specific, irrespective of an intra- or extraoral location, and the vast majority of VX cases are detected as asymptomatic white-to-yellowish lesions. Because of the level of surface keratinization, its color may vary from white to red. The center of the plaque can appear depressed, cup-shaped or crateriform, with or without ulceration. Although relatively flat lesions can be seen, similar to the case presented, the majority exhibit a prominent papillary and verrucous appearance [5, 8]. Therefore, oral VX may resemble a squamous papilloma, verruca vulgaris, or a mucosal fibroma [5, 8]. Because of its verrucous nature, verrucous carcinoma should be also added to the list of differential diagnoses. The variation in the clinical appearance of these lesions and its rarity are factors making its clinical recognition problematic. Histopathological confirmation is required. However, verrucous carcinoma can be distinguished from VX, by the presence of invasive epithelial proliferation, cellular atypia, and the lack of foamy histiocytic infiltrate. Less aggressive clinical diagnoses such as squamous cell papilloma, verruca vulgaris, and condyloma acuminatum must alsobe kept in mind. These entities do not contain lipid-laden macrophages and they exhibit varying degree of viral cytopathic change, so called koilocytic change, which are known to be absent in VX. In addition to this, the rete ridges in condyloma acuminatum and verrucous carcinoma tend to be bulbous, as opposed to the long and slender ones in VX [8].

The pathologist must not confuse xanthoma cells with lingual dorsum taste buds in the connective tissue papillae; however differentiation from other maxillofacial lesions with foamy or granular histiocyte-like cells is not difficult because VX is the only lesion to have these cells confined to the papillae. On the other hand, granular cell tumor may mimic oral VX because it exhibits pseudoepitheliomatous hyperplasia and is characterized by an extensive granular histiocyte-like cellular infiltrate. However, granular cell tumor typically presents with a subepithelial zone free of such cells.

Differential diagnosis of cutaneous VX includes mainly verruca vulgaris, other xanthoma types, and non-Langerhans cell histiocytoses [4, 20]. Tuberous xanthoma, tendinous xanthoma, and xanthelasma demonstrate relatively similar histology that is composed of foam cell infiltration in the dermis and lack the accompanying lymphocytic, neutrophilic, and eosinophilic infiltrate, which is usually seen in eruptive xanthoma and non-Langerhans cell histiocytoses [20] (Table). It is noteworthy that epidermal hyperplasia, which is present in cutaneous VX, is absent in other xanthoma types [20].

Verruciform xanthoma is usually treated by a conservative excision. To date, only three cases of recurrence have been reported [8]. One patient, a heavy smoker, has been reported as developing a VX recurrence within an in situ carcinoma of the posterior floor of the mouth [21]. However, there is no evidence of that VX is a precancerous lesion.

Conclusion

Verruciform xanthoma is characterized by a superficial normolipemic mucocutaneous xanthoma, probably reflecting a multifactorial chronic reactive process unrelated to HPV. Therefore, the current literature findings suggest that VX may be a clinical variant of dystrophic xanthoma. Dentists, dermatologists, or ENT specialists may confront asymptomatic VX lesions in the routine clinical examination. The clinical diagnosis may be challenging; however, the histological features are diagnostic and well defined. It is noteworthy that in a small and superficial biopsy, xanthoma cells may be scanty and their presence can be missed, especially if one is unfamiliar with the existence of this lesion [8]. Its recognition and correct diagnosis is critical because VX can occur in conjunction with systemic and cutaneous inflammatory diseases; further clinical assessment for these is required.

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