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Review Article

Treatment Options and Outcomes for Squamous Cell Carcinoma of the Nail Unit: A Systematic Review

Ning, Anne Y. MD*; Levoska, Melissa A. MD; Zheng, David X. BA*; Carroll, Bryan T. MD, PhD; Wong, Christina Y. MD

Author Information
doi: 10.1097/DSS.0000000000003319


Squamous cell carcinoma is the most common malignancy of the nail unit (nSCC).1 Clinical presentations are highly variable and there is currently no established treatment algorithm or definitive standard of care for nSCC.2–8 Since the 1980s, treatment options for nSCC have included topical therapies, radiation therapy, cryotherapy, curettage, wide surgical excision (WSE) or local surgical excision (LSE), Mohs micrographic surgery (MMS), and amputation.9–13 Recent studies emphasize MMS as a promising treatment option for nSCC given the low observed recurrence rates, but little is known about its efficacy compared with other treatment options.2,13–15 The objective of this study was to review the literature to identify trends in nSCC treatments and evaluate current treatment options based on reported outcomes in the literature for both invasive and in situ nSCC.


The authors performed a systematic review following the PRISMA 2009 guidelines and searched PubMed (1966-), Scopus (1966-), and MEDLINE (1946-) for articles published from inception to April 30, 2020. Search terms were “squamous cell carcinoma” and “nail”/“nail unit”/“subungual” and “treatment”/“wide excision”/“local excision”/“en bloc excision”/“amputation”/“functional/conservative/topical treatment”/“cryotherapy” and “recurrence”/“metastasis”/“survival.” Case reports and series with fewer than 5 patients, reviews, editorials, and non-English articles were excluded. Full-text articles and references were reviewed for eligibility and assessed for bias using the risk of bias assessment tool for non-randomized studies (RoBANS).16 All articles meeting above criteria (n = 15) were used to assess temporal trends in reporting of nSCC treatment. Study type, patient age, tumor invasion, treatment modality, and follow-up time frames were recorded for all articles. To evaluate treatment outcomes, articles in which outcomes could not be separated based on degree of cancer invasion (n = 8) were excluded and the remaining articles (n = 7) were used. The primary outcomes were local recurrence (LR) and persistent disease (PD). Local recurrence was defined according to the Leitenberger criteria as appearing within the area of the original tumor when possible; otherwise, recurrence was reported as defined by the articles' authors.17 Disease was classified as PD when positive margins were reported after treatment. The secondary outcomes were regional metastases, distal metastases, and disease-specific death. Treatments were defined as reported by the original authors. Wide surgical excision includes en bloc excision of the nail unit. All medical and surgical treatments reported in eligible studies were included. Chi-square and Fisher exact tests were performed as appropriate (SPSS 27; IBM, Armonk, NY).


Of the 276 articles identified, 15 met the inclusion criteria for evaluation of nSCC treatment outcomes over time (See Supplemental Digital Content 1, Figure S1, Most were retrospective cohort studies (73%, n = 11); 4 were case series. All articles had a level of evidence of 4 based on study design and overall low risk of bias using RoBANS (Table 1). No articles directly compared treatment options for in situ and invasive nSCC.

TABLE 1. - Risk of Bias Based on the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS)
Article Selection of Participants Confounding Variables Measurement of Exposure Blinding of Outcome Assessments* Incomplete Outcome Data Selective Outcome Reporting
Carroll, 1976 Low High Low Low Low Low
Goldminz and colleagues, 1992 Low Low Low Low Low Low
de Berker and colleagues, 1996 Low Low Low Low Low Low
Figus and colleagues, 2006 Low Low Low Low Low Low
Dalle and colleagues, 2007 Low Low Low Low Low Low
Grootenboers and colleagues, 2007 Low Low Low Low Low Low
Dika and colleagues, 2012 Low Low Low Low Low Low
Young and colleagues, 2012 High Low Low Low Low Low
Lecerf and colleagues, 2013 Low Low Low Low High Low
Wollina, 2015 Low Low Low Low Low Low
Dika and colleagues, 2015 Low Low Low Low Low Low
Tang and colleagues, 2015 Low Low Low Low Low Low
Topin-Ruiz and colleagues, 2017 Low High Low Low Low Low
Lee and colleagues, 2019 Low Low Low Low Low Low
Gou and colleagues, 2019 Low Low Low Low Low Low
*Studies with no blinding of outcome assessments and outcomes not likely influenced by the lack of blinding as assessed by review authors were marked as low risk.

