To the Editor:
Verruciform xanthoma (VX) is an uncommon benign lesion that affects skin and mucosal surfaces. It is characterized by an exophytic growth pattern, epithelial hyperplasia without dysplasia, extensive parakeratosis, neutrophilic exocytosis, and accumulations of xanthomatous histiocytes in the papillae of the epithelium.1 This presence of xanthomatous histiocytes is the key diagnostic characteristic of VX. We report a peculiar case of mammary retroareolar VX with a cystic arrangement, an anatomical location not previously described for this lesion. In addition, it resulted positive for p16 protein in the epithelial component, in the absence of detectable human papillomavirus (HPV) genetic material.
The case corresponded to a 30-year-old woman with a history of recurrent mastitis and a long-lasting retroareolar nodule in her left breast. On the ultrasound study, it was well defined and hypoechoic with posterior enhancement, measuring 1.5 cm in size (BI-RADS 2) (Fig. 1A). The surgical specimen showed a well-delimited nodule, 1.5 cm in maximum diameter, with a cystic appearance on cut surface. Histologically, it corresponded to a cystic lesion (Fig. 1B) lined by squamous epithelium without atypia and with papillomatosis, acanthosis, and neutrophilic exocytosis (Fig. 1C). The connective vascular cores of the prominent papillae were filled by large foamy cells with central non-atypical nuclei (Fig. 1D) enmeshed with an abundant chronic inflammatory infiltrate composed of mature lymphocytes and plasma cells. There was no foreign material. The foamy cells were negative with Periodic acid-Schiff (PAS) technique and strongly stained for CD68 (Fig. 1E), whereas S-100 protein was negative. The p16 protein immunostaining was positive in the cytoplasms of the squamous cells (Fig. 1F). The narrow margin of connective tissue that surrounded the cystic lesion contained numerous bundles of well-organized smooth muscles (Fig. 1C), as it corresponds to the nipple–areola area of the breast.
Both polymerase chain reaction (PCR) amplifications with consensus primers MY9/MY11 and GP5+/GP6+ and PCR genotyping (Roche, Genomica) for genetic material of HPV resulted negative.
VX is an infrequent benign lesion whereof more than 300 cases have been reported.2,3 It affects skin and mucocutaneous surfaces, mainly oral mucosa and anogenital area. Other exceptional locations are esophagus and upper aerodigestive tract, but in all our knowledge, mammary cases have not been reported.
This entity was described by Shafer1 40 years ago, and it is considered an inflammatory, nonmalignant condition. In some cases, relationship with predisposing local factors was demonstrated. In alveolar mucosa and gingiva, minor but repeated traumas have been proposed to play a role in its pathogenesis.4 In penis and vulva, it is frequently associated with lichen sclerosus, lichen planus, and other inflammatory diseases of the skin.5 In cutaneous cases of VX outside the perineum, it is also the common concurrence of inflammatory skin conditions or chronic lymphedema. The immune theory has also been proposed inasmuch as it has been related with cases of graft versus host disease6 or other immune diseases.7 However, other VXs are not associated with any predisposing known conditions. We believe that the present case emerges from the squamous epithelium lining the galactophorous duct near the nipple and it is developed because of the recurrent inflammatory stimulus underlying the mastitis that our patient suffered from. Therefore, we include it among the cases of VX associated with inflammatory entities.
According to Nowparast et al,8 there are 3 different architectural VXs under light microscope: (1) wart-like VX with warty changes, (2) papillary VX with papillary or cauliflower-like architecture, and (3) flat VX. Some cases show a mixed pattern. On rare occasions, the process can be organized as a cystic structure. Our case shows this latter arrangement, but we think that it may be secondary to the location inside a galactophorous duct, rather than a primary structure of the VX.
Although occasional relationship between VX and HPV6 has been previously documented in scrotum,9 subsequent studies have not confirmed these results, and HPV DNA has not been identified in cases of genital VX studied for this virus.10,11 On the other hand, normal ductal epithelium of the breast strongly expresses p16 protein, and this expression does not correlate with cellular proliferation or maturation.12 As p16 protein resulted positive in our case, we looked for HPV involvement in this expression, but both PCR amplifications with MY9/MY11 and GP5+/GP6+ primers and PCR genotyping failed to identify HPV DNA. Therefore, we believe that p16 protein stain in our case is not because of HPV infection but simply corresponds to the normal expression of this protein in ductal mammary epithelium.
In conclusion, we report a case of VX in an undescribed retroareolar location in the breast with cystic growth pattern and positivity for p16 in the absence of detectable HPV genetic material. It is originated from the squamous epithelium lining the milk duct, and we consider that it is related to recurrent mastitis.
The authors thank Dr Beatriz Belosillo of the Parc de Salut Mar (Barcelona) for help in molecular techniques of HPV detection.
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