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Pigmented Lesions of the Nail Unit

Nevares-Pomales, Oscar W., MD*; Sarriera-Lazaro, Carlos J., MD; Barrera-Llaurador, Julian, MD; Santiago-Vazquez, Marely, BS; Lugo-Fagundo, Nahyr, BS§; Sanchez, Julio E., MD; Sanchez, Jorge L., MD

The American Journal of Dermatopathology: November 2018 - Volume 40 - Issue 11 - p 793–804
doi: 10.1097/DAD.0000000000001106
CME Article

Abstract: Pigmented lesions of the nail unit are commonly encountered in the clinical setting. Yet, they often present a unique challenge to clinicians because of a broad differential diagnosis or unfamiliarity with clinical and histopathologic features. A wide variety of causes exist ranging from benign lesions such as subungual hemorrhage to malignant lesions such as subungual melanoma. Identifying the underlying cause is key to appropriate management and follow-up in these patients. Although emerging clinical tools such as dermoscopy can be very useful in evaluation of these lesions, histopathologic analysis remains the gold standard. In this review, we discuss and provide a summary of important clinical and histopathological concepts of pigmented lesions of the nail unit with special focus on longitudinal melanonychia, melanotic macule, melanocytic nevus, subungual melanoma, along with discussion of some nonmelanocytic lesions.

*Resident in Dermatology (PGY4), Department of Dermatology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico;

Physician, San Juan, Puerto Rico;

Medical Student (MS4), School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico;

§Medical Student (MS3), Ponce Health Sciences University, Ponce, Puerto Rico; and

Faculty in Dermatopathology, Department of Dermatology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.

Correspondence: Oscar W. Nevares, MD, School of Medicine, University of Puerto Rico, Medical Sciences Campus, P.O. Box 365067, San Juan, Puerto Rico 00936-5067 (e-mail:

All authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity.

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After participating in this activity, physicians should be better able to:

  1. Assess the embryologic origin of the nail unit and its melanocytes.
  2. Evaluate the different causes of melanocytic and nonmelanocytic lesions of the nail unit.
  3. Compare the different modalities for evaluation of pigmented lesions of the nail unit, including clinical, dermoscopic, and histopathologic evaluation.
  4. Distinguish the main clinical, histopathologic, immunohistochemical, and genetic features of melanocytic lesions of the nail unit and their diagnostic and prognostic value.
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Pigmented lesions of the nail unit refer to a broad clinical term that encompasses diseases as serious as subungual malignant melanoma to innocuous conditions such as subungual hemorrhage. It usually refers to melanonychia or melanin-derived brown to black pigmentation of the nail. Other causes of pigmented lesions of the nail unit include dermatological conditions such as psoriasis, lichen planus, amyloidosis, systemic lupus erythematosus, localized scleroderma; nonmelanocytic tumors such as onychomatricoma, Bowen disease, myxoid pseudocyst, basal cell carcinoma, verruca vulgaris, and subungual fibrous histiocytoma; systemic disorders such as Addison and Cushing disease; mucocutaneous syndromes such as Laugier–Hunziker, Peutz–Jeghers, and Touraine; chronic trauma; and iatrogenic or drug-induced melanonychia.1

This review aims to provide a summary of important clinicopathologic concepts related to pigmented lesions of the nail unit; especially melanotic macule, melanocytic nevus, and subungual melanoma (SM).

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Basic Concepts and Melanocyte Embryology

During the first trimester of embryogenesis, a quadrangular, proximal and lateral, demarcated zone can be recognized in the distal dorsal surface of each digit. At this stage, 3 layers can be identified: the surface, intermediate, and germinative layers. At 9 weeks, the proximal and distal matrix is defined by the proximal migration of germinative cells and the distal formation of the lunula. At 14 weeks, 4 layers (basal, spinous, granular, and cornified) are histologically evident on the nail bed.2 At this point, the nail matrix, the nail bed, the proximal and lateral nail folds (collectively known as paronychium), and the hyponychium constitute the main parts of the nail unit.3,4 The nail matrix, which serves as the germinative epithelium for keratinocytes, will give rise to the nail plate by week 20.3–5 Differentiation of these matrix keratinocytes occurs distally and in a diagonal fashion. Distal nail matrix keratinocytes ultimately form the ventral nail plate, whereas proximal nail matrix keratinocytes form the dorsal nail plate.3–6