Temporal Trends in Reporting of Nail Squamous Cell Carcinoma Treatment

From 15 articles, 404 patients with 418 nSCCs were included (See Supplemental Digital Content 2, Table S1, Most patients were male (73%, n = 277 of total 379 patients with reported sex), and most tumors occurred on fingernails (88%, n = 345 of total 393 nSCCs with reported location). The most common treatments performed were MMS (44%, n = 185), WSE (20%, n = 83), and amputation (15%, n = 62).

While the first article to report MMS for nSCC treatment was published in 1992, the first article to suggest MMS as the first-line treatment for nSCC was published in 2001.18,19 In the 1990s, the most common treatments reported were amputation (43%, n = 26 of 60 total), MMS (42%, n = 25), fixed-tissue MMS alternative (13%, n = 8), and WSE (2%, n = 1). In the 2000s, 53 reported nSCCs were treated by WSE (47%, n = 25), radiation therapy (23%, n = 12), LSE (17%, n = 9), and amputation (13%, n = 7). In the 2010s, the most commonly reported treatments were MMS (52%, n = 160 of 305 total) and WSE (19%, n = 57).

Since the 2000s and particularly in the 2010s, reports of nSCC treatment have increased (Figure 1). Reported MMS use varied from 42% in the 1990s (n = 25 from a total of 60 reported cases) to 0% in the 2000s (n = 0, 53 total reported cases) and 52% in the 2010s (n = 160, total 305 reported cases). Similarly, fixed-tissue MMS alternatives for nSCC were reported in the 1990s (13%, n = 8 of 60) and 2010s (4%, n = 12 of 305), but not the 2000s. Conversely, reports of WSE increased from 2% in the 1990s (n = 1 of 60) to 47% in the 2000s (n = 25 of 53) and decreased to 19% since 2010 (n = 57 of 305). Radiation therapy for nSCC was initially reported in the 2000s (23%, n = 12 of 53) but seldom reported in the 2010s (0%, n = 1 of 305). Techniques including incisional biopsy (IBx), curettage, and phototherapy were reported only after 2010.

Figure 1.:
Temporal trends in reporting of nSCC treatment by decade. IBx, incisional biopsy; IBx + TA, incisional biopsy with topical adjuvant therapy; LECM, limited excision until clearing of margins; LSE, limited surgical excision; MMS, Mohs micrographic surgery; WSE, wide surgical excision.

Treatment Based on Degree of Invasion

Seven articles reporting 156 nSCCs in total (65 in situ, 91 invasive) specified degree of invasion (See Supplemental Digital Content 3, Table S2,–26 Most patients were male (n = 111 of total 152, 73%), and most nSCCs were located on the fingernails (n = 127, 81%). Sample sizes were inadequate for comparison between noninvasive and invasive disease based on treatment type, and there was no statistically significant difference in the overall recurrence rate based on invasion. Regional and distal metastases were reported in 1 case.20 In situ nSCC was most commonly treated with MMS (37%, n = 24 of 65 total) or LSE (22%, n = 14). Invasive disease was most commonly treated with MMS (22%, n = 20 of 91 total) or WSE (20%, n = 18). Follow-up ranged from 2 months to 16 years. Outcomes based on invasion were assessed for each reported treatment.

In Situ Nail Squamous Cell Carcinoma

A total of 65 nSCCs in situ were reported with an overall recurrence rate of 26% (n = 17).

