The vexing verruciform xanthoma

By Warren R. Heymann, MD, FAAD
February 23, 2022
Vol. 4, No. 8

Verruciform xanthomas (VX) were first described 50 years ago, and they are still a source of debate. Only the most astute dermatologists will make the diagnosis clinically, with the possible exception of recognizing such lesions in patients with the CHILD syndrome (see below). Indeed, in a series of genital VX from 24 patients, the diagnosis was never suspected clinically, but were considered with diagnoses ranging from fibroepithelial polyp to squamous cell carcinoma. (1)

VX are very uncommon papillary growths seen chiefly in the oral mucosa, with an incidence rate of 0.025-0.05% of all pathology cases. The gingiva, alveolar mucosa and hard palate are the most common intraoral sites of its occurrence. (2) Rarely, the tongue may be involved. (3) The other major site of involvement is the anogenital region; in a study of Taiwanese patients, more genital than oral lesions were observed, with a male:female ratio of 6.75:1. (4) Rarely, VX may present on the extremities, including the sole (5) and subungual region. (6)

What makes VX so challenging is that the lesion is not a specific entity. The hallmark in the diagnosis of VX is the histologic presence of foam cells in the connective tissue papillae between the epithelial rete ridges. (2) These histopathological features may accompany a number of inflammatory diseases such as pemphigus, lichen planus, and graft-versus-host disease. (7)

Special attention is required in selected genodermatoses. VX has been reported in cases of recessive dystrophic epidermolysis bullosa and keratitis-ichthyosis-deafness syndrome, both of which may be at risk for the development of squamous cell carcinoma. (8, 9) Although there is no evidence that verruciform xanthoma is potentially malignant, it has also been reported concurrently with squamous cell carcinoma. (10) The mimicry of VX with SCC in the context of these disorders warrants clinical vigilance and skin biopsies.

CHILD syndrome is an acronym for an X-linked dominant disorder characterized by congenital hemidysplasia with ichythyosiform erythrodema and limb defects. The mutations are lethal in hemizygous males (OMIM #308050). CHILD syndrome is due to a mutation (missense, nonsense, or stop mutations) in the NAD[P]H steroid, dehydrogenase-like protein gene which is also known as the NSDHL gene. The NSDHL gene is located on the long arm of the X chromosome at position 28 (Xq28), encoding for the enzyme 3beta-hydroxy sterol dehydrogenase that is involved in cholesterol pathways. Skin lesions of patients with CHILD syndrome usually reveal a psoriasiform epidermis with hyperkeratosis and parakeratosis. The papillary dermis usually also has foam cells that express surface markers such as CD68 and CD163 which are specific for macrophages (11), representing VX. A peculiar, distinct variant has been described as raspberry, “drumstick-like” (tympanoxyloid) lesions by Jurati et al. (7)

The pathogenesis of VX is unknown. With the exception of rare reports, VX are not HPV-related. It has been proposed that degenerated epithelial cell membranes become engulfed by histiocytes, becoming foamy because of lipid phagocytosis. As macrophages subsequently produce a host of growth factors, epithelial hyperplasia could then be induced. In a fascinating study, Getz et al extracted DNA from archived paraffin-embedded tissue of sporadic oral VX and control cases. Polymerase chain reaction (PCR) was then used to screen exons 4 and 6 of the NSDHL gene for the presence of 4 known germline mutations associated with CHILD syndrome and 1 somatic mutation previously identified in VX lesions with no known association with CHILD syndrome. Of the 16 oral VX tissue samples, 8 (50%) had known missense mutations associated with CHILD syndrome. Furthermore, 2 of these 8 tissue samples also had an additional missense mutation previously identified in cutaneous VX lesions. No mutations of exons 4 and 6 were found in the 5 negative control tissue samples. The authors concluded that NSDHL gene mutations associated with CHILD syndrome are common in sporadic oral VX cases, suggesting that these mutations confer a greater risk for the development of epithelial barrier defects that promote recurrent oral VX lesions and the potential for direct germline transmission of oral VX susceptibility. (12)

Managing VX is challenging and depends on the clinical setting. Solitary lesions may be excised or extirpated by destructive modalities such as cryosurgery, electrosurgery, radiation, pulsed dye laser, or carbon dioxide laser. (13,14) Recurrences are common following most modalities. Imiquimod was reported to be successful in treating vulvar lesions in a 2 year-old girl. (15) Lesions appearing in the context of chronic trauma or inflammation should also have these associated conditions treated as well as possible. Long-term monitoring is advised. (8)

Point to Remember: Verruciform xanthomas are uncommon lesions presumed to be reactive to trauma or chronic inflammation. The main clinical significance lies in recognizing the lesion in the right context and avoiding confusion with potentially malignant lesions.

