Verruciform Xanthoma

Updated: Nov 07, 2019
Author: W Clark Lambert, MD, PhD; Chief Editor: William D James, MD 



Verruciform xanthoma is an uncommon lesion with a predilection for the oral mucosa of middle-aged persons or on the scrotum of middle‒aged-to-elderly Japanese men. The most common site for verruciform xanthoma is the oral mucosa. Extraoral verruciform xanthoma is extremely uncommon; it has been reported on the anogenital skin such as the vulva, scrotum, penis, and extremities.[1, 2] Lesions on the perineum or on the skin often have some predisposing factor, such as lymphedema[3] or an epidermal nevus.[4, 5] Verruciform xanthoma can also occur in association with CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome.[6]

Most commonly, the lesion has a verruciform appearance, but it may appear polypoid, papillomatous, or sessile. Rarely, verruciform xanthomas have been found to occur in cysts. The primary distinguishing feature of verruciform xanthoma is the presence of large numbers of lipid-laden foamy histiocytes in, and essentially limited to, the connective-tissue papillae in the lesion.

Note the image below.

Xanthelasma. Courtesy of Duke University Medical C Xanthelasma. Courtesy of Duke University Medical Center.


The pathophysiology of verruciform xanthoma remains unknown.


The etiopathogenesis of verruciform xanthoma remains largely unknown. Many authors consider it a reactive process rather than a true neoplasm. In this respect, it may be analogous to malakoplakia occurring in the urinary bladder and elsewhere. Damage to the squamous cells with increased epithelial cell turnover, leading to the deposition of epithelial cell debris that is engulfed by macrophages in the corium, may lead to the development of this lesion. Rawal et al reported that the histologic changes in verruciform xanthomas resemble those of a chronic reactive process.[7]

An immunologic etiology has also been proposed. Khaskhely et al reported a case of verruciform xanthoma associated with human papillomavirus (HPV).[8] Studies using DNA sequencing technology, however, have been negative for viral signal. It has been proposed that several etiopathogenic mechanisms may produce this disorder.[8, 9]

Ide et al report on the development of verruciform xanthoma related to oxidized low-density lipoprotein, suggesting that macrophage-dependent debris disposal may perpetuate verruciform xanthoma.[10]

Zegarelli et al[11] and Mohsin et al[2] have suggested that an unknown inciting agent, potentially trauma, leads to keratinocyte damage and the release of chemotactic chemokines, which attract neutrophils to the site, facilitating keratinocyte degradation. The necrotic neutrophils and keratinocyte debris are phagocytized by macrophages, leading to the eventual formation of foam cells. Further study is needed.[1]

Ide et al and others have suggested possible oral agents such as a wet microenvironment, periodontal pathogens, mechanical stimuli, tobacco, alcohol, drugs, sensitizing or allergic substances or foodstuffs, and dental materials may play a role.[12, 10] Shahrabi Farahani et al has suggested that the histopathological process might be associated with immunosuppression related to chronic oral inflammatory lesions.[13] Poor oral hygiene may be a risk factor.[14]

There have been at least six cutaneous cases reported of verruciform xanthoma in immunocompromised patients, with a proportion greater than expected considering the low prevalence of cutaneous lesions. A suggested explanation is that immunocompromised patients may have a lower number of epidermal Langerhans cells, which results in decreased removal of degenerated keratinocytes and increased dermal macrophage phagocytosis.[15, 16]



Verruciform xanthoma is uncommon, with a frequency of 0.025-0.095%.[17, 18, 19] To date, at least 300 cases have been reported in the oral cavity,[19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29] seven on the lip,[30, 31, 32] 24 on the penis,[1, 2, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54] 20 on the vulva,[40, 55, 56, 57, 58, 59, 60, 61, 62, 63] one in the anal region,[64] three on the nose or nasal vestibule,[65, 66] two on the ear,[67] four on the distal extremities (including three on the feet),[68] and individual cases elsewhere on the skin. At least 23 cases have been reported on the scrotum, almost all of them in Japanese men.[69, 70, 71] Three cases of esophageal verruciform xanthoma have been reported.[40, 72, 73, 74] A single case of multiple verruciform xanthoma lesions has been reported in internal organs; the lesions were in the upper aerodigestive tract of a child with a systemic lipid storage disease.[75]


Most cases of verruciform xanthoma are reported in whites, but blacks are also affected.[76] Most scrotal cases of verruciform xanthoma occur in middle‒aged-to-elderly Japanese men. This may be caused by chronic pressure associated with the Japanese tradition of sitting on the floor.[70]


Verruciform xanthoma has a slight male predominance,[17, 12] and it also has a tendency to occur on the scrotum of middle‒aged-to-elderly Japanese men.


