- Email: [email protected]
Pigmented Nail Disorders
Dermatol Clin 24 (2006) 329–339
Pigmented Nail Disorders Josette Andre´, MD*, Nadine Lateur, MD Department of Dermatology, CHU Saint-Pierre, Brugmann, HUDERF, 129, Bd de Waterloo, B-1000 Brussels, Free University of Brussels, Belgium
Definition Nail pigmentation is defined by the presence of melanin in the nail plate. All other pigments (eg, iron, pyocyanin) are responsible for nail dyschromia and are beyond the scope of this article. Melanin in the nail plate most frequently has the appearance of a longitudinal pigmented band, called longitudinal melanonychia (LM). This term should be reserved for bands appearing in the matrix region and extending to the tip of the nail (Fig. 1). Total melanonychia and transverse melanonychia are much rarer. Except for subungual linear keratotic melanonychia, pigmented lesions in the nail bed usually do not cause LM and are viewed through the nail as a grayish to brown or black spot [1,2]. Where does the melanin in the nail plate come from? Melanin in the nail plate comes from matrix melanocytes. In the adult, matrix melanocytes are about 200/mm2 in number, compared with 1150/mm2 in the epidermis. In the proximal nail matrix, most melanocytes are dormant. In the distal nail matrix, there are two compartments of roughly equal importance: an active melanin synthesis compartment and a dormant melanocyte compartment. This difference in activity explains why LM originates more frequently in the distal nail matrix. A small number of dormant melanocytes (45/mm2) also can be detected in the normal nail bed [3]. Nail matrix melanocytes differ from melanocytes located elsewhere in the skin not
* Corresponding author. E-mail address: [email protected] (J. Andre´).
only by their smaller number and their usual quiescence, but also by their location. In the proximal matrix, they are located within the lower two to four germinative cell layers, whereas in the distal nail matrix, which is thinner, they are located in the first and second layers [3]. When melanocytes are activated, melanin-rich melanosomes are transferred by way of dendrites to differentiating matrix cells, which migrate distally as they transform into nail plate onychocytes. The melanized onychocytes constitute a linear band visible as LM.
Clinical aspect Because LM may indicate melanoma of the nail apparatus, close monitoring of the condition is paramount. Signs and symptoms of LM are varied and may include: involvement of one or several digits, color variation of the band from light brown to black, homogenous or heterogeneous appearance, variability of band width (in most cases band widths range from 2–4 mm), and sharp or blurred borders [4]. Extension of pigmentation to the skin adjacent to the nail plate involving the nail folds or the fingertip is called Hutchinson sign. This sign is an important indicator for nail melanoma. It is not exclusive for it, however. Pseudo-Hutchinson sign may be observed in various conditions that are described elsewhere in this article [5].
Cause From a histologic point of view, there are two broad groups of LM: melanocytic activation and melanocytic hyperplasia. Transverse melanonychia is always attributable to melanocytic activation.
0733-8635/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2006.03.012
derm.theclinics.com
330
ANDRE´ & LATEUR
than 50. Bands are more frequently located in the digits used for grasping (thumb, index finger, and middle finger), or those prone to trauma (eg, big toe). The number and width of the streaks tend to increase with age [4]. The nail plate of patients who have darker phototypes exhibit LM more easily when one of the causes of melanocyte stimulation is present. Local and regional causes Fig. 1. In LM the pigment extends to the tip of the nail.
Longitudinal melanonychia by melanocytic activation LM by melanocytic activation or stimulation is called functional melanonychia. A melanic pigmentation of the matrix epithelium and nail plate is observed, without any increase in the melanocyte number. Melanocytic activation is responsible for 73% of single LM in adults [6]. Several factors may cause LM; these are numerous and can be classified as physiologic, local and regional, dermatologic, systemic, and iatrogenic [7]. LM observed in Laugier-Hunziker syndrome or Peutz-Jeghers and Touraine syndrome are attributable also to melanocytic activation. Physiologic causes Racial melanonychia and pregnancy can be considered as physiologic causes of LM. The incidence of racial LM is affected by the phototype of the person. LM is unusual in whites (1%) and occurs in 10% to 20% of Japanese people. The frequency of LM may be as high as 77% in African Americans (Fig. 2) 20 years of age and older, and is visible in almost 100% of those older
Fig. 2. Racial melanonychia with pseudo-Hutchinson sign.
A frequent cause of LM is chronic traumatism. Repeated trauma can be seen in the toenails of patients who have ill-fitting shoes or overriding toes. It often is symmetric and affects the lateral and external part of the fourth or fifth toenail (Fig. 3) and the big toe, if the second toe is longer and rubs against it. Onychotillomania, nail biting, or occupational trauma are other causes of LM often associated with abnormalities of the nail plate or the periungual tissues. Carpal tunnel syndrome also can be added to this list [8]. Dermatologic causes Melanocytes can be activated by inflammatory changes accompanying skin diseases located in the nail unit, such as psoriasis (Fig. 4), lichen planus, amyloidosis, and chronic radiodermatitis. LM is observed most often as a single light-brown streak after resolution of the inflammatory process. LM in connective tissue diseases is unusual. Melanonychia caused by involvement of the nail matrix by systemic lupus erythematosus has been described recently, however [9]. Four cases of LM
Fig. 3. Frictional LM and horn in a fourth toenail.