Twenty-four cases of nSCC in situ were treated with MMS with an LR rate of 17% (n = 4). The average time to second presentation of disease was 47 months.22,23,25,26 Of the 4 cases with reported recurrences, 3 presented as in situ nSCC (75%) while 1 case presented as invasive nSCC (25%). Two of 3 patients treated with LSE reported recurrence for an LR rate of 67%.24,26 Two patients with in situ nSCC were treated by amputation; both reported LR (100%).20,24 One patient had negative margins after amputation and reported LR (location unspecified) at 19 months. Margins were not reported for the second patient, who had LR at the site of amputation at 2 months with subsequent RM, DM, and DSD. Six patients with in situ nSCC were treated with en bloc ablation of the nail unit with 6-mm margins with an LR rate of 33% (n = 2).24 The 2 patients with recurrent disease had clear margins reported pathologically following the procedure. Eight patients with in situ disease were treated with a fixed-tissue alternative to MMS termed limited excision until clearing of margins (LECMs) with 1 reported LR (13%).24

Eleven cases of nSCC in situ were treated with IBx alone. Of these, 2 reported LR (18%).24 Five additional patients were treated with a combination of IBx and adjuvant therapy, including topical imiquimod with bleopuncture (n = 3), topical imiquimod with bleopuncture and complementary excision (n = 1), and photodynamic therapy (n = 1). Of these 5 patients, 3 presented with recurrent disease (60%). Two patients were treated with curettage alone, resulting in a 50% LR rate (n = 1). One additional patient was treated with combination curettage and topical fluorouracil with no reported recurrence (0%).

Among the 45 cases of in situ nSCC for which margins were reported, 7 cases reported PD after treatment (16%).23,24 Treatments with the highest PD rate for in situ nSCC were, in descending order, IBx with topical adjuvant (40%, n = 2 of 5), IBx alone (36%, n = 4 of 11), and MMS (9%, n = 1 of 11). No positive margins were reported after LECM (n = 8), en bloc ablation (n = 6), curettage alone (n = 2), curettage with topical adjuvant (n = 1), or amputation (n = 1).

Invasive Nail Squamous Cell Carcinoma

A total of 91 cases of invasive nSCCs were assessed, from which 13 recurrences were reported for an LR rate of 14%.

Twenty invasive nSCCs were treated with MMS with an LR rate of 5% (n = 1) reported at 13 months.22,23,25,26 Eighteen invasive nSCCs were treated by WSE; surgical margins were not reported.20,26 Local recurrence occurred in 1 patient at 36 months (6%). Ten patients with invasive nSCC were treated with LSE with a 50% LR rate (n = 5) and average time to recurrence of 14 months.20,26 Twelve patients with invasive nSCC were treated with amputation with no reported recurrences (0%).20,24,26 Ten patients with invasive disease were treated with en bloc ablation with 6-mm margins; 2 patients developed recurrent disease for an LR rate of 20%.24 One of 12 patients with invasive nSCC of the hand treated with radiation therapy alone reported LR (8%) at 23 months.21 The patient was treated with amputation because of radiation necrosis of the digit and had no evidence of further recurrence at 30-month follow-up. Four patients with invasive nSCC were treated with LECM with 1 reported LR (25%).

Margins after treatment were reported for 22 cases of invasive nSCC.23,24 Six had positive margins for an overall PD rate of 27%. Treatments with the highest rates of PD were IBx (100%, n = 1 of 1), MMS (50%, n = 1 of 2), LECM (25%, n = 1 of 4), partial ablation (25%, n = 1 of 4), and en bloc ablation (20%, n = 2 of 10). The remaining case was treated by amputation and reported clear margins.

