Squamous cell carcinoma of the nail apparatus: Histopathology and immunohistochemistry correlation study.

BACKGROUND: Nail squamous cell carcinoma (NSCC) is the most frequent ungual malignant tumor, but its incidence remains low. The histopathological description is sparse. We aim to characterize NSCC histopathological aspects, search for a correlation with clinical subtypes, and investigate immunohistochemistry expression of p16, p53, and Ki67. METHODS: This retrospective study collected NSCC diagnosed in our dermatology department between 2007 and 2021. The histopathological features were correlated with the clinical signs and immunohistochemistry. RESULTS: A total of 48 patients were included, and immunohistochemistry was available for 36 of them. Two histopathological patterns became prominent: a blue-basaloid type characterized by koilocytosis (p < 0.001), and a pink-keratinizing type. Mean ages were similar when comparing basaloid and periungual versus keratinizing and subungual (p < 0.001). p16 was positive in 31 of 36 cases: 18 basaloid and 13 keratinizing (p = 0.167). p53 and Ki67 were all abnormal. CONCLUSIONS: Our study described two histopathological NSCC subtypes and associated them with the two clinical subtypes: the blue-basaloid type, HPV-induced, in situ, of periungual localization in younger males; and the pink-keratinizing type, non-HPV-induced, invasive, of subungual site, in elderly. Immunohistochemistry was not contributing on its own, but p16 positivity associated with basaloid histopathological profile helps support HPV etiology.

Subungual melanoma with cartilaginous differentiation: Molecular insights.

Melanoma's rare capacity to undergo heterologous differentiation can create significant diagnostic challenges. The molecular mechanisms underlying this phenomenon are not well understood. We present an unusual case of subungual melanoma exhibiting extensive cartilaginous differentiation and provide insights into its molecular and cytogenomic features. Histopathologically, the tumor was predominantly composed of nodules of malignant cartilage in association with a smaller population of nested epithelioid to rhabdoid cells. Immunohistochemically, the tumor cells in both components were positive for S100, SOX10, and PRAME, and were negative for Melan-A and HMB-45. Molecular analysis by whole exome DNA sequence did not detect any pathogenic variants in genes commonly implicated in melanoma. Additional analysis by SNP chromosomal microarray revealed a complex genome characterized by numerous chromosomal losses and gains, including a homozygous deletion of the CDKN2A locus and a heterozygous deletion of the locus containing EXT2, a tumor suppressor implicated in hereditary multiple osteochondromas and secondary chondrosarcomas. This case underscores the importance of recognizing cartilaginous differentiation as a rare manifestation of melanoma, particularly at subungual sites, and suggests that at least some of these melanomas may be driven by non-canonical molecular pathways.

Perianal and perineal keratoacanthoma: Two cases demonstrating histologic similarity to subungual keratoacanthoma.

Perianal keratoacanthomas are rare, with 10 cases reported to date. Perineal keratoacanthoma has not previously been described. In this report, we describe two cases of keratoacanthoma, one perianal and one perineal. Both lesions show prominent dyskeratotic keratinocytes, with striking and curious histologic resemblance to subungual keratoacanthoma.

The nail as an investigative tool in medicine: What a dermatologist ought to know.

The nail is an important skin appendage, but not many dermatologists are aware of the importance it receives outside our specialty. This article focuses on the nail in non-dermatological contexts. The nail is a keratinized matrix capable of continuous growth with the ability to incorporate various compounds within its structure. Therefore it can be used to monitor long-term consumption of drugs. It is also an excellent source of germ-line DNA for genetic analyses. With an increased undrstanding of nail physiology, there is now a better understanding of its connection to various pathologies as well. Nails, being peripherally placed, are easy to sample without significant discomfort to the patient, making them a valuable diagnostic tool. For this narrative review, we carried out a PubMed search using the key words "nail clipping," "nail DNA," "nail diabetes mellitus;" "nail clipping oncology," and "nail forensics". Retrieved articles were searched for information pertaining to non-dermatologic uses of nail for evaluation, which is presented in a narrative fashion. It is clear from recent literature that the nail is not just an inert skin appendage, but a dynamic window into the ever-changing metabolic and genetic milieu. We highlight the numerous roles of nail specimens, as well as point towards future research needed therein.

Subungual leiomyoma in the left thumb of a 16-year-old female.