PIGMENTED NAIL DISORDERS
331
Fig. 4. Total melanonychia in a Pakistani patient who has psoriasis.
associated with localized scleroderma also have been reported [10]. In onychomycosis, several mechanisms can be responsible for a tan band [7]. Some fungi can produce naturally pigmented hyphae (dematiaceous) or they can produce a diffusible black pigment (Trichophyton rubrum var nigricans) (Fig. 5). In some cases presenting with paronychia (Candida spp) melanocytes are stimulated by inflammation and as a result melanin can be seen in the nail plate along with the fungus. Rarely, nonmelanocytic tumors of the nail apparatus can be associated with LM. Stimulation of melanocytes has been evoked in onychomatricoma [11] and Bowen disease [12]. Myxoid pseudocyst (Fig. 6), basal cell carcinoma, subungual fibrous histiocytoma, and verruca vulgaris are other examples [4].
Systemic causes Endocrine disorders, such as Addison disease, Cushing syndrome, Nelson syndrome, hyperthyroidism, and acromegaly, can be responsible for melanocyte stimulation. Bands of LM usually are multiple and affect fingernails and toenails. In
Fig. 5. Black longitudinal dyschromia caused by Trichophyton rubrum var nigricans.
Fig. 6. LM aligned with a myxoid pseudocyst.
Addison disease they are associated with cutaneous and mucosal pigmentation. Multiple bands of LM also can be accompanied by mucosal or cutaneous pigmentation in nutritional disorders. Hemosiderosis, hyperbilirubinemia, alcaptonuria, and porphyria have been described as causes of LM [4]. In the nails, graft versus host disease can be responsible for lichen planus–type changes accompanied by LM. In patients who have AIDS, LM is not always related to zidovudine intake. Multiple bands of LM can be seen together with hyperpigmented macules on the soles, the palms, and the mucous membranes [13]. Transverse melanonychia also has been reported [14]. Iatrogenic causes Melanocyte activation can be secondary to phototherapy, x-ray exposure, electron beam therapy [14], or drug intake. LM is more common in people with heavily pigmented skin rather than in fair-skinned individuals and can be associated with skin hyperpigmentation. Several digits can be affected on the hands and the feet. In terms of drug intake, chemotherapeutic agents yield the first place but other drugs have also been implicated (Box 1) [15–17]. The presentation can vary. Sometimes several symptoms can be observed in one patient, particularly in those receiving chemotherapeutic agents: pigmentation of the nail bed, transverse melanonychia, or LM. The pigmentation usually fades after drug withdrawal
332
ANDRE´ & LATEUR
Box 1. Drugs that may induce melanonychia Chemotherapeuticals Bleomycin sulfate Busulfan Cyclophosphamide Dacarbazine Daunorubicin hydrochloride Doxorubicin Etoposide 5-Fluorouracile Hydroxyurea Melphalan hydrochloride Methotrexate Nitrogen mustard Nitrosourea Tegafur Others ACTH Amodiaquine Amorolfine Arsenic Chloroquine Clofazimine Clomipramine Cyclines Fluconazole Fluoride Gold salts Ibuprofen Ketoconazole Lamivudine Mepacrine Mercury MSH PCB Phenytoin Phenothiazine Psoralen Roxithromycin Steroids Sulfonamide Thallium Timolol Zidovudine
(Fig. 7); however, this can take years. For antimalarial drugs (mepacrine, amodiaquine, and chloroquine) color change may be attributable not only to melanin production but also to ferric
Fig. 7. Regressing LM six months after the end of chemotherapy.
dyschromia. The vast majority of transverse melanonychia belongs to this category. Laugier-Hunziker syndrome, Peutz-Jegher and Touraine syndrome Laugier-Hunziker syndrome is a chronic mucocutaneous disease without systemic involvement or family history. It predominantly affects white adults and usually starts between 20 and 40 years of age. The most distinguishing clinical finding is the frequent association of pigmented mucosal macules, especially on the lips and oral cavity, with one or several LMs that are localized more frequently on the fingers than the toes (Figs. 8 and 9). A pseudo-Hutchinson sign may be present. Mucosal pigmented macules are an important clue in the differential diagnosis of melanonychia and should always be looked for during examination. Peutz-Jeghers and Touraine syndrome has cutaneous manifestations close to those of Laugier-Hunziker syndrome; however, its transmission is autosomal dominant and the pigmented macules usually appear during childhood, with
Fig. 8. Laugier-Hunziker syndrome: multiple bands of melanonychia in a 50-year-old patient. (Courtesy of B. Richert, MD, Lie`ge, Belgium.)
333
PIGMENTED NAIL DISORDERS
Fig. 9. Laugier-Hunziker syndrome: pigmented macules on the tongue (patient shown in Fig. 8). (Courtesy of B. Richert, MD, Lie`ge, Belgium.)
perioral involvement. It is important to diagnose Peutz-Jeghers and Touraine syndrome because it is associated with intestinal polyposis and carries an increased risk for gastrointestinal and pancreatic malignancies.
Longitudinal melanonychia by melanocytic hyperplasia Melanocytic hyperplasia is defined as an increase in the number of matrix melanocytes. Benign melanocytic hyperplasia can be subdivided into lentigo when nests are absent or nevus when at least one nest is present. In children 77.5% of LM is because of benign melanocytic hyperplasia [18]. In situ and invasive melanoma of the nail apparatus are malignant melanocytic hyperplasia. Lentigo
Fig. 10. Nevus in a young child.