Bone Invasion

Data specifying bone involvement in nSCCs with recurrence were obtained for a total of 76 unique nSCCs.22,26,27 Bone invasion was present in 21 cases (28%), 19 of which were detected radiographically (90%). The assessment of bone involvement in the remaining 2 cases was unspecified.26 All cases were treated with MMS (43%, n = 9), an LR rate of 22% (n = 2), or amputation (57%, n = 12), an LR rate of 0% (n = 0). Follow-up times were not specified.


This systematic review assesses trends in reported nSCC treatments and patient outcomes by treatment based on tumor invasion. Because MMS was proposed as a first-line treatment for nSCC, reports of amputation have decreased; however, the proportion of reports of nSCC treated with MMS has remained stable. Recent literature has seen increased reporting of other surgical treatments for nSCC, including WSE, LSE, IBx, and curettage. Nonsurgical treatments are rarely described and are generally associated with high recurrence rates. Existing literature on the treatment of nSCC demonstrates increasing interest regarding surgical management of nSCC but does not yet reflect a focus on MMS as the first-line treatment option.

Overall recurrence rates for radiation therapy, phototherapy, and curettage were over 3-fold greater than rates reported after surgical treatments.14,26,28 Current evidence suggests nonsurgical interventions alone are not appropriate for treatment due to poor margin clearance and high recurrence rates.29,30 Incisional biopsy implies inadequate margin clearance was associated with a high rate of PD and is not a definitive treatment option for nSCC. The treatments for in situ nSCC associated with the lowest recurrence rates were WSE, LECM, and MMS. For invasive disease, the lowest recurrence rates were observed with amputation, MMS, and WSE.

Rates of both recurrence and PD were higher for in situ disease versus invasive nSCC, although these findings were not statistically significant. In addition, the only metastasis reported occurred after treatment of an in situ nSCC.20 Overall, these data likely reflect the difficulty in determining the degree of invasion of nSCC histopathologically. The structure of the nail unit lends itself to confusion when distinguishing normal histology from tumor invasion, given the acanthotic epidermis and prominent rete ridges of the normal nail matrix.23,27 Nail squamous cell carcinomas further elongate the rete ridges and grow deep into the dermis of the nail bed, which lacks a subcutaneous tissue layer and sits directly on the periosteum. In both in situ and invasive forms of nSCC, the rete ridges may extend to about the periosteum, particularly when located on the nail bed, leading some experts to recommend a single treatment algorithm for both forms of disease under the term “epidermoid carcinoma.”31,32 Because the nail unit is composed of distinct epithelial structures, classification of nSCC based on epithelial origin has also been proposed but requires further study.31,33 Invasive nSCC can also be missed in partial biopsies because of sampling error, and traditional bread loafing may skip foci of invasion.24 Subungual malignancies are not necessarily confined to the anatomical borders of the nail and nonsurgical treatments may create skip lesions, further complicating assessment.25,34 Because of the difficulty in diagnosing invasion, current evidence highlights the need to confirm negative margins after any treatment modality even for in situ nSCC. Although the rate of upstaging nSCC from in situ to invasive disease is just under 10%, similar to that of other skin cancers, many cases of nSCC present as recurrent tumors after previous nonsurgical treatments, even in young patients.14,34 This highlights the importance of establishing proper treatment guidelines and first-line treatment of nSCC.

Wide surgical excision and MMS were associated with low recurrence rates regardless of degree of invasion. Deciding between the 2 treatments involves consideration of patient comorbidities, location on an important functional digit, provider experience, patient preference, and health care expenditures.19,32,35 Recent studies have highlighted MMS as optimal first-line treatment for nSCC.14,24 While WSE is faster and less complex, MMS of the nail unit allows for better preservation of tissue and function.35–38 However, this technique can be challenging and time-consuming due to the complex structure of the nail unit.19,23,39–41 Given the normal architecture of the nail unit, intraoperative assessment of margins requires close attention to orientation.19,23,42 Reports of positive margins and PD after MMS suggest outcomes may also be limited by provider technique and tissue processing.23 Fixed-tissue alternatives to MMS and advancements in nail surgery technique, such as eliminating nail plate avulsion where possible to preserve the epithelium, may improve patient outcomes when used to treat nSCC but require further study.20,24,32,43,44 Mohs micrographic surgery has also been used in conjunction with adjuvant therapies to successfully treat nSCC.11,45 A modified MMS technique that samples bone at the deep margin allows bone to be processed as part of the soft tissue specimen and can be useful in determining bone involvement for nSCC.10,22,32,43,44 Given variation in techniques for surgical excision and tissue processing, standardized reporting of techniques in future literature will improve the ability to compare treatment options. As not all surgeons perform MMS of the nail unit during fellowship, standardized exposure to nail unit MMS may also improve provider technique.36