Cutaneous leiomyomata, which are benign smooth muscle neoplasms, commonly present as dermal-based nodules or papules with smooth borders and firm consistency. Digital, particularly subungual leiomyomata are quite rare. A 16-year-old female presented to nail clinic complaining of discoloration of the lunula of the left thumbnail for 2.5 months. On initial examination, a pink longitudinal band was present in the center of the nail plate, with yellow discoloration and distal onycholysis. The patient had only mild tenderness with firm palpation, and did not recall trauma of the area. A nail matrix biopsy was performed to determine the etiology of the lesion. Microscopic examination demonstrated a well-demarcated dermal-based spindle-cell fascicular proliferation. Bland cells exhibited eosinophilic cytoplasm and elongate nuclei with blunt ends and minimal cytologic atypia. Prominent nucleoli, mitoses or necrosis were not appreciated. Immunohistochemical stains for smooth muscle actin and caldesmon highlighted the cells. Contrarily, S-100, epithelial membrane antigen, p63, factor XIIIa, CD34, CD68 and p75 were all negative. Ki-67 showed a low proliferative index. The immunoprofile combined with the morphologic features were interpreted as subungual leiomyoma. Subungual leiomyoma is a very rare diagnosis. We seek to bring awareness and expedite the diagnosis in patients with this lesion.

Superficial acral fibromyxoma and other slow-growing tumors in acral areas.

Superficial acral fibromyxoma (SAFM) is a rare fibromyxoid mesenchymal tumor with a predilection for the distal extremities and frequent nail bed involvement. Superficial acral fibromyxoma typically arises as a solitary, slow-growing nodule on a toe or finger, with the great toe being the most commonly affected site. Histopathologically, SAFM characteristically presents as a well-circumscribed but unencapsulated dermal tumor composed of spindle and stellate cells in a loose storiform or fascicular arrangement embedded in a myxoid, myxocollagenous, or collagenous stroma. The tumor often occupies the entire dermis and may extend into the subcutis and occasionally the underlying fascia and bone. The characteristic immunohistochemical profile of SAFM includes expression of CD34, epithelial membrane antigen (EMA), and CD99; it is notably negative for S-100 protein. We report 3 cases of SAFM and also provide a review of the literature on the clinical and histopathologic presentations of this unique entity as well as the differential diagnosis.

Invasive onychocytic carcinoma.

Neoplasms originating from nail matrix keratinocytes are very rare. Onychomatricoma and onychocytic matricoma are benign tumors arising from nail matrix keratinocytes. Only one case of onychocytic carcinoma, the malignant counterpart of onychocytic matricoma, has been reported in the literature. Herein, we describe a case of invasive onychocytic carcinoma. Two biopsy specimens of the tumor, obtained at early and invasive stages, were examined histopathologically. The first biopsy specimen showed a retiform proliferation of eosinophilic and basophilic cells in the nail matrix. The second biopsy specimen showed a retiform basophilic cell proliferation with focal keratinization. Similar to normal nail matrix keratinocytes, the proliferating basophilic cells failed to express cytokeratin (CK)1, CK6 and CK10. Focal expression of hair-specific keratins, including K31, K85 and K86, was observed. On the basis of these findings, the tumor was identified as an invasive malignant tumor originating from nail matrix keratinocytes.

Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome.

Keratoderma-hypotrichosis-leukonychia totalis syndrome (KHLS) is an extremely rare, autosomal-dominant disorder characterized by severe skin hyperkeratosis, congenital alopecia and leukonychia totalis. The genetic defect underlying KHLS remained undetermined. By performing whole-exome sequencing in a family with KHLS, we identified a heterozygous mutation (c.23G>T [p.Gly8Val]) in GJA1, which cosegregated with the phenotype in the family. In an additional affected individual, we also found the identical de novo mutation which was absent in his unaffected family members. GJA1 encodes a gap junction protein connexin 43 (Cx43) which is ubiquitously expressed in various organs, including the epidermis and hair follicles. In vitro studies on HEK293 cells expressing Cx43(Gly8Val) found that the protein formed gap junction plaques between adjacent transfected cells, as observed in the wild-type. Dye-transfer experiments by microinjection of Lucifer yellow displayed functional gap junction of the Cx43(Gly8Val) mutant. Using patch clamp and Ca(2+) imaging methods, we observed that the Cx43(Gly8Val) hemichannel had significantly more openings than Cx43(WT), facilitating Ca(2+) influx at resting potential. Such gain-of-function effect might result in cytoplasmic Ca(2+) overload, accelerated apoptosis of keratinocytes and subsequent skin hyperkeratosis. Taken together, our results demonstrated that, with probably enhanced hemichannel activities, a mutation in GJA1 is linked to KHLS without extracutaneous involvement.

Nuclear and cytoplasmic localization of ß-catenin in the nail-matrix cells and in an onychomatricoma.

ß-catenin plays an important role in hair morphogenesis. Previously, the nuclear and cytoplasmic localizations of ß-catenin were identified in hair-matrix cells. To evaluate ß-catenin expression in the nail matrix, we obtained human nail units. Immunohistochemistry for ß-catenin was used to evaluate sections of normal nail units and of sections from a single case of onychomatricoma. In the nail unit, ß-catenin was expressed in the nucleus and cytoplasm of the suprabasal nail-matrix cells. Of the other epithelial-cell types, only the cell membrane was ß-catenin-positive. In the nail tissue from the onychomatricoma case, ß-catenin was expressed in the nucleus and cytoplasm of the upper epithelial layers. Our result suggests that ß-catenin plays an important role in nail formation. In addition, ß-catenin expression in onychomatricoma supports the presence of nail-matrix cells in this condition. To our knowledge, this is the first report of ß-catenin expression in the nucleus and cytoplasm of the nail matrix.

