Nail plate pigmentation (melanonychia) is a rather common clinical occurrence.1 The incidence of melanonychia varies according to skin pigmentation with percentages that may be as high as 77% in African-Americans over 20 years of age and more in those over 50 years of age but varying with depth of skin color, 10% to 20% in Asians, and about 1% in Caucasians.2
Specifically, melanonychia striata, or longitudinal melanonychia (LM), is characterized as either a dark brown or brown-black longitudinal band on a toenail or fingernail.3
The three most common variants of LM are melanocytic nevus, melanotic macule, and melanoma in situ.2 Although there have been reports of melanocytic nevus and melanotic macules progressing to melanomas, a primary diagnosis of melanoma in situ is of particular clinical concern.2 Therefore, clinicians must be especially prudent when diagnosing LM to rule out malignancy.

Differentiating Lesions
Commonly, a melanocyte-related lesion of longitudinal melanonychia may be a melanotic macule, a junctional nevus or in situ melanoma.
• Melanotic macules. Histologically, a melanotic macule exhibits melanin pigment within the matrix epithelium but no melanocytic proliferation.
• Junctional nevus. Histologically, a junctional nevus shows discrete nests of melanocytes along the base of the matrix epithelium.
• Melanoma in situ. Histologically, an in situ melanoma exhibits an asymmetric proliferation of mainly singly displaced melanocytes within the matrix epithelium.

To properly evaluate the pigmented lesion, the clinician must often perform an appropriate biopsy. But in order to do this, it is critical that you understand the origin of the pigment in LM.
LM lesions have their origin in the nail matrix.1-4 Although the proximal nail matrix contains melanocytes, they are mostly dormant. The biopsy must usually be taken from the distal nail matrix, which contains most of the melanocytes with active melanin synthesis. Depending on the location and width of the band, biopsy of the nail matrix may be performed using a punch biopsy or a transverse elliptical biopsy. The affected area can generally be biopsied with low risk of permanent nail dystrophy especially if taken from the distal matrix, which forms the undersurface of the nail plate.2,4
High-quality biopsy techniques are of utmost importance to permit correct orientation, embedding and sectioning of the specimen. The specimen should include both nail matrix and plate.5

Diagnosing Subungual Melanoma
Levit et al. have outlined some general guidelines to aid a clinician in making an appropriate assessment of LM. SM is very rare with reported incidences between 0.7% and 3.5% in the general population. But, this systematic approach does not reduce the necessity of a biopsy to arrive at a definitive diagnosis. They outline the following most salient features of SM employing the ABCDEF mnemonic: 13
A stands for the age and race of most commonly afflicted patients (African-American, Native American, and Asian American). SM has been reported in ages ranging from 20 to 90 with peak incidence in the fifth and seventh decades. Although cutaneous melanomas are rare in darker skin complexions, melanoma occurs in these populations at a disproportionally higher rate. SM comprises 15% to 20% of all melanomas in African-Americans, 33% in Native American and 10% to 31% in Asians.4, 10, 14
B stands for the brown or black band most commonly seen in melanoma in situ.15 In addition, a lesion with a breadth of 3 mm or more or a blurred variegated border increases the likelihood of melanoma.16,17
C points the clinician to a recent pattern of change in the nail morphology. If the lesion has become wider, “streakier” (light and dark areas), or has darkened significantly in a short period of time, this is definite cause for concern.
D represents the digit involved. SM more commonly involves the thumb, hallux or index finger of the dominant hand. If more than one digit is involved, this may decrease the suspicion of SM and point to some of the previously mentioned exogenous causes or be simply due to pigmented nail bands of ethnic origin.18,19
E stands for Hutchinson’s sign, the extension of the pigment to involve the cuticle or proximal and lateral nail fold. Hutchinson’s sign corresponds to the radial growth phase of SM, and is therefore a very consistent indicator of SM. But, Hutchinson’s sign is not always pathonogmonic for SM. There are certain variants called pseudo-Hutchinson’s sign that occur in the absence of SM.11,16 These variants do not negate the importance of Hutchinson’s sign. However, they oblige the clinician to consider diagnostic possibilities other than SM such as ethnic nail fold hyperpigmentation.2
F urges the physician to get a complete family history paying specific attention to a history of dysplastic nevi or previous melanomas.

What causes Longitudinal melanonychia?
The cause of LM is still rather elusive. While the relationship between solar exposure and cutaneous melanoma has been well established, a relationship between subungual melanoma (SM) and sunlight is uncertain6,7 Many authors have suggested that SM is associated with trauma. In one particular study, the authors hypothesized that fibroblast growth factor (FGF) plays a role in SM due to the association between FGF in healing wounds and SM.8

Exogenous Causes
It is important to also consider the exogenous causes of nail pigmentation when a patient presents with nail dyschromia. Trauma resulting in a persistent hematoma, fungal infection (onychomycosis) caused by Aspergillus or Scopulariopsis, and bacterial infections with persistent Pseudomonas aeruginosa are important non-melanocytic origins of dyschromia. In cases of an onychomycosis, the clinician should not overlook the possibility of melanoma and fungal co-morbidity. In addition, certain drugs including minocycline, cancer chemotherapy agents, and anti-malarial drugs may cause nail dyschromia.1,9-12 However, in these situations, the pigmentation often involves more than one nail and a careful patient history may place melanoma lower on the list of differential diagnosis.