The nail matrix also harbors the melanocytes of the nail unit and is responsible for melanocytic lesions of the nail. Melanocytes are derived from neural crest cells, pluripotent embryonic cells with multiple functions.7 The density of melanocytes in the nail matrix is far smaller than in normal skin, about 200 mm2 compared with 1150 mm2.8–10 Nail bed melanocytes range from absent to about 50 mm2; a finding that explains why nail bed melanomas tend to be amelanotic.8–11 Generally, pigmented lesions that do not involve the nail matrix or fold are not melanocytic in origin.12,13

Melanocytic proliferations of the nail typically arise from the distal matrix because it is composed of both active and dormant melanocytic compartments (∼50% active). This is in contrast to the proximal matrix which is composed mostly of the dormant melanocytic compartment.1,8,10,11 Distal matrix melanocytes, unlike proximal matrix melanocytes, stain positive for DOPA, and thus, may be stimulated to produce pigment, which explains why most pigmented nail lesions arise from the distal matrix and are found in the ventral area of the nail plate.11 When stimulated, melanosomes are transferred to matrix cells which then migrate distally and form nail plate onychocytes, which are ultimately responsible for the clinically visible melanonychia.1

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Dermoscopy in Evaluation of the Nail Unit

Clinical distinction of the different melanocytic lesions can be difficult and new tools such as dermoscopy have been developed to help in this process. Unlike skin dermoscopy, nail unit dermoscopy evaluates the sites of melanin deposition rather than the underlying patterns in the nail matrix.14 Attempts have been made to develop a practical algorithm for dermoscopic nail unit evaluation.15–22 Many of these studies use a stepwise algorithm where they first discard hemorrhage, then evaluate for melanotic macule versus melanocytic proliferation, and finally, attempt to distinguish benign from malignant proliferations by checking for concerning signs such as the micro-Hutchinson sign (cuticle pigmentation invisible to the naked eye).19,20

A consensus statement by “The Study Group on Melanonychia” in 2013 performed a review of the literature in an attempt to simplify dermoscopic evaluation of longitudinal melanonychia (LM) by examining lesion colors and patterns.15 More recently, Sawada et al16 proposed a 3 type classification system for LM, developed during an 8-year study with 137 patients using clinical and dermoscopic data. Their system provided good guidance for the management of type I and type III lesions (defined in their study); but, 37% of their patients fell in a “gray area” were clinical distinction of benign and malignant lesions was more difficult.

It is unlikely that a perfect system for clinical distinction of benign LM and SM will ever be developed, but continued research in the area will help minimize unnecessary nail biopsies while continuing to detect malignant lesions at the earliest possible time.

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The most common and classic pigmented nail lesion is known as LM. This is a clinical description defined as a brown-to-black, pigmented band that extends from the proximal nail fold up to the free edge of the nail plate.23 Causes include melanotic macules, melanocytic proliferations (including blue nevi),24–27 hemorrhage, internal and external pigments,28 bacterial or fungal infections,29–31 drugs,32,33 and nonmelanoma subungual tumors.24,34

In LM, the main cause of pigmentation is due to melanocytes increasing melanin production, increasing in number (hyperplasia), or both. When nail matrix melanocytes are stimulated, their melanosomes (containing melanin) are transferred through dendrites to differentiating matrix cells, which in turn migrate distally because they transform into onychocytes of the nail plate, forming the pigmented linear band of LM.1 In melanotic macules, there is an increase in production of melanin with or without an increase in number of melanocytes.35 In melanocytic nevi, there is an increase in number of melanocytes which leads to increased melanin production and clinical nail pigmentation. These melanocytes tend to be well organized in nests which may manifest as LM. In SM, there is a significant and irregular increase in melanocyte density. This irregularity can lead to clinically suspicious lesions.