Most oral cases of verruciform xanthoma occur in middle-aged persons (mean age, 40-60 y), and most scrotal cases occur in middle‒aged-to-elderly Japanese men (mean age, 65 y). However, the age at occurrence varies widely; verruciform xanthoma can occur in persons aged 2.5-89 years.[62]

Verruciform xanthoma is exceedingly rare in children aged 10 years or younger, except in epidermal nevi or in the context of CHILD syndrome.


The prognosis for verruciform xanthoma is excellent after local surgical excision, and verruciform xanthoma typically does not require medical, chemical, or radiological treatment after surgery.[77] Recurrence is rare.

Patient Education

Patients should be reassured after adequate excision and accurate diagnosis that verruciform xanthoma is cured.




Patients usually present with a history of an asymptomatic or tender lesion on the skin or mucosa.

Physical Examination

The clinical appearance of a verruciform xanthoma is not diagnostic; the diagnosis is almost always made at histologic examination. Depending on the nature of the individual lesion, verruciform xanthoma may clinically resemble any verrucous, papillary, or lichenoid oral lesion, particularly any such lesion that is also hyperkeratotic. It is frequently misdiagnosed at clinical examination as a papilloma.

The lesion may appear as a verrucous, papillary, or flat-to-lichenoid process varying from 0.2-2 cm in diameter, although one lesion 4 cm in diameter has been reported. A giant verruciform xanthoma measuring 15 cm x 20 cm was reported in a 54-year old man with developmental delay.[78] Depending on the degree of keratinization, the xanthoma may appear gray to reddish pink. The process may be pedunculated but usually is sessile. At least two cases occurring in cysts have been reported.

Although almost any part of the mouth may be involved, the alveolar ridge, hard palate, and gingiva have been noted as preferential sites.[79] Because of this predilection, inflammation caused by mild trauma has been proposed to play a role in the etiopathogenesis.[28, 41] A second hypothesis suggests that the verrucous and papillary epithelial architecture may be secondary to the presence of foamy cells, which affect the metabolism of the epithelial cells, leading to hyperkeratotic change.[28, 80]

The lesions that occur on the oral mucosa or scrotum are usually not associated with any predisposing disorder.

The lesions that occur on the feet are often associated with lymphedema.

The skin lesions that occur outside of the perineum or those that are multiple are often associated with another disease process.

Examples include several cases of epidermal nevi and congenital hemidysplasia with ichthyosiform erythroderma and limb defect (CHILD) syndrome,[81, 82] in which verruciform xanthomata may be the only ostensible sign,[83] and one case each of chronic eczema with ichthyosis, chronic severe sun damage, recessive dystrophic epidermolysis bullosa,[84] and discoid lupus erythematosus.[85] Lesions have also been found in the oral cavity in association with lichen planus,[59, 86] pemphigus vulgaris,[87] oral bullae, carcinoma in situ,[88] or frank squamous cell carcinoma[46, 89] ; the lesions were also found in a bone marrow transplant recipient.[90]


Verruciform xanthoma can be easily cured by surgical excision without complications. However, if an underlying disease is present, such as the CHILD syndrome (see above), this must be managed.  Two cases of verruciform xanthoma associated with squamous cell carcinoma have been reported, so careful scrutiny of the histopathology for associated keratinocyte atypia is warranted, especially in lesions associated with penile phimosis.[1, 46]



Diagnostic Considerations

The clinical differential diagnosis of verruciform xanthoma varies depending on the site. The differential diagnosis includes verruca vulgaris/condyloma acuminatum and oral papilloma.

