Periungual Cyst or Pseudocyst Featuring Low-Grade Dysplasia Associated With High-Risk Human Papillomavirus Infection: A Cystic Presentation of Human Papillomavirus-Related Intraepithelial Neoplasia of the Nail Bed?

To the Editor: There are various epithelial cysts that may develop within the nail area.1–6 These unusual lesions, which show either epidermal-like (epidermoid) or trichilemmal-like (onycholemmal) keratinization, generally occur in the subungual region although cases arising in the periungual area have been reported, too.1–7 These cysts, which all differ in terms of histogenesis and clinical presentation, comprise the usually small-sized and occasionally multiple subungual epidermoid inclusions, the so-called implantation epidermoid cyst (EC) that is indistinguishable from any EC arising elsewhere in the skin, and the very rare onycholemmal cyst, which is lined by an epithelium that closely resembles the epithelium of the nail bed.1–6 Herein, we describe a periungual cyst or pseudocyst that probably developed from nail bed epithelium, in which the epithelial lining displayed metaplastic and dysplastic changes related to high-risk (HR) human papillomavirus (HPV) infection. A 32-year-old man with a history of hidradenitis suppurativa presented with a painful and cystic lesion located in the lateral nail fold of the left ring finger. According to the patient, this lesion appeared shortly before and gradually enlarged. The patient did not mention any relationship with a previous trauma. He did not take any treatment and did not complain of any other problem. The lesion, which vaguely resembled a skin abscess, was excised for diagnostic and therapeutic purposes. Microscopic examination revealed a cystic structure measuring 0.6 cm, filled with lamellar keratinous material, and lined by a squamous epithelium devoid of granular cell layer and showing acanthosis, mild papillomatosis, hyperkeratosis, and parakeratosis (Figs. 1A, B). Parakeratosis was particularly prominent in the lamellar keratinous material (Fig. 1B). Some squamous cells showed koilocytosis or dyskeratosis, but there were no coarse intracytoplasmic keratohyalin granules, however (Figs. 1B, C). Although mild-to-moderate atypia was occasionally seen, features suggestive of squamous cell carcinoma (SCC) were absent (Fig. 1D). Mitotic activity was slightly increased and limited to the lower part of the epithelial lining.FIGURE 1.: Illustrations of the periungual cyst or pseudocyst. A–D, Hematoxylin and eosin (H, E) stained sections. A, This low-power view shows a cystic lesion filled with lamellar keratinous material. Note the peculiar appearance of the squamous epithelium, which shows moderate acanthosis and mild papillomatosis. There is no granular cell layer. B, C, At higher magnification, the stratum corneum is thickened and shows parakeratosis. The stratum spinosum contains some dyskeratotic cells and koilocytes. D, Note cellular atypia suggestive of mild-to-moderate dysplasia and mitotic activity, in the lower part of the epithelium. Original magnifications: (A) ×10, (B) ×100, (C) ×400, (D) ×400.Immunohistochemistry using monoclonal antibody directed against HPV (clone K1H8, Dako) demonstrated a few positive cells in the covering epithelium (Fig. 2A). By contrast, a large portion of this squamous epithelium was labeled with monoclonal antibody to p16 protein (clone E6H4, Ventana), like the typical “block-positive” pattern of p16 expression seen in some HPV-related squamous intraepithelial lesions (SILs) of the anogenital area (Fig. 2B).8 Finally, monoclonal antibody against Ki-67 antigen (clone MIB-1, Dako) demonstrated a higher proliferative activity, especially in atypical cells (Fig. 2C). To substantiate further the presence of an underlying HPV infection, molecular studies were performed on DNA extracted from the paraffin block. Polymerase chain reaction analysis using the cobas 4800 HPV genotyping assay (Roche Diagnostics) confirmed the presence of HR HPV belonging to the spectrum of HPV types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, or 68. Further analysis using the BD Onclarity HPV Assay (Becton, Dickinson and Company, BD Life Sciences-Integrated Diagnostic Solutions, Sparks, MD) demonstrated a viral genotype related to HPV 56, 59, or 66. Based on these findings, a diagnosis of EC featuring HPV-related dysplastic changes was initially made. Because of the proximity of the surgical margins and the increased risk of developing SCC in the setting of HR HPV infection, a complete re-excision was also recommended. Unfortunately, the patient has been lost for follow-up, shortly after the diagnosis.FIGURE 2.: IHC on paraffin sections, using monoclonal antibodies directed against HPV, p16, Ki-67 antigen, and cytokeratin 17, respectively. A, The