Given the morbidity associated with nail matrix biopsies, clinically discerning between malignant and benign lesions reliably has been the subject of much study. Specifically, efforts have been placed into distinguishing benign LM from SM. Baran and Kechijian initially enumerated clinical clues for identification of melanoma including de novo single-digit lesions in older patients, abrupt appearance of lesions, blurred/irregular borders, sudden changes in color, development of Hutchinson sign (proximal nail fold pigmentation), and history of melanoma.36 An ABCDEF mnemonic was also developed for clinical assessment of SM.37 Braun et al38 listed several concerning findings largely congruent with those already mentioned, including abrupt development of a single pigmented band in the 4th–6th decades of life, location on thumb, index finger, or large toe, history of melanoma, presence of Hutchinson sign, and occurrence after trauma without evidence of hemorrhage. It is also important to note whether the patient is interested in biopsy, regardless of clinical presentation.39 Either for cosmetic reasons or because of concern for melanoma, biopsy of the nail matrix may be considered, making sure that the patient understands the risks of the procedure.

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Melanotic Macule of the Nail Unit

Melanotic macule is defined clinically as a flat, pigmented lesion occurring in mucous membranes, skin, or nail unit; and sometimes on those sites concurrently.35 It is the most common underlying cause of LM in adults.1 It usually presents itself clinically as a single macule smaller than 1 cm in diameter. Sometimes more than 1 macule is apparent. The lesion tends to be brown and rather sharply delimited (Figs. 1A, B).14



Nail unit melanotic macules may have several different underlying causes including physiologic, traumatic, inflammatory, systemic, and iatrogenic causes.1,40,41 Physiologic etiologies include race and pregnancy.1 Races with darker skin color tend to be more commonly affected. Incidence as high as 100% has been reported in African Americans older than 50 years.1,36,42–44 Hispanics are also commonly affected, but the epidemiology is unclear. Whites are rarely affected (1%)12 which may justify a lower threshold for biopsy in this population, especially when de novo lesions develop at an advanced age.37 One study in whites found that 73% of single nail LM is due to melanotic macule and not melanoma.45 Two smaller studies on Hispanics similarly described 56% and 68% of LM as being due to melanotic macule.24,46

Chronic trauma such as friction from tight shoes, onychotillomania, and manicures1,19; dermatological conditions such as psoriasis, lichen planus, amyloidosis, systemic lupus erythematosus,47 localized scleroderma,48 and onychomycosis40; and nonmelanocytic tumors such as onychomatrichoma,49 Bowen disease,50 myxoid pseudocyst, basal cell carcinoma, verruca vulgaris, and subungual fibrous histiocytoma have all been associated with melanotic macules presenting as LM.1,36,45 Systemic disorders such as Addison disease, Cushing syndrome, hyperthyroidism, and AIDS also play a role in formation of melanotic macules.1,51 Iatrogenic or drug-induced melanonychia commonly involves multiple nails and the pigmentation, which can be transverse or longitudinal, usually fades away once the culprit drug is withdrawn.1,19 Implicated drugs include chemotherapeutic agents, antimalarials, antiretrovirals, psoralens, some metals, among others.1,19 Last, mucocutaneous syndromes such as Laugier–Hunziker, Peutz–Jegher, and Touraine may also present as melanotic macules.1

Histopathologically, the melanotic macule is characterized by an increase in the amount of melanin within the surface epithelium with or without an increased melanocyte count. The increase in melanocytes usually occurs in the basement membrane and rarely above the midportion of the spinous zone (Figs. 1C–F).14

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Melanocytic Nevi

Benign melanocytic proliferations (nevi or lentigo) are the culprit of LM in 77.5% of children.1,52 Nests of melanocytes are absent in lentigo, whereas in nevus there is presence of 1 or more nests. Lentigo has been reported to occur in 9% of adults and 30% of children with LM.1,19,45 Nevi are also more common in children than in adults (48% vs. 12%) as the cause of LM.1,45,52 Nevi can be congenital or acquired and are usually found on the thumb or toenails (Fig. 2A), and one-third of them have a periungual pigmentation known as a “benign pseudo-Hutchinson sign” (Fig. 2B).1,19 In children, clinical features of nevi that are red flags and warrant further pathological analysis include presence of the Hutchinson sign (periungual pigmentation), variation in width of the pigmented band, and color variation of the band.19