Tumors of the nail unit. A review. Part I: acquired localized longitudinal melanonychia and erythronychia.

The article aims to be a guide to the interpretation of tumors specific to the nail, that is, tumors presenting peculiar histological features linked specifically to the nail unit. Therefore, the classical epithelial, fibroepithelial, and fibrous skin tumors occurring in the nail region are not analyzed. The interpretation of nail biopsies requires the identification and integration of the 2 main clinical modes of presentation of nail tumors, the acquired localized (monodactylous) longitudinal (ALL) band pattern, and the "masked" nail tumor. The ALL band pattern often allows the recognition of a nail tumor in its early phase of progression, with a limited differential diagnosis. The masked nail tumor mimics an inflammatory nail process, as a clinically misleading reactive benign lesion, which delays diagnosis with the subsequent development of partial nail loss and a locally destructive evolution. ALL band pattern appears as a longitudinal band starting at the matrix and extending to the tip of the nail plate. The band is usually single, rarely bifid. This clinical pattern can divided into 2 presentations. The generic term of ALL maculonychia could be proposed to define the macular aspect of the colored band of the nail plate. It encompasses 3 syndromes: longitudinal melanonychia, longitudinal erythronychia, and longitudinal leukonychia. ALL pachyonychia is a rare presentation. Pachyonychia indicates a localized thickening of the nail plate specific to the matrical nail tumor. In this group, there is differentiation toward cells of the nail matrix. The prototype tumor is the onychomatricoma, which present classically with a yellow (xantholeukonychia) band pattern. Recently, a new clinical band pattern has been described as longitudinal pachymelanonychia with 2 etiologies: pigmented onychomatricoma and onychocytic matricoma. The first part of this review delineate, in the first section, the distinctive microanatomical features of the nail unit and the second is dedicated to the most important pitfalls in pathological diagnosis of nail tumors because of nail surgery techniques. In the third section, the histopathology of ALL melanonychia and ALL erythronychia is discussed in a detailed description.

Onychocytic carcinoma: a new entity.

We have recently described a new nail tumor known as onychocytic matricoma. Herein, we describe its malignant counterpart. Clinically, the tumor simulates onychomatricoma (OM). Histologically, this in situ malignant epithelial tumor exhibits a distinct picture of onychocytic differentiation with signs of both nail matrical differentiation and nail plate differentiation. We have proposed the name onychocytic carcinoma for this singular adnexal neoplasm. Given the peculiar thickening of the nail plate observed in OM, onychocytic matricoma, and onychocytic carcinoma, the clinical individualization of a new type of nail band pattern could be proposed. It presents as an acquired localized (monodactylous) longitudinal pachyonychia. Such longitudinal pachyonychia allow the recognition of the matrical nail tumor, which has a limited etiological spectrum. Xantholeucopachyonychia suggests mainly OM and rarely onychocytic carcinoma. Pachymelanonychia suggests onychocytic matricoma and rarely pigmented OM or onychocytic carcinoma.

GJB6, of which mutations underlie Clouston syndrome, is a potential direct target gene of p63.

BACKGROUND: Clouston syndrome is a rare autosomal dominant condition characterized by hypotrichosis, nail dystrophy, and occasionally palmoplantar keratoderma. The disease is caused by mutations in GJB6 gene, which encodes a gap junction protein connexin 30 (Cx30). OBJECTIVE: To disclose the molecular basis of Clouston syndrome in a Lebanese-German family, and also to determine precise expression of Cx30 in normal skin of humans and mice, as well as transcriptional regulation for the GJB6 expression. METHODS: We searched for mutations in the GJB6 gene using DNA of the family members with Clouston syndrome. We performed immunostaining to localize the Cx30 expression in normal human skin and mouse embryos. In addition, we did a series of in vitro studies to investigate if the GJB6 could be a direct transcriptional target gene of p63. RESULTS: We identified a recurrent heterozygous mutation c.31G>C (p.Gly11Arg) in the GJB6 gene in the Lebanese-German family with Clouston syndrome. Immunostaining in normal human skin sections demonstrated predominant expression of Cx30 in hair follicles, nails, and palmoplantar epidermis, which partially overlapped with p63 expression. We also showed co-expression of Cx30 and p63 in developing mouse hair follicles and nail units. In cultured cells, the GJB6 expression was significantly upregulated by ΔNp63α isoform. Further in vitro analyses suggested that ΔNp63α was potentially involved in the GJB6 expression via binding to the sequences in intron 1 of the GJB6 gene. CONCLUSION: Our data further underscore the crucial roles of Cx30 in morphogenesis and development of skin and its appendages.