Redefining the Epidermal Hamartoma Presenting as Longitudinal Pachyleuconychia: Histologic Re-examination as Onycholemmal Hamartoma and Implications Regarding the Clinical Value of Polydactylous Onychopapillomas in the Early Detection of BAP1 Tumor P

To the editor: A 1996 report1 described a new nail genodermatosis characterized by polydactylous longitudinal leukonychia. The investigators proposed that this nail genodermatosis was a variant of epidermal hamartoma as longitudinal pachyonychia (EHLP). This hamartoma, transmitted in an autosomal dominant pattern, was analyzed in 8 members from 3 generations of the same family. It was not accompanied by any skin, hair, sweeting, teeth abnormalities, or others conditions such as neoplasms. The histologic features analyzed in 1 case1 showed papillomatosis of the nail bed with small foci of keratogenic zones, nests of sebaceous differentiation, and a longitudinal keratinization with a texture relatively similar to that of the nail plate. The aim of this letter is to reinterpret the histologic features of the archival material of 1996 case and discuss their implications for the early detection of BRCA1-associated protein (BAP1) tumor predisposition syndrome (TPDS).2 Three blocks were available: the laterolongitudinal excision of 1 of the white bands (WB), and the avulsed nail that had been cut transversely at the lunular region and the distal region. Immunohistochemistry for LEF-1 (clone EPR2029Y, dilution 1:100, Abcam), beta-catenin (clone14, dilution 1:50, Cell Marke, Rocklin, CA), and adipophilin (cloneAP125, dilution 1:250, Tebu) was performed using a fully automated system (Dako, Glostrup, Demark, En Vision Detection System). LEF-1 and beta-catenin have been used as the most sensitive markers for onychogenic tumors.3,4 In the normal nail, LEF-1 staining is restricted to the basaloid compartment of the matrix, while the nucleocytoplasmic staining of beta-catenin is limited to the prekeratogenous/keratogenous zone.3,4 In addition, adipophilin is well established as a good marker of mature sebocytes. The deep lateral longitudinal excision was optimal respecting the area of the extensor tendon.3 Therefore, the deep part of the proximal matrix hypodermis rich in adipose tissue3 was not included in the surgical specimen (Fig. 1A). On the first longitudinal sections, the epithelium was largely adherent to the dermis (Figs. 1 and 2). Papillomatosis began at the distal matrix (Fig. 1A). The pattern of parallel ridges of the nail bed was identified in the matrical area in the form of a thin, long epithelial digitation parallel to the surface (Figs. 1B, C). This papillomatosis was accentuated in the nail bed associated distally with multiple filiform superficial papillae (Fig. 2A). The nail bed epithelium showed a superficial eosinophilic layer without a granular layer (Figs. 2A, C). At this level, the basaloid compartment did not express LEF-1 (Fig. 2D). The eosinophilic layer of the nail bed showed a membranous staining of beta-catenin without nucleocytoplasmic staining (Fig. 2E). As previously noted,4 this pseudokeratogenous zone corresponded to the superficial eosinophilic layer of the onychopapilloma with its abrupt onycholemmal keratinization without the formation of a granular layer. The deep serial sections of the longitudinal excision showed large zones of de-epithelialization. The lunular region of the avulsed nail plate showed, on serial transverse sections, the epithelium of the nail bed and its dermal papillae corresponding to 1 of the WB (Figs. 3A–C). The superficial layer of glassy keratinocytes without interposition of a granular layer clearly revealed the beginning of the onycholemmal keratinization (Fig. 3A). The lack of specific expression of onychogenic markers LEF-1 (Fig. 3B) and beta-catenin (Fig. 3C) confirmed that the distal matrix had differentiated early into nail bed epithelium with the formation of an onychopapilloma. The distal transverse section of the avulsed nail plate (Fig. 3D) revealed 2 areas of longitudinal cornification corresponding to the WB. The clear orthokeratotic onycholemmal keratin was perforated by multiple cavities because of the multiple superficial epithelial filiform digitations of the nail bed. As previously illustrated (see Fig. 1D on Ref. 4), this subungual onycholemmal keratosis mimicked a thickened nail plate with cavities. The longitudinal thinning of the nail plate with a ventral groove and the