C. Meg Mclachlin
University of Western Ontario
London, ON, Canada
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A 60 year old woman presented with a 0.8 cm lesion on the posterior forchette of the vulva. It was
white, well demarcated, and had a rough surface. The remainder of the vulva did not show any significant
abnormality. She has a past history of squamous and basal cell carcinomas of the face. She was
concerned that this lesion had been slowing increasing in size over the past few months.
The lesion showed marked acanthosis with areas of flat and papillomatous architecture.
There was marked parakeratosis but the granular layer was not prominent. There was no nuclear atypia
or koilocytosis in the upper layers of the epithelium.
The dermal papillae were elongated and contained abundant foamy cells. The foam cells stained
strongly positive with PAS with diastase. HPV in situ hydridization using a broad spectrum probe
including types 6/11 was negative.
The differential diagnosis of vulvar lesions that present clinically as a "wart" and share the common
features of acanthosis and hyperkeratosis includes both HPV and non-HPV associated entities. Condyloma
acuminatum, squamous hyperplasia, seborrheic keratosis, squamous papilloma, VIN, squamous carcinoma and
verrucous carcinoma, among others should be considered.
Condyloma acuminatum should be distinguished on the basis of koilocytosis, parakeratosis and nuclear
atypia confined to the upper third of the epithelium. Koilocytes should contain a distinct halo and
pyknotic or slightly enlarged nucleus. Bi/multinucleation is frequently present, as is parabasal
hyperplasia and a prominent granular layer. Even in young children the presence of papillary/verruco
architecture, binucleation and atypical parakeratosis was strongly associated with the presence of HPV
. It has been shown that nearly all genital condylomata contain HPV 6 or 11 DNA but that 20-50% may
also harbor co-infection with another type of HPV including the oncogenic types . Only 50 % of
condylomata will be positive by standard immuno-histochemistry for capsid antigen . In situ
hybridrization for HPV 6/11 will be positive in the vast majority of cases. However HPV has been
demonstrated in occasional cases of "non-wart" lesions of the vulva such as seborrheic keratosis .
Therefore the diagnosis of condyloma should be made primarily on the basis of H&E features with DNA
testing reserved for confirmation. As HPV vaccination becomes more widespread and the vaccinated
population ages, the presence of genital warts may serve as an indicator for an individual's protection
with the quadrivalent vaccine. The precise diagnosis of genital warts may become a contentious issue as
over diagnosis may lead to confusion regarding an individual's response to the quadrivalent vaccine and
Benign lesions such as squamous hyperplasia, seborrheic keratosis, squamous papilloma lack
significant nuclear atypia and although they may be associated with an inflammatory infiltrate, they do
not contain dermal foam cells. VIN and squamous carcinoma should demonstrate obvious nuclear
pleomorphism and mitotic activity. Verrucous carcinoma may enter the differential, especially if only a
superficial biopsy is taken. The bulbous epidermal downgrowth rather than the narrow epidermal ridges
seen in this lesion should aid in distinquishing the two . Finally, with the presence of foam cells,
a granular cell tumour should be considered. In this case the granular cells can involve the superficial
and deep dermis and although pseudo-epitheliomatous hyperplasia can occur, elongated papillae are not
Verruciform xanthoma (VX) represents less than 1% of all benign lesions of the vulva but has
distinctive diagnostic features. These lesions are most commonly seen in the oral mucosa of middle-aged
men and women. The literature contains over 300 reports of this lesion, of which less than 10 involve
Verruciform xanthoma can involve many mucocutaneous sites often occurring in the skin
with an underlying condition such as lymphedema. There appears to be a predilection for Japanese males
where the scrotum is a not uncommon site of occurrence . The lesion has also been reported as part of
the CHILD syndrome combining multiple ipsilateral anomalies with scaling dermatoses .
Verruciform xanthoma is not a clinically distinct entity and shares features with the warty growths
that occur on the vulva. It is usually asymptomatic but can be tender. It appears as a single
cauliflower like growth that can be papillary or sessile. The margins are sharply delineated and
slightly raised. Depending on the degree of keratinization VX can be pink to grey. On microscopic exam
the lesion is exophytic with papillomatosis containing uniformly hyperplastic epithelium. The epithelium
does not demonstrate significant nuclear atypia. Marked hyperkeratosis and parakeratosis is common but
the granular layer is not prominent. The diagnostic feature is the presence of foamy macrophages within
the dermal papillae. These cells often fill and elongate the papillae but usually do not extend beyond
the base of the epithelial pegs. These foam cells are positive with PAS and are diastase resistant.
Electron microscopy has shown that they contain abundant fat . The foam cells stain positively for
CD68 (KP1) and are negative for cytokeratins and S100 consistent with a macrophage lineage .
