Introduction: Onycholemmal carcinoma (OC) is a rare subtype of squamous cell carcinoma (SCC) that originates from the epithelium of the nail bed. It is characterized by distinct histopathologic features including small clusters of atypical squamous epithelium devoid of a granular layer, with abrupt onycholemmal keratinization. Case Presentation: We present a case of a 75-year-old male with right thumbnail onycholysis, yellow-green nail plate discoloration, as well as bleeding and purulence of the lateral nail fold. Histopathologic evaluation revealed high-grade squamous dysplasia, small clusters of severely atypical epithelial cells, and a pattern of abrupt keratinization consistent with the diagnosis of SCC carcinoma with onycholemmal features. GMS and PAS staining indicated concomitant onychomycosis. Pathologic analysis also disclosed residual SCC and concomitant amyloidosis, possibly light chain related and hence reflective of his underlying multi-organ lymphoplasmacytic lymphoma. The patient subsequently underwent Mohs micrographic surgery. Conclusion: Clinical presentation of nail unit SCC with onycholemmal features is highly variable, making differentiating between similarly presenting benign and malignant nail disorders particularly challenging. This case report demonstrates clinical and histopathological features of nail unit SCC with onycholemmal features to improve diagnosis and management.

© 2023 The Author(s). Published by S. Karger AG, Basel

Established Facts

• Nail unit squamous cell carcinoma with onycholemmal features is characterized by clusters of severely atypical epithelial cells and a pattern of abrupt keratinization.

• It is likely underdiagnosed due to its indolent nature and similar clinical presentation to other nail conditions.

Novel Insights

• Prior to our case, there have been only 15 other cases.

• It typically presents in middle-aged to older adults with onychodystrophy of a single fingernail. Since diagnosis is often delayed, physicians should have a low index of suspicion to perform a biopsy when a patient presents with painful onychodystrophy involving a single nail.

Introduction

Onycholemmal carcinoma (OC) is a rare variant of subungual squamous cell carcinoma that arises from the nail bed epithelium [1]. OC was first described in 2004 as a subungual malignant epithelial tumor with onycholemmal keratinization reminiscent of trichilemmal keratinization of outer root sheath follicular derivation [1, 2]. Patients typically present with a slow-growing nodule that may be associated pain, edema, erythema, bleeding, erythronychia, onycholysis, or bony involvement in the later course of the disease [1–5]. Herein, we present a case of subungual SCC with features of the OC subtype and review the existing literature.

Case Presentation

A 75-year-old male presented with a 2-year history of pain and lifting of his right thumbnail. He reported that his nail bled starting 4 months prior to presentation. He also reported throbbing and swelling. His medical history was significant for basal cell carcinoma of the nose, follicle center lymphoma, Waldenström macroglobulinemia, first-degree atrioventricular block, portal hypertension, and autoimmune hemolytic anemia. On physical examination, his right thumbnail was onycholytic with yellow-green discoloration and heme-crust and purulence of the lateral nail fold (shown in Fig. 1). His other fingernails and toenails were completely normal. Wound culture of the affected nail grew Pseudomonas aeruginosa, coagulase-negative staphylococcus, Staphylococcus lugdunensis, Corynebacterium, and gram-positive cocci. A longitudinal excision including the nail plate, matrix, and bed was performed. Histopathology showed high-grade squamous dysplasia with both in situ and invasive components. There were also small clusters of severely atypical epithelial cells and a pattern of abrupt keratinization known as “onycholemmal keratinization.” These histopathological findings were consistent with a diagnosis of a distinct but rare subcategory of SCC of the nail unit known as onycholemmal carcinoma (shown in Fig. 2). There was an incidental finding of amyloid deposition in the nail and a light chain variant would be reflective of his underlying Waldenstrom’s macroglobulinemia. Periodic acid-Schiff (PAS) and the Grocott methenamine silver (GMS) staining revealed septated hyphal elements in the horn and plate. These features were diagnostic of subungual SCC with features of OC with concomitant onychomycosis. The patient was treated with Mohs micrographic surgery and the tumor was cleared in two stages. He also received subsequent treatment for onychomycosis.

Fig. 1.

a Clinical appearance of OC on the thumbnail with onycholysis, yellow-green discoloration, and heme-crust of the lateral nail fold. b Dermoscopy of OC showing yellow-green discoloration with medial fading and sparing of the proximal nail plate.

Fig. 2.

The biopsy shows fragments of nail plate, detached nail bed, and nail matrix (H&E, ×20 (a)). There is a very atypical epithelial proliferation that assumes an endophytic growth pattern within the corium (H&E, ×40 (b)). The epithelial islands show severe keratinocytic atypia compatible with squamous cell carcinoma. Coursing through the corium are infiltrative lobules of malignant squamous epithelium with abrupt central keratinization, defining a classic architectural and cytomorphologic clue to the diagnosis of onycholemmal carcinoma (H&E, ×400 (c, d)). The arrows in (c, d) outline the neoplastic lobules.