Nail apparatus melanoma Nail apparatus melanoma (NAM) is rare and accounts for 0.18% to 2.8% of melanomas in whites [20]. The relative incidence of NAM is much higher in nonwhites; up to 23% of melanomas in Japanese and 25% in African Americans are located in the nail apparatus. Nevertheless, the absolute incidence of NAM may well be similar among various racial groups [21]. Most tumors are located on the thumbs, index fingers, and big toes. The mean age at diagnosis is 60 to 70 years. Acrolentiginous melanoma is the most frequent type; superficial-spreading melanomas and nodular melanomas are encountered less frequently. A delay in the diagnosis of NAM is common and is associated with poor prognosis. Delays can be attributable to the patient and to the medical staff. Nail plate pigmentation, usually an LM, is the first manifestation of NAM in 38% to 76% of the cases (Fig. 11) but only one third of patients consult a physician at this stage [20,22]. Medical misdiagnosis occurs in 52% of the cases
Benign melanocytic hyperplasia without nests (Fig. 1), also called lentigo, is observed in 9% of the adult cases and 30% of the pediatric cases of single-biopsied LM [6,18]. Nevi Nevi can be congenital or acquired. They represent 12% of LM in adults but almost 50% of LM in children. The nevi prevail on fingers, mainly the thumb. Their width measures 3 mm or more in half of the cases. A brown-black coloration is observed in two thirds of the cases (Fig. 10) and a periungual pigmentation (benign pseudoHutchinson sign) in one third. It should be remembered, however, that nail matrix nevi also can present as scarcely pigmented bands [6,7,18,19].
Fig. 11. In situ melanoma in a 28-year-old woman. Rapid enlargement of the band from 2 to 7 mm in 6 months’ time.
334
ANDRE´ & LATEUR
and is responsible for an 18-month median delay [23]. This misdiagnosis is true particularly for amelanotic melanoma, which represents at least 20% of NAM [20]. (Amelanotic melanoma is not considered in this article devoted to nail pigmentation.) In LM, the problem is probably different because most physicians are aware that LM can be the sign of a melanoma. The problem is knowing when it is necessary to biopsy the lesion and how to perform the sampling. When examining a white patient with a single digit LM, the threshold for biopsy should be low, especially when the LM is located in the thumb, index finger, or big toenail, in a patient more than 60 years of age, or in a patient who has a history of melanoma. LM that is large, dark, heterogeneous, and has blurred borders, or an LM accompanied by periungual pigmentation (Fig. 12), nail dystrophy, subungual tumor, or ulceration necessitates prompt biopsy. The ABCDEF rule to improve early clinical detection of subungual melanoma may be of use [24]. Rarely, subungual melanoma may be present as a brown to black spot in the matrix or nail bed [7]. It may be homogeneous or irregular. Hutchinson sign, an extension of brown-black pigmentation from the matrix and nail bed onto the surrounding tissues, represents the radial growth phase of subungual melanoma. Its presence dictates removal of the entire affected part of the nail without prior incisional biopsy. This course of action is important for the correct diagnosis of NAM by the pathologist and to avoid dissemination of the tumor. Clinicians must proceed with caution, however, because the possibility of a pseudo-Hutchinson sign must be
Fig. 12. Nail apparatus melanoma with Hutchinson sign in an 80-year-old woman. (Courtesy of P. Bruderer, MD, Brussels, Belgium.)
considered and other signs evocative of melanoma should be assessed [4,5]. A delay in diagnosis is believed to be the main reason that NAM has a worse prognosis than cutaneous melanoma. At the Sydney Melanoma Unit, the mean Breslow thickness of NAM at diagnosis is 3.05 mm compared with a mean of less than 1.0 mm for cutaneous melanoma, and significantly fewer patients present with local disease without metastasis [20]. In a British study of 105 patients who had NAM, the mean Breslow thickness was 4.8 mm. The five-year survival rate was 88% for a Breslow thickness of 2.5 mm or less and only 40% for a thickness greater than 2.5 mm [25]. It should be mentioned that ungual melanoma is extremely rare in children but does exist [7,26,27].
Differential diagnosis Black nail Hematoma is the main differential diagnosis of black nail [1,28]. The patient is not always aware of a prior trauma, because it may have been minor and chronic (eg, rubbing in a sports shoe). In most cases it grows out with the nail plate, exhibiting a proximal border that reproduces the shape of the lunula. On occasion, a hematoma does not migrate because of repeated daily trauma. An extended, non-migrating hematoma should be considered suspicious, however. Trauma has been evoked in the pathogenesis of melanoma, and a hematoma could hide an underlying melanoma. Dermoscopic examination is characterized by blood spots with well-limited, rounded proximal edges and a purple to brown color [29]. A hole punched in the nail plate (Fig. 13) allows for the visualization of the underlying nail bed and confirmation of the nature of the coloration. Pseudomonas and Proteus species have been reported to cause black nails [7]. Systemic medication, such as clofazimine, tetracycline, gold salts, and antimalarials, can provoke a dark nail dyschromia not related to stimulation of melanin synthesis [17]. As in internal causes, discoloration follows the shape of the lunula. Exogenous discoloration can be caused by topical applications, such as potassium permanganate and silver nitrate. In this case, discoloration follows the shape of the proximal nail fold. It usually can be scraped off the nail surface. In subungual linear keratotic melanonychia, the pigmented band consisting of a subungual
PIGMENTED NAIL DISORDERS
335
History It is important to know the age, occupation, and hobbies of the patient. The duration of the evolution of the band, the intake or application of drugs, the history of melanoma, and dysplastic nevus syndrome should be recorded. It is essential to question the patient about any recent changes appearing in the band. Clinical examination
Fig. 13. Hematoma.