All nSCCs with bone invasion were treated with either amputation or MMS. These cases were associated with the overall lowest recurrence rate, with no recurrences reported after amputation, supporting amputation as the standard of care for nSCC with bone invasion.46 However, there is currently no standard protocol for imaging of nSCC to detect bone involvement, and routine imaging before treatment has not been shown to influence choice of treatment.47–50 On radiographic imaging, nSCC involving the bone cannot be distinguished from other causes of bone marrow edema, including subungual keratoacanthoma.51,52 Subungual keratoacanthoma can cause resorption of underlying bone and appear lytic on imaging but is pathologically distinct from nSCC.53,54 Plain films have low sensitivity and specificity for detecting bone invasion, and although ultrasound may be helpful in differentiating subungual tumors, it has not been studied as a tool to assess nSCC invasion.38,49,50 Histopathologic analysis, whether through bone biopsy or modified MMS, remains necessary to confirm bone invasion of nSCC. Once confirmed, a multidisciplinary approach to amputation using MMS for primary tumor excision combined with subsequent amputation may maximize digit preservation and function but requires further study.38 Although amputation was also associated with low recurrence rates for invasive nSCC without bone invasion, more conservative surgical treatments are often more appropriate due to persistent functional deficits associated with amputation.2


Limitations include small sample sizes, reporting bias, retrospective studies, and a lack of standardized outcome reporting. Future studies on nSCC treatment and recurrence should reference the Leitenberger criteria for recurrence when applicable and would benefit from established criteria for LR after nonexcisional treatment. Clear and consistent reporting of follow-up times in future articles will allow for better evaluation of recurrence rates associated with nSCC treatment and improve future comparisons between treatment options. Risk factors such as high-risk human papillomavirus infection can increase nSCC recurrence rates and will warrant additional considerations.55 Standardized reporting of treating specialty, previous treatments, and specific treatment methods, including modified MMS techniques, would provide greater insights into patient outcomes. Prospective studies and randomized controlled trials are needed to confirm the gold standard treatment for in situ and invasive nSCC.


In recent years, reports of surgical treatments for nSCC other than amputation, such as WSE, LSE, and MMS, have increased. Although MMS has been suggested as a first-line treatment for nSCC, reports of MMS for the treatment of nSCC in the literature have remained stable relative to other treatment options. The lack of significant difference in the recurrence rate for in situ and invasive nSCC highlights the importance of confirming invasion and establishing negative margins after treatment regardless of tumor stage. Although current data favor complete surgical excision by either WSE or MMS for treatment of nSCC not involving the bone regardless of degree of invasion, there is low sensitivity and specificity for detecting bone invasion of nSCC on radiographic imaging (Figure 2). Thus, the use of modified MMS techniques allowing for histological confirmation of bone invasion intraoperatively may confer an advantage over WSE in treatment of nSCC. If bone invasion is present, amputation is the standard of care and quality of life may be optimized through a multidisciplinary approach. Nonsurgical treatments for nSCC are associated with high recurrence rates but may be considered if surgery is contraindicated. Additional prospective studies and randomized controlled trials are needed to directly compare outcomes for nSCC after complete surgical excision and different MMS modifications.

Figure 2.:
Proposed treatment algorithm for biopsy-proven nail squamous cell carcinoma (nSCC).


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