Discussion

Herein, we report a case of SCC of the nail unit with distinct features of the previously described variant, OC, presenting as a very rare slow-growing malignant tumor arising from nail bed epithelium [4]. Since it was first described by Alessi et al. [4] in 2004, there have only been 15 previously reported cases in the English literature, which are summarized in Table 1[1–10]. Previously reported cases of OC have presented with varying clinical manifestations. Clinical presentation can include pain, onychodystrophy, onycholysis, edema, erythema, erythronychia, bleeding, or ulceration [1–5]. In some reported cases, including ours, OC is described as painful but reporting on symptomatology is inconsistent and it is possible that some are painless. As with other subtypes of SCC involving the nail unit, the indolent nature and variable clinical features of OC may contribute to missed and delayed diagnosis [1, 2, 9–11].

Table 1.

Summary of onycholemmal carcinoma cases in the English scientific literature

CaseReferenceAge/sexLocationSizeClinical duration1Alessi et al. (2004) [4]69, MR5Not reportedNot reported2Inaoki et al. (2006) [2]70, MR55 mm5 years3Rashid and Cutlan (2010) [5]73, FL12 cm1 year4Perrin et al. (2012) [6]58, ML3Not reported3 years5Chaser et al. (2013) [1]39, FL41 cm5 years6Chaser et al. (2013) [1]84, FR4Not reported6 months7Chaser et al. (2013) [1]64, ML1 (Toe)“At least 5 mm”“Extended period”8Chaser et al. (2013) [1]53, ML3Not reported“Extended period”9Chaser et al. (2013) [1]56, MNot reportedNot reportedNot reported10Chaser et al. (2013) [1]73, FR1Not reported5 years11Debarbieux et al. (2015) [7]77, MNot reportedNot reportedNot reported12Han et al (2017) [8]77, ML21 × 1 cm4 years13Maffeis et al. (2018) [9]65, FL21.7 × 1.1 cm1 year14Gaddis et al. (2018) [10]69, FR41.5 × 1 cm4 years15Bagla and Agrawal (2020) [3]70, FR22 mm3 months16Present case75, MR10.5 × 1.0 cm2 yearsCaseClinical presentationImaging findingsTreatment methodRecurrenceFollow-upMetastasis1Subungual discoloration with apparatus destruction and bleeding ulcerXR: osteolysis of the phalangeal boneDisarticulationNo4 yearsNo2Indolent onycholysis and periungual crustsXR: No osteolysisResection and disarticulationNo7 monthsNo3Pain, edema, erythema, and cracked nailMRI: no osteolysis, enhancing soft tissueAmputation with SLNBNo1 yearNo4Indolent onycholysis and yellow discolorationNo osteolysisAmputationNo2 yearsNo5Ulcer of periungual skinNot reportedaMohs surgeryNo1 yearNo6Pain and swelling resembling paronychiaNot reportedaDebridement, excisionNo3 monthsNo7Pain and swelling of nail resembling paronychiaNot reportedaAmputationNo4 yearsNo8Hyperkeratotic plaque of nailNot reportedaNail apparatus excisionNo4 yearsNo9Not reportedNot reportedaAmputationNot reportedNot reportedNot reported10Onycholysis and erythemaNot reportedaRadiationNo8 monthsNo11Nail bed tumor with reddish structureless area on dermoscopyNot reportedNot reportedNot reportedNot reportedNot reported12Slow-growing, painful lobulated massXR: osteolysisAmputationNot reportedNot reportedNot reported13Slow-growing ulcerated nodule and onychodystrophyXR: periungual soft tissue calcifications
MRI: soft tissue edemaAmputationNo1 yearNo14Erythronychia, then onycholysis; later, bleeding, painful subungual tumorXR: no osteolysisMohs surgeryNo3 monthsNo15Not reportedXR: no osteolysis
MRI: no osteolysisDisarticulationNo3 monthsNo16Slow growing mass with pain, edema, onycholysis, and yellow-green discolorationNot reportedMohs surgeryN/AN/AN/A

The most common signs and symptoms in the 16 OC cases were pain (43%), onycholysis (36%), and edema (36%), while discoloration (29%), erythema (21%), bleeding (21%), ulceration (14%), crust (7%), onychodystrophy (7%), and hyperkeratotic plaque (7%) were less common. The average time to diagnosis was 2 years and 9 months with a range of 3 months to 5 years.

