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Melanonychia: Etiology, Diagnosis, and Treatment

Melanonychia is a very worrisome entity for most patients. It is characterized by brownish black discoloration of nail plate and is a common cause of nail plate pigmentation. The aetiology of melanonychia ranges from more common benign causes to less common invasive and in situ melanomas. Melanonychia especially in a longitudinal band form can be due to both local and systemic causes. An understanding of the epidemiology, pathophysiology and clinical details is necessary for adequate patient care and counseling. It not only helps in the early recognition of melanoma but also prevents unnecessary invasive work up in cases with benign etiology. An early diagnosis of malignant lesion is the key to favourable outcome. Though there are no established guidelines or algorithms for evaluating melanonychia, a systematic stepwise approach has been suggested to arrive at a probable etiology. We, hereby, review the aetiology, clinical features, diagnostic modalities and management protocol for melanonychia.

exposure, dermatological diseases, and racial pigmentation typically involve multiple nails, lentigines and nail matrix nevus are monodactylic (involving single nail/digit).

Morphological Classification
A simple morphological classification of melanonychia is given in [ Table 1 and Figures 1-3].

Pathogenesis
Though melanocytes are present in both nail matrix and bed, majority of them lie quiescent or dormant. [6] Melanocyte activation following trauma, infection, or inflammation initiates melanin synthesis and then the melanin-rich melanosomes are transferred to the differentiating matrix cells through dendrites. These matrix cells migrate distally and eventually become nail plate onychocytes, resulting in visible pigmentation in the nail plate. [6,7] Alternatively, melanonychia may also result from nail matrix melanocyte proliferation with (nevus) or without nest formation (lentigine).

There are two main mechanisms of melanonychia [Figure 4]
normal number of activated melanocytes in the nail matrix. [8] It is also known as melanocyte stimulation and results from numerous causes listed in Figure 4 2. Melanocyte proliferation-Means increased melanin pigment secondary to increased number of melanocytes in the nail matrix. [8] The melanocytic hyperplasia or proliferation can be benign or malignant.
Nail matrix nevus and constitutional nail pigmentation are the most common causes. [1] The percentage distribution of the aforesaid causes varies in different population. The most common cause in a study evaluating melanonychia of all morphologies was found to be subungual hemorrhage (29.1%), followed by nail matrix nevus (21.8%), trauma (14.5%), lentigo (11.6%), and race (8.0%). [9] While in a study evaluating only longitudinal melanonychia, racial melanonychia was seen in 68.6%, trauma in 8.5%, fungal in 7.1%, and mixed etiology in 4.5% of cases. [10] Benign melanocytic   Figure 3] Transverse band running across the width of nail plate Drugs Indian Dermatology Online Journal | Volume 11 | Issue 1 | January-February 2020

Racial melanonychia
It is commonly encountered in skin phototypes IV, V, and VI, that is, darkly pigmented races including Blacks, Asians, Middle-East, and Hispanics. [11] The incidence reportedly varies from 1% in whites, 10%-20% in Japanese and Asians, and 77-100% in African Americans. [7] Racial melanonychia is more common in fingers (thumb, index finger), generally involves multiple nails [ Figure 5] and the band width increasing with age.