The pathogenesis of VX is unclear although an immunologic mechanism is favoured . In the oral cavity
the lesions most commonly occur in sites predisposed to irritation or trauma such as the gingival margin
. In extraoral sites VX often arises in the background of inflammation giving rise to the
speculation that this lesion is more a morphologic reactive process than a true entity . A process
of keratinocyte damage and macrophage response has been postulated since the mid1970s . Recently Hu
and colleagues  have found that Matrix Degrading Metalloproteinases 2&9 (MMP) are strongly
expressed in the epithelium and foam cells of VX. They postulate that MMPs degrade the basement membrane
leading to "reciprocal induction" of the epithelium and mesenchyme resulting in cell breakdown and foamy
macrophage production. In the CHILD syndrome 3B hysroxysteroid dehydrogenase is inactivated through
mutation. Mehra et al has found a novel mutation in this gene in cases of VX associated with the CHILD
syndrome . They postulate that VX arises due to excess formation of lipid storage droplets.
Given the morphologic features, it is not surprising that several investigators have looked for an
association with HPV. To date most studies have been negative using both in situ and amplification
techniques . Khaskely was able to demonstrate HPV 6 within a VX arising on the scrotum of a 67 year
old male . They also speculated that HPV was causing keratinocyte damage and initiating foam cell
response. However the association of HPV with VX remains uncertain.
VX is generally treated with local surgical excision. Reich has reported one case of recurrent VX of
the vulva, eight years after initial excision  but this appears to be an exception.
- McLachlin, CM, Kozakewich H, Craighill M, O'Connell B, Crum, CP. Histologic Correlates of Vulvar Human Papillomavirus Infection in Children and Young Adults 1994;18(7):728.
- Lacey CJN, Lowndes CM, Shah KV. Chapter 4: Burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease. 2006 Elsevier Ltd 2006;24(S3):S3/35,S3/41.
- Iwasaki T, Sata T, Sugase M, Sato Y, Kurata T, Suzuki K, et al. Detection of capsid antigen of human papillomavirus (HPV) in benign lesions of female genital tract using anti-HPV monoclonal antibody. J Pathol 1992;168:293-300.
- Bai H, Cviko A, Granter S, Yuan L, Betensky RA, Crum CP. Immunophenotypic and viral (human papillomavirus) correlates of vulvar seborrheic keratosis. Hum Pathol 2003;34(6):559-64.
- Philipsen HP, Reichart PA, Takata T, Ogawa I. Verruciform xanthoma - biological profile of 282 oral lesions based on a literature survey with nine new cases from Japan . 2002 Elsevier Sciences Ltd. 2003;39:325-36.
- Santa Cruz D.J., Martin SA. Verruciform xanthoma of the vulva. Am J Clin Pathol 1979;71(2):224-8.
- de Rosa G., Barra E., Gentile R. Boscaino A., Di Prisco B., Ayala F. Verruciform xanthoma of the vulva: case report. PMID:2807284 1989;65(4):252-4.
- Reich O, Regauer S, Sigrid . Recurrent Verruciform Xanthoma of the Vulva. Int J Gynecol Pathol 2004;23(1):75-7.
- Nakamura S, Kanamori S., Nakayama K., Aoki M. Verruciform xanthoma on the scrotum. J Dermatol 1989;16(5):397-401.
- Hashimoto K., Prada S., Lopez A.P. CHILD syndrome with linear eruptions, hypopigmented bands, and verruciform xanthoma. Pediatr Dermatol 1998;15(5):360-6.
- Cobb C.M., Holt R., Denys F.R. Ultrastructural features of the verruciform xanthoma. J Oral Pathol 1976;5(1):42-51.
- Hu JA, Li S. Verruciform xantoma of the oral cavity: clinicopathological study relating to pathogenesis. Report of three cases. APMIS 2005;113:629-34.
- Mehra S., Li L., Fan C., Smoller B., Morgan M., Somach S. A Novel Somatic Mutation of the 3B-Hydroxysteroid Dehydrogenase Gene in Sporadic Cutaneous Verruciform Xanthoma. Arch Dermatol 2005;141:1263-7.
- Zegarelli D., Zegarelli-Schmidt E.C., Zegarelli E.V. Verruciform xanthoma. Further light and electron microscopy studies, with the addition of a third case. Oral Surg Oral Med Oral Pathol 1975;40((2)):246-56.
- Khaskhely NM, Uezato H, Kamiyama T, Maruna M, Kariya K, Oshiro M, et al. Association of Human Papillomavirus Type 6 With a Verruciform Xanthoma. Am J Dermatopathol 2000;22(5):447-52.
- Reich O, Regauer S. Recurrent verruciform xanthoma of the vulva. Int J Gynecol Pathol 2004; Jan;23(1):75-7.