monoclonal antibody against HPV decorated lesional cells in a focal but distinct manner. B, Note the p16 expression pattern by the squamous epithelium, that is “block-positive.” C, Labeling of atypical cells by monoclonal antibody to Ki-67 antigen, which reinforces the impression of a superimposed dysplasia. D, Most cells within this cystic lesion strongly express cytokeratin 17. Original magnifications: (A) ×200, (B) ×20, (C) ×100, (D) ×10. IHC, immunohistochemistry.On review, greater attention was paid to the epithelial lining of this cystic lesion. A complementary immunohistochemistry using a monoclonal antibody directed against cytokeratin 17 (clone E3, Dako) was, therefore, performed, which showed strong and homogeneous expression of this cytokeratin by epithelial cells, like the outer root sheath of hair follicles or the epithelium of nail bed (Fig. 2D).9 Based on this immunohistochemical characteristic, we can assume that such finger's lesion arose from nail bed epithelium located in the lateral nail fold, because of the proximity to this nail bed and the absence of hair follicles in this area. This epithelium probably underwent epidermal-like metaplasia and dysplastic changes, both induced by HR HPV infection. Likewise, proliferative activity associated with such viral infection may have accentuated the normal invagination of the lateral nail fold, which led to cystic outgrowth. HPV can be demonstrated in some cutaneous cysts, not only in those originating from the infundibular part of the follicles or the eccrine ducts located on the palms and soles, both displaying epidermal-like keratinization, but also in those showing trichilemmal keratinization (so-called pilar cysts), which illustrates the ability of HPV to target various parts of the cutaneous adnexae.10–13 Moreover, cases of SCC developing in such HPV-infected cysts have also been described, which demonstrates that progression to SCC may occur in rare instances.14,15 To our knowledge, however, HPV infection has never been documented in a subungual or periungual cyst. The proximity of some HPV-associated ECs to warts or condylomata acuminata has led some authors to suggest that virions produced during infection may infect nearby adnexal structures.11,16 Unfortunately, we do not know whether our patient had concomitant condylomata or warts, or even a history of such lesions. Interestingly, clinical investigations in a patient with an EC of the back featuring HPV 16 and 59 infections did not show any association with condylomata acuminata.16 Our findings are also consistent with the fact that periungual or nail SCC is frequently associated with HR HPV infection,17 to the extent that nail apparatus has been considered by some authors as a potential reservoir of HR HPV for sexually transmitted infections.17 Such affinity of HPV for the nail bed epithelium can be promoted by infection or trauma, which may explain why HPV-associated Bowen disease or SCC of the nail often occurs in the lateral or proximal nail fold or the hyponychium.17 Indeed, these areas of the fingers are particularly exposed to trauma or abrasion.17 Although it may be relatively simplistic to transpose a single model of carcinogenesis to the various mucosal cancers associated with HPV infection, our findings resemble those classically reported in other HPV-related low-grade SILs, including vulvar intraepithelial neoplasia 1. Therefore, the present case can be virtually considered as a low-grade SIL of the nail bed (nail bed intraepithelial neoplasia 1) or otherwise as a low-grade variant of nail apparatus intraepithelial neoplasia, according to Shimizu et al.17 Whether our patient's lesion does represent a precursor to onycholemmal carcinoma (OC) remains yet to be demonstrated, too. In this regard, the rare cases of OC tested for HPV were negative.18,19 However, because of the morphologic similarities that exist between OC and SCC,18 we cannot rule out that some cases of HPV-associated SCC of the nail unit reported as such may in fact represent true OC. In summary, our findings demonstrate that cysts or pseudocysts arising in the periungual area and originating from the nail bed epithelium may occasionally exhibit metaplastic and dysplastic changes related to HR HPV infection. Therefore, these unusual lesions may possibly be considered as cystic presentation of nail bed intraepithelial neoplasia or nail apparatus intraepithelial neoplasia. It is also noteworthy that such HPV-related epithelial changes can be relatively subtle at low-power view and thus easily overlooked, if examining the lesion too superficially. So, it is advisable to look for any morphologic feature that suggests HPV infection or dysplasia in subungual or periungual cystic lesions, for appropriate treatment.