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Predictor of Subungual Melanoma against Benign Longitudinal Melanonychia: A Retrospective Cohort Study from Korea

Background Longitudinal melanonychia (LM) is a common clinical finding. Most cases of LM are benign, and a wait-and-see approach is preferred in the management of this condition. Nevertheless, it is important for clinicians to distinguish subungual melanoma (SUM) from other benign LMs. Objective To evaluate the demographic and clinicopathologic characteristics of LM in the Korean population and to identify the predictor of SUM against other benign conditions. Methods This was a single-center retrospective cohort study including patients who underwent nail biopsy for LM from January 2000 to May 2019. To identify the predictor of SUM, receiver operating characteristic (ROC) analyses was performed. Results A total of 68 cases of biopsy-proven LM were included in the analysis. Among the 68 cases, 8 were SUM. In univariable analysis, patients diagnosed with SUM were older (p=0.035) and had a longer disease duration (p=0.004). They also showed multicolor pigmentation of LM (p=0.022), a larger width of LM (p<0.001), and associated nail plate dystrophy (p=0.010) than patients diagnosed with benign conditions. In multivariable logistic regression, width of LM showed statistical significance (odds ratio, 1.083; 95% confidence interval, 1.018~1.153). ROC analysis suggested that an LM width >28% of the whole nail was the predictor of SUM (area under the curve=0.883; p<0.001). Conclusion SUM has distinct demographic and clinical features. The width of LM can predict SUM against other benign LMs.


INTRODUCTION
Longitudinal melanonychia (LM) refers to a brown-black pigmented streak in the nail plate that runs from the proximal nail fold and extending to the distal nail plate longitudinally 1,2 . LM can be caused by exogenous pigments or hyperactivation or hyperplasia of melanocytes. Chronic local trauma, infections, medication, and ethnic melanonychia (occurring in dark-skinned persons) are the common causes of increased activation of melanocytes, whereas hyperplasia of melanocytes is due to lentigo of the matrix, nail matrix nevus or subungual melanoma (SUM) [1][2][3] . Although most cases of LM are benign and a wait-and-see approach is preferred in the management of this condition, it is important for clinicians to distinguish SUM from other benign LMs [1][2][3] .
In this study, we retrospectively evaluated the demographic and clinicopathologic characteristics of LM in the Korean population. In addition, we also sought to identify demographic and clinical features for distinguishing SUM from other benign conditions.

Patients and data acquisition
After obtaining approval from the institutional review board at Chungnam National University Hospital (approval no. 2019-03-032-002), we retrospectively reviewed patients who visited our hospital and underwent nail biopsy for LM from January 2000 to May 2019. We retrieved the data of demographic and clinical characteristics, such as age, sex, past medical history, duration of LM, involved digit, change in LM features, and pathologic report of nail biopsy from the electronic medical records. Clinical photographs were also reviewed, and the color, width, pigment variegation (monochromic: LM in a single color and heterochromic: LM in multiple colors), and border of LM were evaluated. In addition, the presence of nail plate dystrophy and Hutchinson's sign was also assessed. The width of LM was measured at the line perpendicular to the longitudinal axis of the nail at the midpoint of the nail plate. The width of LM was calculated as the ratio of the LM to the whole nail. All patients enrolled in the study underwent nail biopsy for histologic diagnosis. The procedure for nail biopsy was as follows: lidocaine was injected for local anesthesia; the nail plate was extracted after making longitudinal incisions at the lateral ends of the proximal nail fold; and the nail matrix was exposed. The specimen was obtained at the darkest matrix portion of LM. The histopathologic diagnosis of LM was categorized as follows: melanocytic activation (increased pigmentation in the basal layer of the matrix without an increase in the number of melanocytes), melanocytic proliferation (increased number of melanocytes in the basal layer of the matrix without atypia), and SUM.

Statistical analysis
The demographic, clinical, and histologic variables were analyzed to determine the differences among the causes of LM.

RESULTS
During the study period, we enrolled 68 patients with LM whose pathologic diagnosis was hyperactivation or hyperplasia of melanocytes (  (Table 4). Lastly, the ROC analysis revealed that when cutoff point for the width of LM was 0.28, the sensitivity and specificity was 0.750 and 0.883, respectively (area under the curve=0.883, p＜0.001) (Fig. 2).