keratinized epithelial ridge originates in the nail bed. The origin of the melanin pigment is linked to its synthesis within the acanthoma. The lesions are reminiscent of pigmented seborrheic keratoses [2]. Pseudo-Hutchinson signs Hutchinson sign is an important presumptive clue to the diagnosis of subungual melanoma. There are, however, exceptions to consider when evaluating a patient suspected of having a subungual melanoma. The possibility of pseudoHutchinson variants must be kept in mind to avoid overdiagnosing a malignancy. These conditions can be subdivided into benign, nonmelanoma, and illusory categories [5]. Benign conditions can be associated with pigmentation of the tissues surrounding the nail plate. This pigmentation can be seen in racial melanonychia (Fig. 2), Lauzier-Hunziker and Peutz-Jeghers syndromes, radiation therapy, malnutrition, minocycline-induced dyschromia, patients who have AIDS, and congenital nevus. Benign pseudo-Hutchinson sign can be induced by chronic trauma. Malignant nonmelanoma tumors, such as Bowen disease, also can be responsible for periungual hyperpigmentation. Pseudo-Hutchinson sign can be illusory: pigmentation confined to the nail bed and matrix can shine through the transparency of the cuticle. Very rarely, blood from a subungual hematoma can spread to the nail folds and hyponychium.
Clinical examination should focus on patient phototype and the number and location of the affected nails. The following aspects of LM should be recorded: color; width; homogeneity; aspect of the lateral borders; and presence of a periungual pigmentation, nail plate dystrophy, subungual tumor, or ulceration. Dermatoscopy Both histologic types of LM, namely melanocytic activation and melanocytic hyperplasia, also can be identified by dermatoscopy [29]. In melanocytic activation, a grayish background color is observed, frequently associated with regular thin gray lines, whereas prominent melanocytic hyperplasia is characterized by a brown coloration of the background and longitudinal brown-black lines. LM color, thickness, and spacing, along with parallelism, should be recorded carefully. Nevi are characterized by regular parallel lines, whereas in melanoma the lines are irregular with some disruption of parallelism. Dermatoscopy also has been used to distinguish benign and malignant Hutchinson sign [30]. Nail plate sampling In cases in which there is a doubt about the nature of the pigment, nail plate samples should be taken, either with nail clippers or a punch. Samples can be submitted for direct microscopy, culture, and histology. Direct microscopy and culture mainly are used to exclude onychomycosis. Histology can confirm melanic pigmentation (positive Fontana staining) (Fig. 14) and location within the nail plate. The difference between ferric and melanin pigment is seen easily by ultrastructural techniques [31].
Management
Biopsy
Confronted with a single-digit LM, the diagnosis of melanoma should always be kept in mind. Clinicians should consider the following:
It is important to emphasize that the precise nature of the lesion responsible for LM can be confirmed only by matrix biopsy. Clinicians
336
ANDRE´ & LATEUR
Fig. 14. Melanin in the nail plate (Fontana staining).
should be aware that partial biopsy can lead to a delayed diagnosis [28]. Partial biopsies should be restricted and considered on a case-by-case basis only. Partial biopsies may be necessary when clinical follow-up is difficult or to reassure an anxious patient with a stable, wide, black LM, for example. In these cases, a 3-mm punch biopsy can be performed at the origin of the darkest part of the band. Histologic diagnosis of atypical melanocytic hyperplasia necessitates the complete removal of the lesion, without exception. Glat and colleagues [32] characterized three clinical categories of LM and discussed distinct management algorithms. The categories are single digit in whites, single digit in nonwhites, and multiple digits. For single digit in whites, the policy is to biopsy every lesion with excisional biopsy if possible. For single digit in nonwhites, Glat and colleagues advocate to biopsy evolving LM, LM broader than 6 mm, LM that are brownish with variegated shades or homogeneously black, and LM accompanied by periungual pigmentation. LM in multiple digits usually are benign. Nonetheless, the threshold for biopsy should remain low, and any nails with suspicious features should undergo histologic evaluation. LM in children rarely represents NAM. Their management can be more conservative [33].
The two largest histologic studies dealing with LM were published by Tosti [6] and Goettmann [18]. Tosti and her coauthors [6] considered 100 isolated LM in patients aged 1 to 72 years. A nevus was observed in all 11 pediatric cases. Among adult patients, melanocyte activation was recorded in 73% of the cases, benign melanocytic hyperplasia (lentigo) in 9%, nail matrix nevus in 12%, and melanoma in 6%. Goettmann and colleagues [18] considered 40 cases of longitudinal or total melanonychia in children aged 2 to 16 years. They found melanocytic activation in 22.5%, lentigo in 30%, and nevus in 47.5%. There was no melanoma. In both studies the vast majority of ungual nevi were junctional: 19 of 22 for Tosti and 17 of 19 for Goettmann (Fig. 15). In practice, histologic diagnosis of melanocytic tumors can be difficult for several reasons. To start, a poor-quality biopsy may not be representative of the tumors. The biopsy can be too small or too superficial, jagged, or infected [34]. It may have been taken from the wrong location, for example, in the nail bed and not in the matrix. The orientation also is important. The pathologist must be informed about the type of biopsy performed so that it is oriented correctly. Longitudinal multiple sections are essential. Eventually, there are also interpretation problems. Immunostaining with HMB 45 and Melan A often is necessary to determine whether there is genuine melanocytic hyperplasia or simple hyperpigmentation. Melanocytic intraepithelial lesions showing some nuclear atypia and discrete pagetoid spread in the most superficial layers
Pathology On histologic examination, LM can reveal Melanocytic activation (melanin hyperpigmentation without any increase in the number of melanocytes) Benign melanocytic hyperplasia represented by lentigo and nevus Atypical intraepithelial melanocytic hyperplasia (see later discussion) In situ or invasive melanoma
Fig. 15. Junctional nail matrix nevus.