Histopathologically, an increased number of melanocytes arranged in crowded (and sometimes irregular) nests limited to the basal and suprabasal layer may be seen (Figs. 2C–D).8,24 Cytologic atypia may be present, but there is lack of pagetoid spread, cell necrosis, or increased mitoses. When present, these findings are more suggestive of melanoma, although they have been rarely reported in nevi.8

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Subungual Malignant Melanoma

Malignant melanoma of the nail apparatus is rare and comprises 0.7%–3.5% of all forms of melanoma.53 The frequency of nail unit melanoma ranges from 0.18% to 2.8% in whites, 10%–23% in Asians, and 25% in African Americans.1,36,54 The mean age at diagnosis is 60–70 years and it is rare in children. It usually occurs in the first toenail (24%–53%) and the thumbnail (18%–31%).19,55,56 Although ultraviolet radiation is the main environmental risk factor for melanoma,57 SM is not believed to be associated with UV light exposure because of nail plate protection.58,59 Associated trauma has been reported in many patients with SM, despite no proven link.60–64 Clinical differential diagnosis is broad and includes aforementioned melanocytic lesions as well as subungual hematoma, paronychia, pyogenic granuloma, onychomycosis, subungual bacterial infections, vascular tumors, squamous cell carcinoma, glomus tumors, and subungual exostosis.65 It may (Fig. 3A) or may not (Fig. 3B) present as LM. Hutchinson sign has historically been the most worrisome clinical marker for SM66 but is not necessarily the most common.55 Amelanotic SM has been reported at rates between 15% and 50%.55,62,67–70 By comparison, amelanotic melanomas account for roughly 2%–8% of melanomas in other sites.71 This may be one of the reasons for the late detection and poor prognosis associated with SM and its 5-year survival rate ranging 16%–87%.1,19,55,72



Histopathologically, melanoma of the nail unit is characterized by an asymmetric proliferation of atypical melanocytes organized as irregular nests and solitary units at all layers of the nail epithelium (pagetoid) and stroma.24 These melanocytes may be multinucleated or may possess enlarged hyperchromatic nuclei, protuberant nucleoli, increased mitoses, long branching dendrites, uneven pigment distribution, variable nail plate hyperpigmentation, a lichenoid inflammatory reaction, and/or cellular necrosis (Figs. 3C–K).24,73

Melanocytic intraepithelial lesions showing some nuclear atypia and pagetoid spread in the superficial layers (commonly termed as atypical intraepithelial melanocytic proliferation) may represent very early stages of melanoma and complete excision is often recommended by pathologists.11 Amin et al74 noted that an increase in intraepidermal melanocyte density was one of the earliest histological alterations in melanoma in situ (MIS).19,74 The mean melanocyte density of MIS samples was about 4 times greater than that of benign lesions such as lentigos.74 Duarte et al75 outlined the histopathologic spectrum of MIS. Histopathologically, challenging lesions (termed “early” by Duarte et al) consist of irregular melanocyte crowding in the basal and suprabasal layers, confluence of melanocytes, multinucleated cells, and a focal or diffuse lichenoid infiltrate. Better defined lesions (termed “late” by Duarte et al) are characterized by the presence of dense aggregations of melanocytes on the basal layer with large and atypical nuclei, long dendrites, and pagetoid spread of cells to the upper layers of the matrix epithelium and into the nail plate.74

Genetic alterations associated with melanoma have recently garnered considerable attention. Mutations in KIT (CD117), in particular, are worth discussing, given their high prevalence in acral melanomas.76–78 KIT encodes a tyrosine kinase receptor for the stem cell factor and plays a key role in melanocytic development, migration, and proliferation.79 Contrary to melanomas arising in sun-exposed skin, acral melanomas are less likely to harbor BRAF mutations, but more commonly have KIT mutations.79 This has been described in multiple studies; with frequency of KIT mutations on acral melanomas ranging between 23% and 36%.78–80 Unfortunately, only one of these studies (Dai et al) had available, detailed clinical information on the acral melanomas studied. Eight of the patients in their study had SM; 3 of them (37.5%) with KIT mutations. At least 1 recent case report described a patient with subungual amelanotic melanoma and an associated KIT mutation.81 No studies specifically on SM genetics were identified. Some studies have evaluated the possibility of predicting the presence of KIT mutations through immunohistochemical analysis but have failed to demonstrate a significant correlation between KIT immunohistochemical expression and KIT mutations.79 The gold standard for diagnosis of KIT mutations remains molecular analysis.