In almost all cases, apart from 1 case where it presented in a toenail, the tumor involved a single finger [1]. OC presented on the left (46%) and right (54%) hands with similar frequency. The first, second, and fourth digits were each affected in 23% of the cases, while the third and the fifth were affected in 15% of the cases. The average size among those reported was 10.5 mm and ranged between 2 mm and 2 cm. The average age of diagnosis was 67 years old with a range of 39–84 years of age. There was a slight male predominance (56%). In the eight reports that included imaging, only 3 cases showed osteolysis, soft tissue edema, calcifications, or enhancement. The length of time between treatment and follow-up ranged from 3 months to 4 years with an average of 1 year and 7 months, with no identified recurrences [1–10].

Like other variants of nail unit SCC, nail unit SCC with onycholemmal features may have a clinical presentation that mimics both benign and malignant nail conditions. It must therefore be differentiated from onycholemmal cysts, onycholemmal horns, onychomatricomas, Bowen’s disease, and conventional nail unit SCC, which are summarized in Table 2[9]. Onycholemmal cysts are most often asymptomatic and found incidentally when investigating other diagnoses such as subungual malignant melanoma with biopsy and histopathology [12]. While onycholemmal cysts also derive from the nail bed with abrupt central keratinization, they differ from OC due to their lack of atypical squamous epithelium or infiltrative growth [1, 12, 13]. Nevertheless, there are overlapping features with OC given the lobulated architectural growth pattern of the agminated epithelial lined cysts and the presence of abrupt onycholemmal keratinization. Onycholemmal horns are exceedingly rare, arising from the nail bed and presenting as slow-growing exophytic tumors [14]. Histologically, onycholemmal horns uniquely contain cuboidal basal cells, centrally enlarging pale staining cells, and demonstrate abrupt keratinization [15]. An onychomatricoma is a benign tumor of the nail matrix that may present with splinter hemorrhages, xanthonychia, nail plate thickening, and cavities at the free edge of the nail plate [16]. It is histologically characterized by fibroepithelial projections surmounted by benign epithelium, creating perforations that form channels in the nail plate [17]. Periungual Bowen’s disease is an in situ SCC of the nail [18]. It has a wide range of clinical presentations, varying from a verrucous mass to longitudinal melanonychia and destruction of the nail plate [19, 20]. Classical histological features of Bowen’s disease include larger atypical keratinocytes exhibiting high nuclear to cytoplasmic ratios present throughout the epithelium, prominent dyskeratosis, and atypical suprabasilar mitoses, without evidence of invasion [19]. Some cases are linked to high-risk human papillomavirus (HPV) infection. Invasive subungual SCC may arise from the nail bed, matrix, groove, or nail folds; the precursor lesion is Bowen’s disease, i.e., squamous cell carcinoma in situ. Among the clinical manifestations are onycholysis, erythema, and nail ulceration [21]. However, it lacks the lobulated architectural growth pattern with abrupt keratinization reminiscent of a proliferating pilar tumor that characterizes OC.

Table 2.

Summary of differential diagnoses for onycholemmal carcinoma

Differential diagnosisClinical featuresHistopathological featuresMalignancyOnycholemmal cystOften asymptomaticOriginates from nail bed epithelium, has multiple cysts with some containing onycholemmal keratin, no atypical squamous epithelium or infiltrative growthBenignOnycholemmal hornPainless, slow-growing exophytic tumorOriginates from nail bed epithelium, consists of cuboidal basal cells, centrally enlarging pale staining cells, and typically demonstrate keratinizationBenignOnychomatricomaCan present with splinter hemorrhages, xanthonychia, nail plate thickening, and cavities at the free edge of the nail plateOriginates from nail matrix, fibroepithelial projections surmounted by benign epithelium, perforations in the nail plateBenignBowen’s diseaseCan present with a flat, verrucous mass, onycholysis, longitudinal melanonychia, nail plate destructionVariable origin within the nail unit, large, atypical keratinocytes with hyperchromatic nuclei, prominent dyskeratosis, and atypical suprabasilar mitoses, without evidence of invasionMalignantConventional nail unit SCCCan present with onycholysis, erythema, verrucous growth, ulcerationVariable origin within the nail unit, marked cellular atypia, hyperchromatic nuclei, pathological mitoses, irregular, and incomplete keratinizationMalignant

The diagnosis of OC is largely based on histopathology. While certain histopathological features of OC are similar to the trichilemmal keratinization found in the hair follicle, the keratinization of this tumor is clearly one that is embryologically unrelated to the hair follicle and one reflective of the keratinization encountered in nail bed epithelium, namely, onycholemmal keratinization [4]. The morphologic hallmarks include lobules of mature squamous epithelium exhibiting abrupt central keratinization. The infiltrative lobulated growth pattern and cytologic atypia allow one to designate the atypical proliferative lesion as OC as opposed to representing onycholemmal cysts [1, 4].