Presentation and Prognosis
Unfortunately, SM is frequently misdiagnosed resulting in delays in management. This fact is particularly worrisome considering many SMs have a more aggressive proliferative process when compared to cutaneous melanomas.1,20-22 In addition, nail melanoma — not of the in situ variety — often has a more ominous prognosis with 5-year survival rates reported to be ranging from 18% to 68.5%.11, 19

The delay in diagnosis is further complicated by the varied clinical presentation of patients with SM. It is usually asymptomatic, and patients may present for the first time with thick advanced lesions.
Studies have reported that tumor thickness is the single most prognostic factor for SM. Very few patients (20%) are diagnosed with stage 1 SM compared with four times that figure seen in cutaneous melanoma.8
Reports have indicated that half of the affected patients notice a mass below the nail. The mass can be associated with total loss or partial destruction of the nail plate. Granulation tissue, periungual infection, and ulceration of the nail bed also occur in about one-third of patients. Another one-third present with only nail dyschromia. Actually, quite a high percentage of cases have been reported of patients with amelanotic melanoma (20% to 33%).8,23,24 This percentage is very disconcerting considering only 7% of cutaneous melanomas are amelanotic.

Who Should Receive a Biopsy?
Even with succinct acronyms for risk factors, the burden of proof is still in the hands of the physician to decide which patients to biopsy. LM in a pediatric patient has been shown to generally be a nevus, 25-27 while a melanotic macule is the most likely diagnosis if the pigment is pale, homogeneous and pigmentation of the proximal nail fold (Hutchinson’s sign) is absent.
Although most melanotic lesions are histologically diagnosed to be either melanotic macule or melanocytic nevus, a physician must never be overconfident in the physical examination that a confirmatory diagnosis can be made in the absence of a biopsy.
In addition, some studies have shown evidence of benign LM progressing to melanoma in situ after several years.28 So, even when the histologic finding is benign, a patient must be educated to have regular dermatologic observation to check the pigmented lesion for growth or change in the event that it is not completely removed. Particularly in cases where the most common discoloration, subungual hematoma, is suspected, a clinician must prove that blood rather than melanin is responsible for the black appearance.
There have also been incidences of LM demonstrating spontaneous regression or disappearance, but this is unusual and lesions should not merely be observed with the hope that they will simply go away.
Dermoscopy can also help to make a more accurate decision about whether or not to perform a biopsy. Although no universally accepted criteria have been established to evaluate LM, in their study of 148 patients, 20 of whom had a diagnosis of melanoma in situ, Ronger et al found that “the most powerful criterion suggestive of melanoma was the irregularly colored, spaced and thick pattern of the lines with areas of disruption of their parallelism.”30

In addition, the use of dermoscopy increases the quality of the information obtained about the nail morphology. When this information is paired with the overall patient history and clinical picture, the decision of whether or not to perform a biopsy can be made with increased confidence.31

When Should You Biopsy Pediatric Patients?
While there have been reported cases of nail melanoma in pediatric patients, there is ongoing controversy as to whether those presenting with longitudinal melanonychia striata should be biopsied. SM is extremely rare in children, with most cases of LM being diagnosed as a melanocytic nevus. Of reported cases of pediatric LM, less than 6% have been proven histologically to be in situ melanomas.27, 29 Thus, when deciding whether to perform a biopsy on a pediatric patient, it is important to consider the likelihood of a SM or a LM that could progress to SM over time.
Performing the biopsy runs the risk of causing a permanent nail dystrophy and unnecessary pain and trauma for the child. If biopsy is the chosen course, some clinicians support an excisional biopsy that removes the entire lesion thereby increasing the diagnostic yield of the specimen.5 It is important that the clinician make this decision along with the parents after thorough discussion of the risks.

Treatment
Once the diagnosis of SM has been confirmed histologically, a thoughtful clinical course of action must be pursued. Prompt, early treatment often allows more conservative surgery to be undertaken.
Treatment modalities range from Mohs micrographic surgery to proximal interphalangeal amputation.32 Patients also often receive adjuvant chemotherapy either systemically or in the isolated limb.
A recent study showed that limited excision with partial resection of the distal phalanx only and Mohs surgery to ensure tumor-free margins yielded a more cosmetically acceptable result and had no negative effect on prognosis.33
For early lesions, local excision followed by skin grafting has proven successful.8 Lymph node dissection is still rather controversial and studies have not conclusively shown that it improves survival.6, 23,24,34

Reaching a Diagnosis Before It’s Too Late
Overall, LM is appropriately managed by gathering a complete history from patients and considering all of this condition’s potential causes.
Although SM may sometimes have a poor prognosis, clinicians should feel confident when confronted with patients with LM and use all of the diagnostic tools at their disposal.
It is essential to stress the importance of the pathologist’s role in the diagnosis and careful communication with the clinician when biopsies are taken.
Lastly, there’s no need to feel intimidated by nail biopsies. Keeping all of these points in mind will help you remain confident in arriving at an early diagnosis of a pigmented lesion.

Dr. Scher is Professor of Clinical Dermatology at the Columbia University College of Physicians and Surgeons in New York, NY.
Angela Lamb is a medical student at the Albert Einstein College of Medicine in the Bronx, NY, and participated in a mentorship in the department of dermatology at Columbia.
Dr. Husain is Assistant Professor of Clinical Pathology in the Department of Dermatology at Columbia University College of Physicians and Surgeons.