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Immunostains for Melanocytic Lesions

The clinical and histopathologic diagnosis of melanocytic proliferations of the nail unit is one of the most difficult challenges in dermatology and dermatopathology. These lesions may result from melanotic macules, melanocytic nevi, and melanomas. Clinical distinction of melanotic macules and nevi from melanoma can be difficult. Histopathologic and immunohistochemical evaluation may be necessary to ascertain the diagnosis. Among these stains, S-100, HMB-45, and Melan-A are the most commonly used82 and all stain intracytoplasmic components of melanocytes. S-100 is a calcium-binding F-hand protein which is present in Schwann cells, melanocytes, glial cells, chondrocytes, adipocytes, myoepithelial cells, macrophages, Langerhans cells, dendritic cells, as well as their benign or malignant neoplastic counterparts.83,84 It is useful in the diagnosis of desmoplastic and spindle cell variants of melanomas; both of which fail to react to HMB-45 and Melan-A staining in up to 83% of cases.85–87 In the nail unit, S100 has been reported as weak or negative for melanoma in some studies.88,89 Yet, a recent case report showed staining of melanocytes with S100 in the nail unit while MART-1 stain was negative; leading to a diagnosis of amelanotic melanoma.90

Monoclonal antibody to HMB-45 antigen binds melanosome-specific gp100; a glycoprotein considered to be part of the premelanosome complex. HMB-45 is quite specific for melanocytic neoplasms (96.9%) but less sensitive (75%) than S-100.91–93 In the nail unit, several studies have shown this marker to be most useful; likely because of its intensity of staining making sparse nail unit melanocytes more easily visualized, including in the nail bed.89,94,95

Melan-A protein is a product of the MART-1 gene and it is found in the cytoplasm of mature melanocytes. The genes encoding MART-1/Melan-A are transcribed only by melanocytes and therefore, these markers are more specific than S100 and HMB45 (97%).96 Its sensitivity in melanocytic cytoplasms is also greater than that of HMB45.83,87,88 In the nail unit, Melan-A has been described as similar in sensitivity to HMB45.94,95

Microphthalmia-associated transcription factor (MITF) is an intranuclear transcription factor that has been shown to be a useful immunostain target in MIS. Studies on sun-damaged skin have found it to be at least as effective as Melan-A in visualizing melanocytes in solar lentigo and MIS.97 It has also been reported as a useful adjunct in metastatic melanoma when other, more commonly used markers are negative.96,98,99 In the nail bed, the sensitivity has been reported as inferior to Melan-A and HMB45; including failure to detect nail bed melanocytes in one study.95

Sry-related HMg-Box gene 10 (SOX10); a nuclear transcription factor in humans which plays an essential role in melanocytic cell development in all phases, has received attention because of its high sensitivity and specificity in melanocytic lesions; with sensitivities and specificities over 97% in some studies.100–105 SOX10 is an intranuclear stain which makes visualization of melanocytes easier while avoiding pitfalls such as excessive dendritic staining, as with Melan-A. Giemsa counterstaining can also help more easily visualize melanocytes if there is heavy melanization of the lesion.8,106 This sensitivity and specificity has not translated to lesions of the nail unit, with 1 study failing to show staining of nail bed melanocytes with SOX10.95

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Nonmelanocytic Pigmentation of the Nail Unit

The nail unit may exhibit brown, black, or gray alterations in color that are not due to an increase in endogenous melanin. There is inconsistency in the literature regarding how to name these lesions. Some authors use the term nonmelanocytic melanonychia; others prefer to use the terms chromonychia or nail dyschromia, reserving the term melanonychia exclusively for pigmentation of melanocytic origin.38,107,108 Here, we use the term nonmelanocytic pigmentation to avoid any confusion in terminology.

