Onychopapilloma is recognized as a benign tumor of the nail bed and distal nail matrix. It was first described as “localized multinucleate distal subungual keratosis” by Baran and Perrin (1), and the term “onychopapilloma” was proposed in 2000 (2). It usually occurs on the thumbs of adults (3). Although Kim et al. conjectured that onychopapilloma could be neoplastic hyperplasia of the nail bed epithelium or reactive hyperplasia of the nail bed epithelium due to chronic irritation, trauma or other inflammatory nail diseases (4), there is no definite evidence of this. Whether the onychopapilloma originates from the nail bed, the nail matrix, or both are discussed in this study.

The nail bed is different from the nail matrix in histology and embryology, and there is no transformation between the developed nail bed and the nail matrix. Anatomically, the nail unit is usually recognized as an equivalent of the follicle. Some authors claimed that the nail bed is equivalent to the outer root sheath of the follicle and that the nail matrix is comparable to the hair matrix (5, 6). In recent studies, the expression profiles of hair-related and epithelial keratins have been determined in the human nail unit (6–9). The nail matrix was the only site of expression of hair-related keratins, including HK31, HK34, HK85, and HK86, which could not be detected in the nail bed and hyponychium. HK75, K6, and K16 were explicitly expressed in the nail bed. The unique expression pattern of hair-related keratins and epithelial keratins in the nail unit could be used to identify the differentiation of nail matrix epithelium and nail bed epithelium. However, a comprehensive immunohistochemical analysis of keratin expression in onychopapilloma has not been performed. To define the origin of onychopapilloma, we analyzed the pathologic characteristics of this disease and the expression patterns of hair-related keratins and epithelial keratins in the involved tissue. Furthermore, we hope to search for special markers of onychopapilloma.

Baran and Perrin first reported four subungual keratosis cases with multinucleated cell aggregation according to pathological morphology and named the condition “local multinucleated distal keratosis” in 1995 (1). In 2000, they reported another 14 cases with longitudinal erythronychia and suggested that the term “local multinucleated distal keratosis” should be replaced by “onychopapilloma” (2). Onychopapilloma usually occurs in adults and most commonly in the thumb (2).

Clinically, onychopapilloma typically presents as longitudinal erythronychia with subungual hyperkeratosis. It can also present as longitudinal melanonychia, longitudinal leukonychia, splinter hemorrhages or onycholysis. Although the longitudinal streak can extend from the free edge of the nail plate to the lunula, this does not suggest that onychopapilloma originates from the nail matrix. Halteh suggested that longitudinal erythronychia may be due to the tumor compression of the nail bed causing local nail plate thinning and the formation of the lower erythema (10). The longitudinal leukonychia may be caused by the photorefraction change and fibrosis of the nail bed epithelium. And longitudinal melanonychia may be associated with the activation of melanocytes stimulated by the tumor. Therefore, the specific location and origin of onychopapilloma cannot be determined only through clinical manifestations. The keratotic mass under the nail plate corresponds to the position of the longitudinal streak. The dermoscopic examination can more clearly show the asymmetric keratotic mass under the nail plate with excessive lamellar keratinization. Splinter hemorrhages were observed in some patients, presenting continuous or discontinuous, single or multiple. Therefore, the dermoscopic examination is very important in the diagnosis of onychopapilloma.

In previous studies of onychopapilloma, it was recognized as a benign neoplasm originating from the distal nail matrix. However, the etiology and pathogenesis of onychopapilloma have not reached a consensus yet. Anatomically, the nail bed is different from the nail matrix, and there is no transformation between the two. We hope to determine whether onychopapilloma originates from the nail bed, nail matrix, or both.

On histological grounds, onychopapilloma is characterized by acanthosis and papillomatosis within the nail bed and abundant eosinophilic cytoplasm in the upper cell layers of the nail bed epithelium (matrix metaplasia) (2–4, 10–12). Sometimes, matrix metaplasia cannot be observed because of the surgical method or the quality of the specimen. Thus, in other disease premises, the diagnosis could be made histologically based on acanthosis and papillomatosis within the nail bed epithelium. Additionally, histopathology showed that onychopapilloma was a mixed growth acanthoma that can secrete large amounts of eosinophilic keratin (13). It is associated with subungual hyperkeratosis or subungual keratotic mass. Histologically, hyperkeratosis and parakeratosis are helpful in diagnosis.