Our expert’s viewpoint

Kiran Motaparthi, MD, FAAD
Associate Professor
Residency Program Director
Director of Dermatopathology
Department of Dermatology
University of Florida College of Medicine

As Dr. Heymann notes in his commentary, mutations in NSDHL are identified in both CHILD syndrome and in sporadic/classic VX. However, the verrucous or hyperkeratotic plaques (epidermal nevi) of CHILD syndrome demonstrate a unique clinical appearance compared to sporadic/classic VX and additionally demonstrate abnormal lamellar granules in the context of systemic lipid metabolic impairment. (16) Epidermal nevi of CHILD syndrome often demonstrate identical histopathologic features to those of sporadic/classic VX: verrucous epidermal hyperplasia, orange-red parakeratosis with neutrophils and an inverted wedge shape appearance, and xanthomatous change in the dermal papillae. (17) However, CHILD syndrome may present with only ichythosiform or psoriasiform plaques within the lines of Blaschko and without hemidysplasia or limb defects. (18) Biopsies of these more subtle clinical examples lack xanthomatous changes and closely resemble psoriasis. Nonetheless, one clue may prevent overlooking the diagnosis: the presence of parakeratotic nuclei with a striking rounded appearance (rather than a typical flattened appearance). (17) Importantly, even in patients with mild cutaneous findings, genetic counseling is still important given the risk of severe phenotypes in offspring. (18)

Treatment with topical lovastatin or simvastatin combined with cholesterol has been reported. Monotherapy with a topical statin appears equally effective, suggesting that accumulation of toxic intermediate metabolites in the cholesterol biosynthetic pathway is more relevant to the pathogenesis of CHILD syndrome than downstream cholesterol deficiency. (19)

1. Wang G, Mochel MC, Randall MB, Gandhi JS, Udager AM, Chan MP, Patel RM, Amin MB, Osunkoya AO, Smith SC. Genital verruciform xanthoma: lessons from a contemporary multi-institutional series. Histopathology. 2020 Nov;77(5):841-846. doi: 10.1111/his.14198. Epub 2020 Sep 15. PMID: 32598505.

2. Hegde U, Doddawad VG, Sreeshyla H, Patil R. Verruciform xanthoma: A view on the concepts of its etiopathogenesis. J Oral Maxillofac Pathol. 2013 Sep;17(3):392-6. doi: 10.4103/0973-029X.125205. PMID: 24574658; PMCID: PMC3927341.

3. Atarbashi-Moghadam S, Lotfi A, Kabiri F, Sijanivandi S. Verruciform Xanthoma of the Ventral Surface of the Tongue: A Rare Case Report and Literature Review. Iran J Otorhinolaryngol. 2021 Jan;33(114):55-59. doi: 10.22038/ijorl.2020.45912.2506. PMID: 33654692; PMCID: PMC7897434.

4. Wang YH, Wang HS, Shih IH. Verruciform xanthoma: An elderly male genital predominance trend. Australas J Dermatol. 2021 May;62(2):e290-e292. doi: 10.1111/ajd.13461. Epub 2020 Nov 28. PMID: 33247836.

5. Seo HM, Jang JW, Park SK, Jung YJ, Kim TL, Kim YG, Kim JS. A Case of Verruciform Xanthoma of the Sole. Ann Dermatol. 2021 Feb;33(1):86-88. doi: 10.5021/ad.2021.33.1.86. Epub 2020 Dec 30. PMID: 33911818; PMCID: PMC7875220.

6. Haneke E. Subungual Verruciform Xanthoma. Dermatol Surg. 2021 May 1;47(5):722-724. doi: 10.1097/DSS.0000000000002640. PMID: 33481453.