Verruciform xanthoma can be misdiagnosed as verrucous carcinoma both clinically and microscopically if a superficial biopsy is performed. Verrucous carcinoma is of particular importance because, although it is a carcinoma, it shows little or no epidermal cytologic atypia. For this reason, superficial biopsy of verruciform xanthoma may be misinterpreted as verrucous carcinoma. Verrucous carcinoma can be distinguished from verruciform xanthoma by the presence of invasive epithelial proliferation, cellular atypia, and the lack of foamy histiocytic infiltrate.[12]

Differential Diagnoses



Laboratory Studies

The results of all blood studies, including cholesterol triglyceride level, phospholipid levels, free fatty acid levels, glucose determinations, and lipoprotein serum fraction, are within the reference range in most verruciform xanthoma patients in whom these studies were carried out, with the following exceptions: one patient with diabetes mellitus, one patient with increased serum cholesterol levels, and one patient with a lipid storage disease.

Histologic Findings

Similar to their range of clinical presentations, verruciform xanthomas may appear verrucous, papillary, or cauliflowerlike, or they may show a lichenoid pattern histologically. A mixture of the above patterns may also be observed. A variable degree of parakeratosis is observed that is usually more marked in verrucous and papillary lesions, with parakeratosis present in the crypts between papillae. No epithelial atypia is present. The lesion is exophytic, with the rete ridges in the lesion not extending into the underlying dermis. The connective-tissue papillae are of variable length and thickness; they often extend close to the surface. The papillae may be extremely long and thin. Rarely, the entire process may occur in a cystlike structure.

The most striking and characteristic histologic feature of the verruciform xanthoma is the presence of large foam cells in the connective-tissue papillae.[91] These cells characteristically fill the entire papilla but only rarely extend beyond the base of the papilla. Most or all of the papillae are involved with these cells, which occasionally may also be seen in the epithelium (ie, epidermis, mucosa).

Ultrastructurally, most studies have concluded that the foam cells in verruciform xanthoma are fat-laden macrophages, although other cell types, including Langerhans cells and even fibroblasts, have been proposed. Immunohistochemical analysis revealed these cells to be positive for LCA and CD68 and negative for S100, a marker pattern also characteristic of macrophages. A few S100-negative dendritic or granular cells have been reported in these lesions as well and may represent Langerhans cells. The contents of the cells stain with lipid stains, and the vacuoles that contain this material are decorated by anti–human lysosome antibody. They are also periodic acid-Schiff (PAS) positive and diastase resistant, indicating that the PAS-positive material is not glycogen.

At electron microscopy, this material also demonstrates the appearance of lipid. Chemical studies by gas chromatography of extracted material show a preponderance of cholesterol esters. In addition to the lipid material, Zagarelli et al also noted the presence of what they interpreted as degenerating epithelial cells in the foam cells.[11, 92] Cobb et al described myelin figures and reduplication of the overlying basal lamina and fibroblasts in addition to macrophagelike cells, which contained lipid inclusions.[93]

A slight inflammatory infiltrate may be present beneath the verruciform xanthoma lesion. Occasional verruciform xanthomas have been associated with a massive or lichenoid infiltrate. No granulomatous change has been described other than the presence of the foamy macrophages. Microorganisms are not characteristically present. Although bacteria and fungal hyphae are occasionally described, they appear to play no role in the etiopathogenesis. The results of extensive probing for viruses have been negative.

Dermoscopic Findings

Dermoscopy can be useful for verruciform xanthoma, and it reveals surface papilla containing linear or hairpin vessels, surrounded by a marginal whitish rim. These structures are thought to correspond to dilated vessels in dermal papillae and papillated acanthotic epidermis. Under compression, the vessels disappear, and yellow dots and debris reflecting lipid-laden foam cells become visable.[94]



Approach Considerations

No management guidelines for verruciform xanthoma exist.[40] Local surgical excision is almost always curative for verruciform xanthoma. Recurrence is rare, with only a few cases reported; recurrences may be adequately treated with a second local excision. In some cases, surgical excision can be traumatic and deforming.

A 2-year-old girl with multiple verruciform xanthoma lesions around her anus and vulva was treated with 5% imiquimod on the lesions twice per week. After 4 months, the lesions  appeared to be almost entirely cleared, with no obvious adverse effects.

Cryotherapy, electrosection, pulsed dye laser, and radiation therapy have all failed as reliable therapeutic modalities.[95]