Pregnancy
Skin hyperpigmentation is of common occurrence during pregnancy. Longitudinal melanonychia may also be associated with pregnancy and generally involves several finger and/or toe nails. It is thought to result from the activation of nail matrix melanocytes and may resolve or persist following delivery. [12,13] Infections Fungal melanonychia Fungal melanonychia may be caused by both dematiaceous and nondematiaceous fungi; most common being Trichophyton rubrum and Scytalidium dimidiatum, followed by Alternaria and Exophiala. [14] It is commonly seen in males with frequent involvement of toenails. Fungi produce soluble, nongranular melanin which gets incorporated into the nail plate. [14] The involved nail typically has brown to black bands better seen with dermoscopy [15] and subungual hyperkeratosis with or without periungual inflammation. The pattern of nail involvement may indicate the causative agent. Longitudinal melanonychia is more common with dermatophytes like Trichophyton rubrum while diffuse pigmentation is seen with molds such as Scytalidium, Aspergillus niger [ Figure 6], and Alternaria. [14] Bacterial melanonychia This is frequently caused by Gram negative pathogens; Pseudomonas aeruginosa, Klebsiella and Proteus. [16] The risk factors include wet work and an immunocompromised state. The pattern of nail involvement can be longitudinal streaks with wider proximal edge or diffuse which starts from the junction of proximal and lateral nail folds and spreads with irregular medial border. [16] Viral HIV patients may show diffuse melanonychia or multiple longitudinal or transverse bands in multiple fingers and toenails, often associated with hyperpigmentation of palms, soles and mucous membranes. [17] Longitudinal melanonychia can also be seen with ART drugs like zidovudine. [17] Inflammatory disorders Inflammatory skin conditions like psoriasis, lichen planus, amyloidosis, chronic radio dermatitis, and chronic paronychia in and around nail unit leads to melanocytic activation resulting in melanonychia. [7,18] Longitudinal melanonychia has also been seen in connective tissue diseases like systemic sclerosis and SLE. [19,20] Tumors Longitudinal melanonychia can also occur due to melanocytic activation by nonmelanocytic benign and malignant tumors  such as onychomatricoma, Bowen's disease, squamous cell carcinoma, basal cell carcinoma, subungual fibrous histiocytoma, verruca vulgaris and subungual keratosis. [11,21]

Systemic Diseases
Melanonychia in systemic diseases tends to involve multiple finger and toe nails, and generally presents as either diffuse melanonychia or multiple bands. It is uncommon and is seen in endocrine disorders (Addison's disease, Cushing's syndrome, hyperthyroidism and acromegaly), alkaptonuria, hemosiderosis, hyperbilirubinemia, and porphyria. It can also be seen in Graft Versus Host Disease (GVHD) and AIDS patients. [18,22]

Traumatic Melanonychia
Repeated trauma as seen in onychotillomania, onychophagia, or friction may lead to melanonychia.

Onychotillomania and onychophagia
Trauma to the nail matrix due to nail biting, picking, chewing or pulling leads to nail matrix melanocytes activation. This results in diffuse or regular longitudinal gray parallel bands of nail plate pigmentation, often accompanied by nail plate and periungual signs of trauma [ Figure 7]. [21] Frictional Chronic friction or pressure of ill fitted, tight, or pointed shoes leads to brown pigmentation of a part or whole of the great toe, fourth, and/or fifth toenails without any associated nail plate abnormalities. [21] This is also seen in athletes due to trauma to the proximal nail fold overlying the matrix. [21] Iatrogenic Melanonychia Melanonychia involving several finger and toe nails may be caused by phototherapy, electron beam therapy, X-ray exposure, radiodermatitis, and drugs. The pattern of nail involvement can be diffuse, transverse, or longitudinal.

Drug-induced melanonychia
Drug-induced melanonychia is often associated with other mucosal and cutaneous pigmentations. The type of melanonychia varies with the causative drug; nail bed pigmentation, transverse bands, and longitudinal melanonychia can be seen either alone or together. [7] Transverse melanonychia, although uncommon, is seen almost exclusively due to drugs. [11] The pigmentation involves several nails that fade either partially or completely following drug withdrawal [3] in 6-8 weeks but may take several months to years. [7] The list of common drugs causing melanonychia and their features are listed in Table 2. [7,11] Chemotherapeutic drugs are the most common agents. [7] Intermittent administration of chemotherapy can result in alternating bands of pigmentation. [23] Nutritional Deficiencies Longitudinal melanonychia is seen in malnutrition especially protein energy malnutrition and vitamin D deficiency. [24] Vitamin B12 deficiency produces reversible nail pigmentation that can be longitudinal, diffuse bluish or reticulate probably due to reduced glutathione levels resulting in disinhibition of tyrosinase enzyme involved in melanogenesis. [25] Exogenous Pigmentation Brown to black pigmentation of nails can be seen due to exogenous agents like henna, dirt, tobacco, potassium permanganate, tar, and silver nitrate. [16] It presents as a horizontal band with the distal border parallel to the proximal nail fold and tends to move out with the nail plate [ Figure 8]. [16] Silver nitrate presents with a dark color band with irregular medial border and staining of adjacent skin of nail folds. [16] Syndromes Associated with Melanonychia Laugier-Hunziker syndrome, Peutz-Jegher and Touraine syndrome are characterized by LM along with pigmented macules in oral mucosa and lips. [7] LM involves several nails, generally finger nails with one or more bands. Laugier-Hunziker syndrome appears between 20 and 40 years of age and has no family history. On the contrary, Peutz-Jeghers and Touraine show autosomal dominant inheritance; the pigmented macules usually appear early during childhood and both are associated with intestinal polyposis and an increased risk for gastrointestinal and pancreatic malignancies. [7]