DISCUSSION
In this study, we found that SUM has distinct demographic and clinical features from those of other benign melanocytic lesions. Patients with SUM were older and their disease duration was longer. In addition, they more frequently  Values are presented as mean±standard deviation, number (%), or number only. LM: longitudinal melanonychia. *The detailed symptoms appeared independently or in combination, the number of 'recent change of LM' and the number of detailed symptoms can be different. our results highlight the importance of the width of LM in the differential diagnosis of this disease. Hutchinson's sign has been considered a critical presumptive sign in the diagnosis of SUM 5,7,9 . The extension of pig-mentation from the nail matrix or nail bed to the surrounding tissue represents radial growth of SUM 9 . However, extension of pigmentation to the surrounding tissue has also been found in other benign conditions and such findings were referred to as pseudo-Hutchinson's sign 9 . Previous studies reported that one-third of LMs due to nevi on the nail matrix or nail bed showed pseudo-Hutchinson's sign 9,10 . In this study, 54.5% of LMs due to melanocytic proliferation and 50.0% of SUMs showed pigmentary change of the surrounding nail fold. Among patients with melanocytic proliferation who showed pigmentary change of the surrounding nail fold, the histologic diagnosis in three patients was melanocytic nevus and two of these patients were younger than 5 years. Additionally, we further analyzed the presence of Hutchinson's sign or pseudo-Hutchinson's sign in enrolled patients over 12-year-old, considering the atypical LM found in children. Of the included 56 patients, 44 (78.6%) had LM due to melanocytic activation, 5 (8.9%) had LM due to melanocytic proliferation, and 7 (12.5%) had SUM. Hutchinson's sign or pseudo-Hutchinson's sign was observed in 16.1% of all patients over 12-year-old. When pediatric cases were excluded, the proportion of showing pseudo-Hutchinson's sign was found in 9.1% in melanocytic activation, 40.0% in melanocytic proliferation, and Hutchinson' sign was found in 42.9% in SUM. In particular, there were marked decrease in the melanocytic proliferation group. As melanin pigmentation can be densely observed in cases of melanocytic proliferation, such as melanocytic nevus, pseudo-Hutchinson's sign can be frequently observed. Ohn et al. 11 investigated the dermoscopic features of nail matrix nevi in adults and children and found that pseudo-Hutchinson's sign was observed in 62.1% of nail matrix nevi in children on dermoscopy. Although previous studies emphasized the importance of Hutchinson's sign in the early detection of SUM 5,6,12 , clinicians should consider the possibility of pseudo-Hutchinson's sign, especially when managing LM in children. Therefore, LM in children should be approached with caution through serial inspection, photographs and dermoscopic examination with a longer follow-up period. There are some limitations of this study. First, since this study was conducted on single tertiary medical center, there can be a selection bias. Only patients with severe lesion may have been enrolled in this study. Second, as our study was a retrospective study over a 19-year period, there can be missing information including follow-up. In addition, we could not investigate the dermoscopic findings since the examining the LM with dermoscopy has not been widely used in those periods. Prior study has described the characteristic dermoscopic findings of SUM in situ and reported width of pigmentation at least 3 mm, multicolor pigmentation, asymmetry, border fading, and Hutchinson's sign as the predictive signs for SUM in situ 13 . SUM is a malignant neoplasm of the nail unit with a poor prognosis. Only biopsy can definitely diagnose SUM; however, the risk of nail plate dystrophy after nail matrix biopsy, although the risk is depending on the technical skills, is another limitation in the early detection of SUM. In this retrospective study, we found that SUM had different demographic and clinical features from those of LM of benign causes. Our results also implied that the width of LM can be a predictor of SUM; that is, LM width ＞28% of the whole nail suggests SUM rather than other benign LMs. Clinicians should be cautious when dealing with patient whose the width of LM is over a quarter of the patient's whole nail width. Additional studies are needed to test the predictive values proposed in this study, which can be helpful in establishing the approach for early detection of SUM. In addition, further studies on the usefulness of dermoscopy in the diagnosis of SUM are needed for the early detection of SUM.

CONFLICTS OF INTEREST
The authors have nothing to disclose.

FUNDING SOURCE
None.

DATA SHARING STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.