Nonmelanocytic pigmented nail lesions most commonly occur because of blood (eg, subungual hematoma), exogenous pigmentation, fungal or bacterial infections, drugs, or nonmelanocytic tumors, such as subungual Bowen disease (Figs. 4A, B). It is important to note that although listed here under nonmelanocytic pigmentation, many of these lesions may present with concomitant melanonychia as well.41,107



The main differential diagnosis for these types of pigmentation is subungual hematoma (Figs. 5A, B), which is usually due to trauma, repetitive microtrauma, or friction that the patient may or may not recall.18



Exogenous pigmentation refers to direct staining by occupational/environmental exposures (eg, tobacco, tar, hair dyes, cosmetics, and topical product application). An important clue that suggests an external or exogenous cause is that the pigmentation follows the concave shape of the proximal nail fold (vs. the convex shape of the lunula in internal causes).108

Fungal and bacterial infections are another important cause of nonmelanocytic pigmentation, with fungal being the most common. A variety of fungi have been implicated, including dermatophytes, yeasts, and nondermatophytic molds. In fungal pigmentation, the organism itself can be a source of pigment.109,110

Bacterial pigmentation has also been reported, specifically because of Pseudomonas spp. (pyocyanin pigment) and Proteus spp. (Fig. 6).107,108,111



A multitude of different drugs have been implicated as causing pigmentary changes of the nail unit including tetracyclines, antimalarials, cytotoxic drugs, antiretrovirals, hydroxyurea, etc. The mechanism of pigmentation varies by drug. For example, clofazimine-related melanonychia is due to direct deposition of the drug in the nail plate. By contrast, minocycline-induced pigmentation is possibly due to dermal deposition of iron chelates of the drug in the nail bed.107,108,111,112

In conclusion, there are many different causes of pigmented lesions of the nail unit. Identifying the underlying cause is key to appropriate management and follow-up in these patients. The main focus of the clinical evaluation should be the prompt identification of malignant subungual lesions such as melanoma. Although tools such as dermoscopy can be very useful in the initial evaluation of these lesions, the gold standard remains histopathologic analysis.

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The American Journal of Dermatopathology includes CME-certified content that is designed to meet the educational needs of its readers.

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Please mark your answers on the ANSWER SHEET.

After participating in this activity, physicians should be better able to achieve the following: 1. Assess the embryologic origin of the nail unit and its melanocytes. 2. Evaluate the different causes of melanocytic and nonmelanocytic lesions of the nail unit. 3. Compare the different modalities for evaluation of pigmented lesions of the nail unit including clinical, dermoscopic, and histopathologic evaluation. 4. Distinguish the main clinical, histopathologic, immunohistochemical, and genetic features of melanocytic lesions of the nail unit and their diagnostic and prognostic value.

  1. Most pigmented lesions of the nail unit arise from the distal matrix because:
    • a. The distal matrix is composed of 100% active melanocytes, whereas the proximal matrix is composed of mostly dormant melanocytes
    • b. The distal matrix is composed of 50% active melanocytes, whereas the proximal matrix is composed of mostly dormant melanocytes
    • c. The distal matrix harbors melanocytes, whereas the proximal matrix does not
    • d. None of the above; most pigmented lesions of the nail arise from the proximal matrix
  2. Which of the following clinical features is concerning for subungual melanoma?
    • a. Pseudo-Hutchinson sign
    • b. Abrupt onset of lesion
    • c. Location on the 3rd digit
    • d. Development of lesion in the 2nd and 3rd decades of life
  3. Which of the following histopathologic features is not concerning for subungual melanoma?
    • a. Uneven pigment distribution
    • b. Lichenoid infiltrate
    • c. Hyperchromatic nuclei
    • d. All of the above are concerning for melanoma
  4. Mutations in which of the following genes is associated with acral melanoma and might be implicated in subungual melanoma?
    • a. KIT
    • b. BRAF
    • c. CDKN2A
    • d. VEGF
  5. Which pair of immunostains are the most sensitive in evaluation of nail unit melanocytes?
    • a. Melan-A and S100
    • b. SOX10 and HMB45
    • c. Melan-A and HMB45
    • d. MITF and HMB45



pigmented nail lesions; longitudinal melanonychia; melanotic macule; melanocytic activation; melanocytic nevi; subungual melanoma

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