Sub-ungual Hematoma
Hematoma is the most common cause of nail brown-black pigmentation. It can be either acute (following single heavy trauma) or chronic (repeated, micro trauma). While acute Indian Dermatology Online Journal | Volume 11 | Issue 1 | January-February 2020 subungual hematoma has a deep red/purple band and do not reach the free margin of the nail [ Figure 9], [16] chronic subungual hematoma has a red brown, elliptical shape mimicking a longitudinal streak. [16] A true longitudinal band is seen very rarely. Small, round blood globules are seen at the periphery of hematoma on dermoscopy.

Benign Melanocytic Hyperplasia
It can be either due to nevus or lentigo. Lentigines are often seen more than nevi in adults while nevi are more common than lentigines in children. [11] Nail matrix nevus Nail matrix nevus may be congenital or acquired, majority being junctional. Nevus represents 12% of LM in adults and 48% of LM in children. [8,26] It generally presents as a light brown to black, 3-5 mm broad longitudinal band on fingernails especially thumb [ Figure 10a]. [21] The pigmentation is generally homogenous in intensity and color but dark bands may arise on light background, appreciated better on onychoscopy [ Figure 10b]. Darker bands may be associated with periungual pigmentation (pseudo Hutchinson's sign) in one-third of the cases. [7,21] Histologically, nevus is characterized by the formation of nest of melanocytes. [7] Lentigo Lentigo is characterized by melanocytic hyperplasia with absence of melanocyte nests. Increased melanocytes (5-31 mm) are present within nail matrix epithelium. Lentigo in the nail matrix is more common in adults [ Figure 11] and is observed in around 9% of all LM cases in adults. [8,26] Malignant Melanocytic Hyperplasia Melanoma Nail unit melanoma (NUM) is rare. It comprises about 0.7%-3.5% of all cases of cutaneous melanoma in the western world. [27] The incidence is variable in different races Cyclophosphamide-Diffuse black, longitudinal, or dark gray pigmentation of proximal nail plate [14] Doxorubicin: Alternating bands of dark brown and white lines, and transverse bands [14] Hydroxycarbamide: Distal or diffuse, dark brown [14] ART-Zidovudine, Lamivudine Diffuse blue-brown, transverse or longitudinal bands Fingernails > toenails.

Appears after 3-8 weeks
Reversible within 6-8 weeks, may persist for months Antimalarials-Amodiaquine, chloroquine, mepacrine, quinacrine Melanonychia due to melanin and ferric dyschromia [3] Others-Biologicals, clofazimine, infliximab, psoralens, phenytoin, fluconazole, cyclins, ketoconazole, phenothiazines, sulphonamides Diffuse pigmentation, multiple nails Metals-Arsenic, Thallium, Mercury Indian Dermatology Online Journal | Volume 11 | Issue 1 | January-February 2020 with a higher incidence (10%-25%) reported from Asian countries including Japan, China, and Korea. [27,28] The peak incidence is seen in 5 th to 7 th decades of life. Thumb, great toe, and middle finger are common sites. [7,28] LM is the first manifestation of NUM in 38%-76% of the cases. [27] Variegation in color, irregular/blurred borders of the band, crisscrossing, periungual pigmentation (Hutchinson sign), nail dystrophy, and ulceration or blood spots indicate malignant change [ Figure 12] and a biopsy should be considered. [6,16] In rapidly growing melanomas, the proximal end of the band may be wider than the distal portion known as pyramidal sign [ Figure 13]. NUM carries a poor prognosis as compared to cutaneous melanomas probably due to delay in diagnosis, the average delay being 2 years. [7,29] The five-year survival rate is 51%; 88% for a Breslow thickness of 2.5 mm or less and 44% for a thickness greater than 2.5 mm. [30]

