Foam cells in verruciform xanthoma: A pathognomonic histopathological attribute
Year: 2025
Type: article
Abstract: Foam cells, also referred to as xanthoma cells, originate from the dysregulation of lipid metabolism within mammalian macrophages. When lipid influx surpasses the macrophages’ ability to sustain homeostatic equilibrium, excess lipids become sequestered into intracellular droplets. This progressive lipid accumulation results in the formation of numerous vacuoles within the cytoplasm, imparting the characteristic foamy morphology that defines these cells histologically.[1] The mechanisms underlying foam cell biogenesis exhibit variability depending on the specific disease context. In the context of oral lesions, the emergence of foam cells does not correlate with disruptions in lipid metabolism. Foam cells stain positively with Periodic Acid-Schiff (PAS) and remains diastase-resistant, suggesting that the intracellular material is not glycogen. Origin of Foam Cells in Oral lesions is depicted in Figure 1.Figure 1: Origin of foam cells in oral lesionsFoam cells are observed in variety of oral lesions, including, radicular cyst, periapical granuloma, giant cell granuloma and verruciform xanthoma. Among them, Verruciform Xanthoma (VX) is an uncommon, papillary or exophytic lesion predominantly affecting the oral mucosa. With an incidence of merely 0.025%–0.05% of all pathology cases.[2] VX manifests as a well-circumscribed, asymptomatic lesion with a subtle elevation above the surrounding mucosa. It primarily affects the gingiva, exhibiting a distinct surface architecture that may appear papillary, granular, or verrucous.[3] The lesion’s coloration varies from soft pink to deep red, influenced by epithelial thickness and underlying vascularity. However, its histopathological characteristics serve as definitive diagnostic markers. Extraoral manifestations are exceedingly rare, with only a limited number of reported cases. When occurring outside the oral cavity, verruciform xanthoma is typically linked to underlying systemic conditions such as lymphedema, epidermal nevi, and Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD) syndrome, highlighting its potential association with broader dermatological and developmental anomalies.[4] Apart from that, its occurrence also has been linked to mucocutaneous or inflammatory conditions such as snuff dipper’s keratosis, oral pemphigus vulgaris, carcinoma in situ, regressive dystrophic epidermolysis bullosa, lichen planus, solar keratosis, and discoid lupus erythematosus.[5] This coexistence underscores the potential interplay between VX and underlying pathological processes, necessitating a meticulous clinical and histopathological assessment to delineate its broader etiopathogenic significance. Clinically, verruciform xanthoma is indistinguishable from squamous papilloma, verrucous carcinoma, verruca vulgaris, verrucous leukoplakia, condyloma acuminatum and in some cases, squamous cell carcinoma.[6] The definitive diagnosis of verruciform xanthoma is established through characteristic histopathological findings. Histopathologically, VX lesions manifest as either flat or subtly elevated structures, characterized by a verrucous or papillomatous surface lined with parakeratinized epithelial cells [Figure 2]. The epithelial rete ridges demonstrate uniform elongation, extending into the lamina propria with a consistent depth, contributing to the lesion’s distinct architectural pattern.[7] The quintessential histopathological hallmark is the profuse accumulation of xanthoma cells—large, lipid-laden macrophages distinguished by their finely vacuolated, foamy cytoplasm [Figure 3]. These cells are predominantly localized within the connective tissue papillae, where they extend toward the epithelial interface, imparting a unique histoarchitectural pattern crucial for definitive diagnosis.[8] The precise etiology and pathogenesis of VX remain elusive, despite extensive investigations into its molecular architecture and immunohistochemical profile. However, two principal hypotheses have been postulated in the literature. Zegarelli et al. proposed that the accumulation of lipid-laden macrophages results from epithelial cell degeneration, wherein the degradation of epithelial components releases lipid material that is subsequently engulfed by macrophages. Conversely, Nowparast et al. suggested that the distinctive verrucous and papillary epithelial architecture characteristic of VX arises secondary to the presence of foamy macrophages, which modulate epithelial metabolism and precipitate hyperkeratotic alterations. Both theories underscore a dynamic crosstalk between macrophages, keratinocytes, and chronic inflammatory processes.[9] In the context of epithelial hyperplasia, the apparent elongation of rete ridges is regarded as an optical misinterpretation rather than a genuine downward proliferation of epithelial cells. Instead, this phenomenon is attributed to the upward displacement induced by an underlying aggregation of macrophages, exerting pressure on the overlying epithelium. As a result, it reflects a progressive thinning of the epithelial layer above the macrophage-enriched connective tissue papillae.[10]Figure 2: Photomicrographs of verruciform xanthoma showing (a) numerous foam cells in the lamina propria (×40), (b) foam cells (×100), and (c) Foam cells with lipid-laden cytoplasm (×400)Figure 3: (a) Photomicrograph of verruciform xanthoma showing foam cells with pale eosinophilic to foamy cytoplasm and round to flattened nuclei (×400), and (b) A hand drawn illustration of foam cellsVX represents a chronic reactive process that necessitates differentiation from a spectrum of hyperplastic lesions of oral cavity. Accurate pathological recognition is imperative, as misdiagnosis may lead to unnecessary aggressive interventions. The standard management approach for VX involves conservative surgical excision, with a low recurrence rate reported post-resection. Unlike true neoplastic lesions, VX does not exhibit malignant potential, underscoring the importance of distinguishing it from more aggressive pathologies. Therefore, a thorough histopathological assessment is essential to ensure appropriate treatment planning, prevent overtreatment, and optimize patient outcomes. In summary, the identification of foam cells within oral lesions constitutes a pivotal histopathological feature with significant diagnostic, prognostic, and pathophysiological implications. These lipid-laden macrophages serve as critical biomarkers, not only enabling precise differentiation of various oral pathologies but also elucidating the intricate interplay of chronic inflammation, tissue remodelling, and reparative mechanisms. Their distribution, persistence, and morphological characteristics provide valuable insights into the lesion’s chronicity, underlying pathogenic mechanisms, and potential disease trajectory, thereby enhancing the depth of diagnostic interpretation and clinical correlation. Author Contributions KM, DA and SSV: Concepts, design, definition of intellectual content, literature search, manuscript preparation, manuscript editing, manuscript review, guarantor. Financial support and sponsorship Self-supported. Conflicts of interest Nil.
Authors: Kuntala Mondal, Dominic Augustine, S. V Sowmya
Institution: M S Ramaiah University of Applied Sciences
Language: English
Subfield: Oral Surgery
Field: Dentistry
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7117387804