PIGMENTED NAIL DISORDERS
frequently are described as atypical intraepithelial melanocytic hyperplasia; the process by which these lesions progress remains unclear. Because they can represent very early signs of a melanoma these lesions should be excised completely. Histology, as with clinical assessment, is not an infallible science. Histologic diagnosis is one of the possible reasons for the late diagnosis so frequently observed in NAM. The most accurate diagnosis requires examination of the entire lesion, serial sections, immunostaining, and proper clinical assessment. When there is a discrepancy between the clinical observation and the histologic diagnosis, the clinician must not hesitate to contact the pathologist. The telephone and now E-mail messages and images are, along with the microscope, the pathologist’s best friends. Performing the biopsy To perform a biopsy it is necessary to remove the nail plate to visualize the pigmented area responsible for the LM. It usually is restricted to the matrix area but can extend toward the nail bed and up to the hyponychium in benign nevi and melanoma. Only LM that is very light in appearance defies this rule. No single biopsy method meets the needs of all patients. The chosen procedure depends on (1) the likelihood of NAM, (2) the need to minimize the risk for postoperative dystrophy, (3) the location of the band (median or lateral), (4) the band’s width, and (5) the matrix origin. Patients should be made aware of the cosmetic outcome. If the lateral third of the nail plate is involved, hemi–nail plate avulsion is performed, followed by lateral longitudinal excision of the pigmented lesion. This technique removes the matrix, the proximal nail fold, the cuticle, the portion of the lateral nail fold adjacent to the proximal nail fold, and the nail bed. The patient is left with a narrowed nail. If the midportion of the nail plate is involved, relaxing incisions are made in the proximal nail fold and the proximal nail plate is removed. In light-colored bands, however, the precise origin may be difficult to ascertain after removal of the nail plate (see later discussion). If the band is 2 mm or less and originates in the distal two thirds of the matrix, the origin of the band can be removed by a 3-mm punch excision. For pale-colored LM it is preferable that the punch be performed directly through the nail plate. The proximal part of the nail plate can
337
then be removed, allowing inspection of the surrounding matrix and nail bed. Last, the cylinder of tissue is removed by cutting it off down to the bone. Postoperative dystrophy usually is minimal. If the band is 2 mm or less, but originates in the proximal third of the matrix, the 3-mm punch technique also can be used. The proximal nail fold must be reflected back completely to ensure full exposure of the band. An attempt can be made to minimize the defect by partial approximation (rather than complete closure) with a 6-0 absorbable suture. The risk for postoperative dystrophy is substantial [4]. If the band is between 3 and 6 mm wide and originates in the distal two thirds of the matrix, transverse elliptic incision is indicated. Because the proximal matrix remains intact, a thinned nail plate regenerates postoperatively, limiting the cosmetic damage. For a 3- to 6-mm wide band originating in the proximal one third of the matrix, the releasing flap method of Schernberg and Amiel is advised. This procedure leaves a severe postsurgical dystrophy (longitudinal nail splitting). A partial biopsy can be discussed. For bands wider than 6 mm, or if the full thickness of the nail is pigmented, the underlying disease process is unlikely to be benign. Depending on the clinical circumstances, a biopsy could be proposed or the entire portion of the involved nail apparatus can be excised en bloc. When the risk for postoperative scarring is high, as for bands located in the proximal matrix or bands larger than 6 mm, the shave biopsy technique suggested by Haneke is an interesting alternative [35]. Treatment of NAM Treatment of NAM is not the focus of this article. It must be remembered, however, that the diagnosis of melanoma should lead to further surgical procedures [25,36]. With in situ melanoma, total excision of the entire nail apparatus remains the norm of treatment. Mohs surgery can be used for more limited excision, however [37]. In invasive melanoma, amputation of the distal phalanx usually is recommended, but there is a legitimate move toward less radical therapy for NAM of low Breslow thickness [38]. A recent article suggests that nonamputative local excision with micrographically controlled margin using the Mohs surgical technique is a reasonable
338
ANDRE´ & LATEUR
option in the management of melanoma of the nail apparatus [39]. Adjuvant therapy should be considered for NAM with a poor prognosis [25]. The technique of sentinel node biopsy is increasingly used for NAM with a depth greater than 1 mm and for thinner, ulcerated melanoma, the detection of micrometastasis being one of the most important prognostic factors [40]. Controlled, prospective clinical trials on cutaneous melanoma are ongoing; their results will certainly influence the future evidence-based management of NAM.
Summary LM can be the first sign of a subungual melanoma. Confronted with an isolated LM, the threshold for biopsy should be low. It is important to know when and how to perform biopsy to improve the poor prognosis usually associated with NAM. References [1] Baran R, Haneke E, Drape´ JL, et al. Tumours of the nail apparatus and adjacent tissues. In: Baran R, Dawber RPR, de Berker DAR, et al, editors. Diseases of the nails and their management. 3rd edition. Oxford: Blackwell Science Ltd; 2001. p. 607–30. [2] Baran R, Perrin C. Linear melanonychia due to subungual keratosis of the nail bed: report of two cases. Br J Dermatol 1999;140:730–3. [3] Perrin C, Michiels JF, Pisani A, et al. Anatomic distribution of melanocytes in normal nail unit: an immunohistochemical investigation. Am J Dermatopathol 1997;19(5):462–7. [4] Baran R, Kechijian P. Longitudinal melanonychia (melanonychia striata): diagnosis and management. J Am Acad Dermatol 1989;21:1165–75. [5] Baran R, Kechijian P. Hutchinson’s sign: a reappraisal. J Am Acad Dermatol 1996;34(6):87–90. [6] Tosti A, Baran R, Piraccini BM, et al. Nail matrix nevi: a clinical and histopathological study of twenty-two patients. J Am Acad Dermatol 1996; 34(5):765–71. [7] Lateur N, Andre´ J. Melanonychia: diagnosis and treatment. Dermatol Ther 2002;15:131–41. [8] Aratari E, Regesta G, Rebora A. Carpal tunnel syndrome appearing with prominent skin symptoms. Arch Dermatol 1984;120:517–9. [9] Skowron F, Combemale P, Faisant M, et al. Functional melanonychia due to involvement of the nail matrix in systemic lupus erythematosus. J Am Acad Dermatol 2002;47:S187–8. [10] Baran R. Longitudinal melanonychia in localized scleroderma: report of four cases. J Am Acad Dermatol 2004;50(3):E5.