History
A detailed history including patient's age, history of trauma/any triggering factor, exogenous substance exposure, occupational history, hobbies, drug history, medical and family history is important. The onset (gradual/sudden), duration (short/long), rate of progression of melanonychia, and change in color or width of band must be enquired.

Clinical examination
Examination of all finger and toe nails and a complete muco-cutaneous examination is important for evaluation of melanonychia. One should note: • Number and location of involved nails-single/multiple • Morphology of LM-whether similar or different, if multiple nails involved • Site or location of melanonychia on the nail plate-above, within, or beneath. Examination of the distal free edge of the nail plate or hyponychium might indicate the origin of pigment. Ventral nail plate pigmentation originates from the distal matrix while the dorsal nail plate from proximal matrix. [21] The localization of pigment helps in selecting the anatomic site for exploration and biopsy, and can prevent a visible definitive nail dystrophy if the surgery is confined to the distal matrix [21] • Pattern of melanonychia-complete, longitudinal, or transverse.
Complete melanonychia-The extent and configuration (proximal and distal end including shape of proximal end of pigmentation with respect to proximal nail fold) Longitudinal melanonychia (LM)-Color, homogeneity, regularity, width, whether wider proximally or distally, shape, margins and lateral borders of the band. Pyramid-shaped melanonychia with base toward proximal nail fold is suggestive of NUM • Other nail signs-Nail dystrophy, nail plate changes (abrasion, splitting or fissuring) and periungual pigmentation, bleeding are pointers to NUM. In addition, nail dystrophy and nail plate changes and pigmentation may be seen in fungal melanonychia • Other mucocutaneous sites for any inflammatory disorders, syndromic associations.
The ABCDEF rule helps to distinguish alarming LM from the nonalarming ones: [31] [Box 1]