complete separation between the unstained nail plate and the partially eosinophilic subungual onycholemmal keratin were 2 additional clues supporting the diagnosis of onychopapilloma (Fig. 3D). The nests of sebaceous-like clear cells (Fig. 4A) did not express adipophilin allowing us to rule out sebaceous differentiation (Fig. 4B). Such nests of clear cells have recently been observed as a rare phenomenon in nail tumors.4,5FIGURE 1.: Longitudinal sections of the matrix. DH, distal fibromyxoid matrical hypodermis; DMD, distal matrical dermis; DPH (inset), area of the deep proximal matrical hypodermis that was not included in the surgical specimen; NBD, nail bed dermis; PMD, proximal matrical dermis; SPH, superficial proximal matrical hypodermis.FIGURE 2.: Longitudinal sections of the nail bed. A, PNB, proximal nail bed; FSPDNB, filiform superficial papillae of the distal nail bed. B, high magnification of the distal nail bed; note the superficial eosinophilic layer of the nail bed; arrow indicates sebocyte-like cells. C, high magnification of the proximal nail bed epithelium; note the superficial eosinophilic layer of the nail bed with pycnotic nuclei simulating the keratogenous zone of the nail matrix. D, negative staining of LEF-1. E, nonspecific membranous staining of beta-catenin.FIGURE 3.: Transverse sections of the avulsed nail plate. A–C, lunular region. A, arrow indicates the beginning of the onycholemmal keratinization. B, negativity of LEF-1. C, membranous staining of beta-catenin. D, hyponychium. NP, nail plate.FIGURE 4.: Sebocyte-like keratinocytes. A, H&E. B, negativity of adipophilin.Moulin et al1 initially believed that EHLP presented foci of keratogenic zones and zones of sebaceous differentiation at the nail bed. However, this comprehensive immunohistochemical study provides evidence to the contrary. According to this revisited histologic presentation, EHLP falls into the category of onychopapilloma, recently redefined as a nail bed onycholemmal papilloma.4 I propose that the most appropriate designation for EHPL is “familial onycholemmal hamartoma.” In the 1996 study,1 this nail hamartoma presenting as polydactylous longitudinal leukonychia was analyzed in 8 members from 3 generations of the same family with no family history of neoplasms. The clinical differential diagnosis for polydactylous leukonychia without red lines includes Darier disease, Hailey disease, tuberous sclerosis complex, and multiple onychopapillomas (OPS) associated with BAP1 TPDS. In Darier disease, Hailey disease, and tuberous sclerosis complex, skin involvement characteristic of each disease is typically present.1,2 It has recently been reported that BAP1 TPDS is associated with a high rate of multiple OPS.2 Given that multiple OPS are uncommon in the general population, it has been suggested that polydactylous OPS may be a clinical indicator for identifying individuals at increased risk of the BAP1 TPDS. Although longitudinal leukonychia without longitudinal erythronychia is the most frequent presentation of multiple OPS associated with BAP1TPDS, longitudinal leukonychia associated with longitudinal erythronychia is the second most common.2 In light of the recent histologic re-evaluation of onychopapilloma as onycholemmal papilloma,4 OPS associated with BAP1TPDS2 now fall under the category of familial onycholemmal hamartoma. Familial onycholemmal hamartoma affects predominantly the fingernails and is characterized by multiples onycholemmal papilloma that appears between the ages of 9 and 30 years.1,2The family studied in 1996 suggest that familial onycholemmal hamartoma could present 2 subtypes, 1 with a purely leukonychial profile and an indolent course and the other associated with BAP1 tumor predisposition syndrome presenting either a leukonychial profile alone (55% in the recent study of Lebensohn et al2) or WB associated with red lines (candy canes pattern). BAP1 immunohistochemistry is not a useful adjunct to the histologic differential diagnosis between these 2 potential subtypes of onycholemmal hamartoma because no consistent loss of BAP1 expression is observed in nail biopsies from OPS associated with BAP1 tumor predisposition syndrome.2 The main limitation of this study is that it focuses on a single family studied in 1996. Because such cases are rare, accrual of additional cases is needed to elucidate the biologic potential of the indolent clinical subtype of familial onycholemmal hamartoma.