[11] Fayol J, Baran R, Perrin C, et al. Onychomatricoma with misleading features. Acta Derm Venereol 2000; 80:370–2. [12] Sass U, Andre´ J, Stene JJ, et al. Longitudinal melanonychia revealing an intraepidermal carcinoma of the nail apparatus: detection of integrated HPV-16 DNA. J Am Acad Dermatol 1998;39(3):490–3. [13] Cribier B, Leiva Mena M, Rey D, et al. Nail changes in patients infected with human immunodeficiency virus. Arch Dermatol 1998;134:1216–20. [14] Quinlan KE, Janiga JJ, Baran R, et al. Transverse melanonychia secondary to total skin electron beam therapy: a report of 3 cases. J Am Acad Dermatol 2005;53(2):S112–4. [15] Kar HK. Longitudinal melanonychia associated with fluconazole therapy. Int J Dermatol 1998;37: 719–20. [16] O’Branski EE, Russel EW, Prose NS, et al. Skin and nail changes in children with sickle cell anemia receiving hydroxyurea therapy. J Am Acad Dermatol 2001;44(5):859–61. [17] Piraccini BM, Tosti A. Drug-induced nail disorders. Incidence, management and prognosis. Drug Saf 1999;21(3):187–201. [18] Goettmann-Bonvallot S, Andre´ J, Belaich S. Longitudinal melanonychia in children: a clinical and histopathologic study of 40 cases. J Am Acad Dermatol 1999;41(1):17–22. [19] Le´aute-Labre`ze C, Bioulac-Sage P, Taı¨ eb A. Longitudinal melanonychia in children: a study of 8 cases. Arch Dermatol 1996;132:167–9. [20] Thai KE, Young R, Sinclair RD. Nail apparatus melanoma. Australas J Dermatol 2001;42(2):71–81. [21] Stevens NG, Liff JM, Weiss NS. Plantar melanoma: is the incidence of melanoma of the sole of the foot really higher in blacks than whites? Int J Cancer 1990;45:691–3. [22] Kato T, Suetake T, Sugiyama Y, et al. Epidemiology and prognosis of subungual melanoma in 34 Japanese patients. Br J Dermatol 1996;134:383–7. [23] Metzger S, Ellwanger U, Stroebel W, et al. Extent and consequences of physician delay in the diagnosis of acral melanoma. Melanoma Res 1998;8:181–6. [24] Levit EK, Kagen MH, Scher RK, et al. The ABC rule for clinical detection of subungual melanoma. J Am Acad Dermatol 2000;42(2):269–74. [25] Banfield CC, Redburn JC, Dawber RPR. The incidence and prognosis of nail apparatus melanoma: a retrospective study of 105 patients in four English regions. Br J Dermatol 1998;139:276–9. [26] Takata M, Maruo K, Kageshita T, et al. Two cases of unusual acral melanocytic tumors: illustration of molecular cytogenetics as a diagnostic tool. Hum Pathol 2003;34(1):89–92. [27] Antonovich DD, Grin C, Grant-Kels JM. Childhood subungual melanoma in situ in diffuse nail melanosis beginning as expanding longitudinal melanonychia. Pediatr Dermatol 2005;22(3):210–2.
PIGMENTED NAIL DISORDERS
[28] Dawber RPR, Colver GB. The spectrum of malignant melanoma of the nail apparatus. Sem Dermatol 1991;10(1):82–7. [29] Ronger S, Touzet S, Ligeron C, et al. Dermoscopic examination of nail pigmentation. Arch Dermtol 2002;138:1327–33. [30] Kawabata Y, Ohara K, Hino H, et al. Two kinds of Hutchinson’s sign: benign and malignant. J Am Acad Dermatol 2001;44(2):305–7. [31] Achten G, Andre´ J, Laporte M. Nails in light and electron microscopy. Semin Dermatol 1991;10: 54–64. [32] Glat PM, Spector JA, Roses DF, et al. The management of pigmented lesions of the nail bed. Ann Plast Surg 1996;37(2):125–34. [33] Andre´ J, Goettmann-Bonvallot S. Longitudinal melanonychia. J Am Acad Dermatol 2003;49:776. [34] Blessing K, Kernohan NM, Park KGM. Subungual malignant melanoma: clinicopathological features of 100 cases. Histopathology 1991;19:425–9.
339
[35] Haneke E, Baran R. Longitudinal melanonychia. Dermatol Surg 2001;27(6):580–4. [36] Tseng JF, Tanabe KK, Gadd MA, et al. Surgical management of primary cutaneous melanomas of the hands and feet. Ann Surg 1997;25(5):544–53. [37] Banfield CC, Dawber RPR, Walker NK, et al. Mohs micrography surgery for the treatment of in situ nail apparatus melanoma: a case report. J Am Acad Dermatol 1999;40(1):98–9. [38] de Berker D. The Black Nail dTreatment. Proceedings of the European Nail Society. Amsterdam, September 19, 1999. [39] Brodland DG. The treatment of nail apparatus melanoma with Mohs micrographic surgery. Dermatol Surg 2001;27(3):269–73. [40] Gershenwald JE, Thompson W, Mansfield PF, et al. Muti-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I and II melanoma patients. J Clin Oncol 1999;17(3):976–83.