Laboratory evaluation
Nail plate sampling by nail clipping or punch biopsy can be done in doubtful cases about the nature of the pigment and in cases suspicious of fungal melanonychia. [18] The samples are sent for direct microscopy and culture (to exclude onychomycosis) and for histopathology (to confirm melanic pigmentation by Fontana stain). [18] Dermoscopy of nail apparatus (Onychoscopy) Onychoscopy has become an indispensable tool in the evaluation of pigmented nail lesions as it helps in validating the clinical findings. Onychoscopic examination of nail plate and distal edge is usually done with a magnification of 10 × with a handheld dermoscope or a digital videodermoscope. [32] Polarizing filters are less efficient in evaluation of nail plate due to their optical properties. Due to the convexity of nail plate, oil or gel immersion is required for visualization. [32] Distal edge onychoscopy generally requires more immersion gel or oil. [33] There are three basic steps: [34] 1. Differentiate the melanin and nonmelanin pigmentations. [35,36] [ Table 3]. It is of utmost importance to identify subungual hematoma by the history of trauma and characteristic onychoscopic appearance. A subungual hematoma is identified by globules of various sizes and color-from bright red, brown to black depending upon the depth and duration of hemorrhage [ Figure 14]. However, it should be remembered that subungual hemorrhage does not rule out melanoma 2. Determine the cause of pigmentation-melanocytic activation or proliferation. [24,25] [ Table 4] 3. Distinguish benign and malignant proliferations. [35,36] [ Table 4].
Limitations of Onychoscopy in melanonychia [21] 1. Overlap in various onychoscopic patterns exists. The brown background with lines irregular in color, width, and spacing are not indicative of melanoma in children.
Benign lesions in adults can present with irregular lines and spacing 2. No established accurate onychoscopic patterns in the diagnosis of NUM 3. No criteria for frequency of onychoscopic follow-up in patients with LM 4. No precise onychoscopic criteria for deciding the precise time for biopsy.  Substances adhering to or below nail plate, no longitudinal appearance, homogenous and located near nail folds with advancing margin running parallel to PNF Intraoperative onychoscopy (nail bed and matrix)-This is indicated in suspicious cases while performing nail matrix biopsy. It allows direct visualization of various dermoscopic patterns [Box 2] in nail bed and matrix. [37,38] It also helps in selecting the surgical margins for complete excision of the lesion. [37,38] Biopsy Whenever there is a doubt of NUM on clinical features and onychoscopy, histopathological diagnosis is the gold standard for confirmation of NUM. The preoperative diagnostic accuracy of melanoma ranges from 46% to 55%. [39] There are no standard guidelines or algorithm for indications and time of biopsy in LM. It is suggested that any unexplained melanonychia of a single digit in white races should be biopsied to rule out NUM. On the contrary, LM of single digit in other races or LM in multiple nails may be followed up and biopsied whenever required. [6,39] In children, management is generally conservative as NUM is rare in this age group.
The type and site of biopsy depends upon the morphological characteristics of LM-its width and location of pigmentation in the matrix. [18] The sites and type of biopsies for melanonychia are listed in Table 5. [11,16,18,40] The biopsy sample should be of good quality, representative, adequate and from right location for proper diagnosis. An excisional biopsy whenever possible is recommended and matricial origin of pigmentation should be removed completely. Full-thickness matrix biopsy avoids any misdiagnosis and aids in prognosis by assessing Breslow depth. Nail matrix biopsy can cause nail scarring and deformity. To minimize these, distal nail matrix biopsy is preferred over proximal and the resultant defect of >3 mm should be sutured. [11] The histopathological features in different causes of melanonychia are listed in Table 6. [41,42] Imaging Nail unit ultrasound and MRI can help in the diagnosis of melanonychia suspected due to nail tumors. They can also help in delineating the extent of lesion and involvement of adjacent structures.

Differential Diagnoses and Approach to Melanonychia
The following are the differential diagnoses of melanonychia according to the presentation- [34] 1. Nonmelanin pigmentation: The first and essential step is to establish the melanin or nonmelanin (e.g., exogenous, infections, hematoma) etiology  A comprehensive approach to melanonychia has been summarized in Figure 15.

Treatment
Treatment of melanonychia depends on the underlying cause. The treatment of associated systemic or locoregional disease, withdrawal of offending drug, avoidance of trauma, treatment of infections or correction of nutritional deficiencies may cause regression of pigmentation. Benign causes do not necessitate treatment and can be kept in follow up. Depending on thickness and histopathological characteristics, subungual melanoma may be managed by functional surgical treatment (wide local excision) or digit amputation with or without sentinel lymph node mapping/biopsy. [43]

Prognosis and Follow up
Prognosis of melanonychia depends on its etiology and its benign or malignant nature. Benign lesions can be followed up while NUM may carry a poor prognosis as discussed in the section. There is still no consensus for follow-up of melanonychia which requires periodic medical examinations and photographic and dermoscopic documentations. Onychoscopy can be used for follow ups but there are no precise criteria for its frequency in patients with LM. Good-quality clinical as well as onychoscopic photographs highlighting the involved nail and the pigment morphology, color, and extent is necessary for follow ups. Patients should be counselled for self-examination and to report whenever any morphological change in pigmentation is noticed.

Conclusions
Melanonychia is a challenging symptom for the clinician, irrespective of the patient's' age. With careful history, clinical examination and investigations, it is possible to delineate an etiology; benign or malignant, in majority. Onychoscopy has become an indispensable tool in the evaluation of pigmentary nail disorders and should be performed in all cases. In suspected cases, one should have a low threshold for performing nail matrix biopsy as tissue diagnosis remains the gold standard.

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Conflicts of interest
There are no conflicts of interest.