One case study investigated the relationship between onycholemmal and trichilemmal keratinization, by staining tissue for an OC tumor with antibodies against hair follicle-derived keratins such as CD8/CK15, CK8, CK18, CK19, and CK7. The tumor was negative for almost all the keratins, suggesting the tumor was distinct from hair differentiation [2]. Molecular profiling was performed in another case suggesting that mutations in the p16/Rb/E2F pathway may be responsible for the pathogenesis of OC [9]. Though the etiology of nail unit SCC remains unknown, there is an association with human papilloma virus (HPV), particularly HPV 16 [11]. In a retrospective review of 31 cases of nail unit SCC, 19 cases were tested for HPV and 78.9% were positive [22]. Despite the association of HPV infection with periungual SCC, no relationship with HPV has been identified in two previously reported OC cases [1, 9]. Due to lack of evidence of an established role of HPV in the etiology of nail unit SCC with onycholemmal features and cost to the patient, we did not perform HPV testing.

In this case, histopathological studies also revealed concomitant onychomycosis for which the treatment was deferred until treatment of the tumor. There are no other cases of nail unit SCC with onycholemmal features associated with onychomycosis. However, onychomatricoma and other nail tumors may present with concurrent onychomycosis [23]. While onychomycosis is a frequently diagnosed nail condition, onychomycosis of the fingernail without toenail involvement is rare and should raise suspicion of additional etiologic sources of nail deformity [24]. The association of the tumor with amyloidosis is interesting but of unclear significance pathogenetically. One might question whether the altered composition of the corium immediately beneath the nail bed epithelium provided a local microenvironment conducive to carcinogenesis. The benign counterpart, namely, onycholemmal cyst, has been linked with trauma. However, the evolution of onycholemmal cysts into OC has not been described. We did not demonstrate unequivocally that the amyloid deposits are light chain derived. They could also be of keratinocytic derivation and reminiscent of the pattern of keratinocyte derived amyloidosis seen in the setting of vulvar intraepithelial neoplasia.

No standardized treatment of nail unit SCC with onycholemmal features has been established. Of the reported cases in which the method of treatment was provided (N = 14), nine (60%) were treated with amputation or disarticulation of the involved phalanx, two (13%) were treated with Mohs micrographic surgery, two with excision, and one with radiation [1–10]. One study proposed a method of intraoperative diagnosis of invasive epithelial malignant nonpigmented nail tumors, such as OC, using ex vivo fluorescence confocal microscopy (FCM). The authors suggested that ex vivo FCM can be used to intraoperatively assess the surgical margins of excised tissue during a wide excision procedure, which can shorten surgical management and serve as an alternative to Mohs micrographic surgery for the management of nonmelanocytic nail unit tumors [7]. In 1 case, a sentinel lymph node biopsy was done but no lymph node involvement was found. While bony destruction of the phalangeal bone and soft tissue has been described in 4 cases, most cases have no associated findings in imaging studies [4, 5, 9, 10]. No OC cases resulting in local recurrence, regional lymph node metastasis, systemic spread, or death have been reported to date. Due to the absence of reported metastasis and the optimal patient outcomes attained with Mohs micrographic surgery, radiation, and conservative excision, these less invasive methods may serve as suitable alternatives for amputation and disarticulation. The establishment of these alternative procedures as standard treatment for such cases offers an opportunity for successful local eradication and minimization of physical disability.

Conclusion

Nail unit SCC may rarely present with onycholemmal features on histopathology. Its similar clinical and histological presentations to other nail disorders complicate diagnosis and may lead to delayed diagnosis treatment. Although most reported cases were treated with amputation or disarticulation of the affected digit, less invasive, digit-sparing procedures have demonstrated comparable results while preserving functionality. The OC subtype of nail unit SCC typically presents in middle-aged to older adults with onychodystrophy on a single fingernail. Since diagnosis is often delayed, physicians should have a low index of suspicion to perform a biopsy when a patient presents with onychodystrophy involving a single nail.

Statement of Ethics

Ethical approval was not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and accompanying images.

Conflict of Interest Statement

Kelita Waterton and Dr. Magro have no conflicts of interest. Dr. Lipner has served as a consultant for Hoth Therapeutics, Ortho-Dermatologics, Moberg Pharmaceutricals, and BelleTorus Corporation.

Funding Sources

This article has no funding source.

Author Contributions

Kelita Waterton contributed to the chart review, literature review, drafting, editing, and revision of the final manuscript. Dr. Lipner conceived the project, edited, and revised the manuscript. Dr. Magro rendered the diagnosis, wrote the pathology section of the paper, and provided photomicrographs with figure legends.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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