Pigmented Nail Disorders Josette Andre´, MD*, Nadine Lateur, MD Department of Dermatology, CHU Saint-Pierre, Brugmann, HUDERF, 129, Bd de Waterloo, B-1000 Brussels, Free University of Brussels, Belgium
Definition Nail pigmentation is defined by the presence of melanin in the nail plate. All other pigments (eg, iron, pyocyanin) are responsible for nail dyschromia and are beyond the scope of this article. Melanin in the nail plate most frequently has the appearance of a longitudinal pigmented band, called longitudinal melanonychia (LM). This term should be reserved for bands appearing in the matrix region and extending to the tip of the nail (Fig. 1). Total melanonychia and transverse melanonychia are much rarer. Except for subungual linear keratotic melanonychia, pigmented lesions in the nail bed usually do not cause LM and are viewed through the nail as a grayish to brown or black spot [1,2]. Where does the melanin in the nail plate come from? Melanin in the nail plate comes from matrix melanocytes. In the adult, matrix melanocytes are about 200/mm2 in number, compared with 1150/mm2 in the epidermis. In the proximal nail matrix, most melanocytes are dormant. In the distal nail matrix, there are two compartments of roughly equal importance: an active melanin synthesis compartment and a dormant melanocyte compartment. This difference in activity explains why LM originates more frequently in the distal nail matrix. A small number of dormant melanocytes (45/mm2) also can be detected in the normal nail bed [3]. Nail matrix melanocytes differ from melanocytes located elsewhere in the skin not
* Corresponding author. E-mail address: [email protected] (J. Andre´).
only by their smaller number and their usual quiescence, but also by their location. In the proximal matrix, they are located within the lower two to four germinative cell layers, whereas in the distal nail matrix, which is thinner, they are located in the first and second layers [3]. When melanocytes are activated, melanin-rich melanosomes are transferred by way of dendrites to differentiating matrix cells, which migrate distally as they transform into nail plate onychocytes. The melanized onychocytes constitute a linear band visible as LM.
Clinical aspect Because LM may indicate melanoma of the nail apparatus, close monitoring of the condition is paramount. Signs and symptoms of LM are varied and may include: involvement of one or several digits, color variation of the band from light brown to black, homogenous or heterogeneous appearance, variability of band width (in most cases band widths range from 2–4 mm), and sharp or blurred borders [4]. Extension of pigmentation to the skin adjacent to the nail plate involving the nail folds or the fingertip is called Hutchinson sign. This sign is an important indicator for nail melanoma. It is not exclusive for it, however. Pseudo-Hutchinson sign may be observed in various conditions that are described elsewhere in this article [5].
Cause From a histologic point of view, there are two broad groups of LM: melanocytic activation and melanocytic hyperplasia. Transverse melanonychia is always attributable to melanocytic activation.
0733-8635/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2006.03.012
derm.theclinics.com
330
ANDRE´ & LATEUR
than 50. Bands are more frequently located in the digits used for grasping (thumb, index finger, and middle finger), or those prone to trauma (eg, big toe). The number and width of the streaks tend to increase with age [4]. The nail plate of patients who have darker phototypes exhibit LM more easily when one of the causes of melanocyte stimulation is present. Local and regional causes Fig. 1. In LM the pigment extends to the tip of the nail.
Longitudinal melanonychia by melanocytic activation LM by melanocytic activation or stimulation is called functional melanonychia. A melanic pigmentation of the matrix epithelium and nail plate is observed, without any increase in the melanocyte number. Melanocytic activation is responsible for 73% of single LM in adults [6]. Several factors may cause LM; these are numerous and can be classified as physiologic, local and regional, dermatologic, systemic, and iatrogenic [7]. LM observed in Laugier-Hunziker syndrome or Peutz-Jeghers and Touraine syndrome are attributable also to melanocytic activation. Physiologic causes Racial melanonychia and pregnancy can be considered as physiologic causes of LM. The incidence of racial LM is affected by the phototype of the person. LM is unusual in whites (1%) and occurs in 10% to 20% of Japanese people. The frequency of LM may be as high as 77% in African Americans (Fig. 2) 20 years of age and older, and is visible in almost 100% of those older
Fig. 2. Racial melanonychia with pseudo-Hutchinson sign.
A frequent cause of LM is chronic traumatism. Repeated trauma can be seen in the toenails of patients who have ill-fitting shoes or overriding toes. It often is symmetric and affects the lateral and external part of the fourth or fifth toenail (Fig. 3) and the big toe, if the second toe is longer and rubs against it. Onychotillomania, nail biting, or occupational trauma are other causes of LM often associated with abnormalities of the nail plate or the periungual tissues. Carpal tunnel syndrome also can be added to this list [8]. Dermatologic causes Melanocytes can be activated by inflammatory changes accompanying skin diseases located in the nail unit, such as psoriasis (Fig. 4), lichen planus, amyloidosis, and chronic radiodermatitis. LM is observed most often as a single light-brown streak after resolution of the inflammatory process. LM in connective tissue diseases is unusual. Melanonychia caused by involvement of the nail matrix by systemic lupus erythematosus has been described recently, however [9]. Four cases of LM
Fig. 3. Frictional LM and horn in a fourth toenail.