The differential diagnosis of onychopapilloma mainly includes Bowen’s disease, glomus tumor, Darier disease, and melanoma. There is no distal subungual keratosis in Bowen’s disease, and the pathological features are obvious, with typical anomalous epidermal cells and dyskeratosis cells. Glomus tumor patients usually have severe pain and no distal subungual hyperkeratosis. Longitudinal erythronychia is also a typical manifestation of Darier disease, but it usually involves more than one finger and is often accompanied by longitudinal leukonychia. When onychopapilloma presents as longitudinal melanonychia, the pathological examination should be performed to eliminate melanoma. Usually, clinical manifestation, dermatoscopy, and histopathological examination are sufficient to confirm the diagnosis of onychopapilloma. However, because of the particularity of the histology of the nail unit, it is challenging to distinguish onychopapilloma from other onycho-tumors, such as onychocytic matricoma and onychomatricoma. In these circumstances, the immunohistochemical feature is helpful.

We studied 11 cases of onychopapilloma and confirmed that all histopathologic changes of onychopapilloma were seen in the nail bed rather than the nail matrix. Therefore, we preliminarily conjecture that the onychopapilloma originates from the nail bed.

In recent studies, the expression profiles of hair-related keratins and epithelial keratins have been determined in the standard nail unit (6–9). Hair-related keratins, including HK31, HK34, HK85, and HK86, were specifically expressed in the nail matrix and nail plate but not in the standard nail bed or nail fold. The expression of HK75 was supposed to be limited in the superbasal nail bed epithelium, and K6/K16 was expressed both in the nail bed and eponychium. The special expression pattern of hair-related keratins and epithelial keratins in the nail unit could be used to identify the differentiation of nail matrix epithelium and nail bed epithelium. Thus, we performed an immunohistochemical study to clarify the origin of onychopapilloma. There was no significant difference between the proximal and distal parts of the tumor (Figure 4), so we selected the more prominent portion of the tumor at the distal nail bed. The results showed that HK75 and K6/K16 were strongly expressed positively in the nail bed, especially papillomatosis with acanthosis of the nail bed epithelium. In contrast, hair-related keratins, including HK34, HK85, and HK86, showed negative expression in onychopapilloma. This indicated that onychopapilloma is a benign tumor of the nail bed rather than the nail matrix. Subungual hyperkeratosis was formed by keratin accumulation produced by neoplastic hyperplasia of the nail bed epithelium. However, the expression of HK31 requires an explanation. HK31 was supposed to be expressed only in the nail matrix. Our study showed that it was expressed both in the standard nail matrix and the involved nail bed epithelium, especially in the superficial layer of the nail bed (matrix metaplasia). Previously, the structure of the nail unit is usually recognized as an equivalent of the follicle. In the hair matrix, HK85 is the marker protein that showed persistent positive expression. HK31 is early cortex keratin in the inferior part of the hair cortex, the expression of which disappears at an early stage. While HK86 and HK34 are late cortex keratins in the upper part of the hair cortex, which express at the late stages (14). By analogy with hair follicles, we suspect that the expression of HK31 may be associated with matrix metaplasia of the nail bed epithelium, which leads to an increased ability of the nail bed to produce keratin.

To our knowledge, the current study is the first clinical research to explore the origin of onychopapilloma by immunohistochemistry to date. From our result, the specific expression of HK31, the positive expression of “nail bed-related keratin” (HK75, K6/K16) and the negative expression of “nail matrix-related keratin” (HK34, HK85, and HK86) could be the immunohistochemical characteristic of onychopapilloma. Based on the specific expression of HK31 in the nail bed, we speculate that HK31 can also be used as a marker for the differential diagnosis of onychopapilloma and other nail bed tumors.

Our study suggests that onychopapilloma may originate from the nail bed epithelium. The histopathological characteristics of onychopapilloma include papillomatosis, acanthosis and matrix metaplasia of the nail bed epithelium rather than the nail matrix. In immunohistochemistry, onychopapilloma showed positive expression of HK31 and “nail bed-related keratin,” with negative expression of other “nail matrix-related keratin,” which may provide a new approach for the differential diagnosis of onychopapilloma.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital with Nanjing Medical University, Nanjing, China. The patients/participants provided their written informed consent to participate in this study.

DW: conceptualization, funding acquisition, and resources. ML, FL, XW, ZL, HW, and YZ: investigation. ML, FL, and XW: formal analysis. ML: writing—original draft preparation. FL and XW: writing—review and editing. FL and DW: supervision. ML and DW: project administration. All authors contributed to the article and approved the submitted version.