7. Juratli HA, König A, Happle R. Tympanoxyloid verruciform xanthoma is a distinct feature of CHILD nevus. J Eur Acad Dermatol Venereol. 2020 Feb;34(2):e70-e72. doi: 10.1111/jdv.15917. Epub 2019 Oct 8. PMID: 31502355.

8. Stephens M, Rubin AI, Perman MJ. Verruciform xanthoma in a patient with recessive dystrophic epidermolysis bullosa: Case report and literature review. Pediatr Dermatol. 2020 Mar;37(2):355-357. doi: 10.1111/pde.14079. Epub 2019 Dec 26. PMID: 31876000.

9. Evan-Browning E, Rork J, O'Donnell P, Elaba Z, Deng A, Wiss K. Verruciform xanthoma in recessive dystrophic epidermolysis bullosa and keratitis-ichthyosis-deafness syndrome: Report of two cases and a review of the literature. Pediatr Dermatol. 2020 Jan;37(1):176-179. doi: 10.1111/pde.14046. Epub 2019 Nov 11. PMID: 31710113.

10. Mannes KD, Dekle CL, Requena L, Sangueza OP. Verruciform xanthoma associated with squamous cell carcinoma. Am J Dermatopathol. 1999 Feb;21(1):66-9. doi: 10.1097/00000372-199902000-00015. PMID: 10027531.

11. Ramphul K, Kota V, Mejias SG. Child Syndrome. 2021 Mar 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 29939590.

12. Getz GI, Parag-Sharma K, Reside J, Padilla RJ, Amelio AL. Identification of NSDHL mutations associated with CHILD syndrome in oral verruciform xanthoma. Oral Surg Oral Med Oral Pathol Oral Radiol. 2019 Jul;128(1):60-69. doi: 10.1016/j.oooo.2019.02.015. Epub 2019 Feb 23. PMID: 31078502.

13. Joo, J. , Fung, M. , Jagdeo, J. & (2014). Dermatologic Surgery, 40 (2), 214-217. doi: 10.1111/dsu.12382.

14. Connolly SB, Lewis EJ, Lindholm JS, Zelickson BD, Zachary CB, Tope WD. Management of cutaneous verruciform xanthoma. J Am Acad Dermatol. 2000 Feb;42(2 Pt 2):343-7. doi: 10.1016/s0190-9622(00)90108-7. PMID: 10640929.

15. Guo Y, Dang Y, Toyohara JP, Geng S. Successful treatment of verruciform xanthoma with imiquimod. J Am Acad Dermatol. 2013 Oct;69(4):e184-6. doi: 10.1016/j.jaad.2013.04.026. PMID: 24034392.

16. Xu XL, Huang LM, Wang Q, Sun JF. Multiple verruciform xanthomas in the setting of congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome. Pediatr Dermatol. 2015 Jan-Feb;32(1):135-7. doi: 10.1111/pde.12198. Epub 2013 Oct 22. PMID: 24147604.

17. Gantner S, Rütten A, Requena L, Gassenmaier G, Landthaler M, Hafner C. CHILD syndrome with mild skin lesions: histopathologic clues for the diagnosis. J Cutan Pathol. 2014 Oct;41(10):787-90. doi: 10.1111/cup.12377. Epub 2014 Oct 18. PMID: 25093865.

18. Estapé A, Josifova D, Rampling D, Glover M, Kinsler VA. Congenital hemidysplasia with ichthyosiform naevus and limb defects (CHILD) syndrome without hemidysplasia. Br J Dermatol. 2015 Jul;173(1):304-7. doi: 10.1111/bjd.13636. Epub 2015 May 28. PMID: 25533639; PMCID: PMC4737197.

19. Yu X, Chen L, Yang Z, Gu Y, Zheng W, Wu Z, Li M, Yao Z. An excellent response to topical therapy of four congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome patients with an increased concentration of simvastatin ointment. J Eur Acad Dermatol Venereol. 2020 Jan;34(1):e8-e11. doi: 10.1111/jdv.15838. Epub 2019 Oct 1. PMID: 31374135.

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