PIGMENTED NAIL DISORDERS
331
Fig. 4. Total melanonychia in a Pakistani patient who has psoriasis.
associated with localized scleroderma also have been reported [10]. In onychomycosis, several mechanisms can be responsible for a tan band [7]. Some fungi can produce naturally pigmented hyphae (dematiaceous) or they can produce a diffusible black pigment (Trichophyton rubrum var nigricans) (Fig. 5). In some cases presenting with paronychia (Candida spp) melanocytes are stimulated by inflammation and as a result melanin can be seen in the nail plate along with the fungus. Rarely, nonmelanocytic tumors of the nail apparatus can be associated with LM. Stimulation of melanocytes has been evoked in onychomatricoma [11] and Bowen disease [12]. Myxoid pseudocyst (Fig. 6), basal cell carcinoma, subungual fibrous histiocytoma, and verruca vulgaris are other examples [4].
Systemic causes Endocrine disorders, such as Addison disease, Cushing syndrome, Nelson syndrome, hyperthyroidism, and acromegaly, can be responsible for melanocyte stimulation. Bands of LM usually are multiple and affect fingernails and toenails. In
Fig. 5. Black longitudinal dyschromia caused by Trichophyton rubrum var nigricans.
Fig. 6. LM aligned with a myxoid pseudocyst.
Addison disease they are associated with cutaneous and mucosal pigmentation. Multiple bands of LM also can be accompanied by mucosal or cutaneous pigmentation in nutritional disorders. Hemosiderosis, hyperbilirubinemia, alcaptonuria, and porphyria have been described as causes of LM [4]. In the nails, graft versus host disease can be responsible for lichen planus–type changes accompanied by LM. In patients who have AIDS, LM is not always related to zidovudine intake. Multiple bands of LM can be seen together with hyperpigmented macules on the soles, the palms, and the mucous membranes [13]. Transverse melanonychia also has been reported [14]. Iatrogenic causes Melanocyte activation can be secondary to phototherapy, x-ray exposure, electron beam therapy [14], or drug intake. LM is more common in people with heavily pigmented skin rather than in fair-skinned individuals and can be associated with skin hyperpigmentation. Several digits can be affected on the hands and the feet. In terms of drug intake, chemotherapeutic agents yield the first place but other drugs have also been implicated (Box 1) [15–17]. The presentation can vary. Sometimes several symptoms can be observed in one patient, particularly in those receiving chemotherapeutic agents: pigmentation of the nail bed, transverse melanonychia, or LM. The pigmentation usually fades after drug withdrawal
332
ANDRE´ & LATEUR
Box 1. Drugs that may induce melanonychia Chemotherapeuticals Bleomycin sulfate Busulfan Cyclophosphamide Dacarbazine Daunorubicin hydrochloride Doxorubicin Etoposide 5-Fluorouracile Hydroxyurea Melphalan hydrochloride Methotrexate Nitrogen mustard Nitrosourea Tegafur Others ACTH Amodiaquine Amorolfine Arsenic Chloroquine Clofazimine Clomipramine Cyclines Fluconazole Fluoride Gold salts Ibuprofen Ketoconazole Lamivudine Mepacrine Mercury MSH PCB Phenytoin Phenothiazine Psoralen Roxithromycin Steroids Sulfonamide Thallium Timolol Zidovudine
(Fig. 7); however, this can take years. For antimalarial drugs (mepacrine, amodiaquine, and chloroquine) color change may be attributable not only to melanin production but also to ferric
Fig. 7. Regressing LM six months after the end of chemotherapy.
dyschromia. The vast majority of transverse melanonychia belongs to this category. Laugier-Hunziker syndrome, Peutz-Jegher and Touraine syndrome Laugier-Hunziker syndrome is a chronic mucocutaneous disease without systemic involvement or family history. It predominantly affects white adults and usually starts between 20 and 40 years of age. The most distinguishing clinical finding is the frequent association of pigmented mucosal macules, especially on the lips and oral cavity, with one or several LMs that are localized more frequently on the fingers than the toes (Figs. 8 and 9). A pseudo-Hutchinson sign may be present. Mucosal pigmented macules are an important clue in the differential diagnosis of melanonychia and should always be looked for during examination. Peutz-Jeghers and Touraine syndrome has cutaneous manifestations close to those of Laugier-Hunziker syndrome; however, its transmission is autosomal dominant and the pigmented macules usually appear during childhood, with
Fig. 8. Laugier-Hunziker syndrome: multiple bands of melanonychia in a 50-year-old patient. (Courtesy of B. Richert, MD, Lie`ge, Belgium.)
333
PIGMENTED NAIL DISORDERS
Fig. 9. Laugier-Hunziker syndrome: pigmented macules on the tongue (patient shown in Fig. 8). (Courtesy of B. Richert, MD, Lie`ge, Belgium.)
perioral involvement. It is important to diagnose Peutz-Jeghers and Touraine syndrome because it is associated with intestinal polyposis and carries an increased risk for gastrointestinal and pancreatic malignancies.
Longitudinal melanonychia by melanocytic hyperplasia Melanocytic hyperplasia is defined as an increase in the number of matrix melanocytes. Benign melanocytic hyperplasia can be subdivided into lentigo when nests are absent or nevus when at least one nest is present. In children 77.5% of LM is because of benign melanocytic hyperplasia [18]. In situ and invasive melanoma of the nail apparatus are malignant melanocytic hyperplasia. Lentigo
Fig. 10. Nevus in a young child.
Nail apparatus melanoma Nail apparatus melanoma (NAM) is rare and accounts for 0.18% to 2.8% of melanomas in whites [20]. The relative incidence of NAM is much higher in nonwhites; up to 23% of melanomas in Japanese and 25% in African Americans are located in the nail apparatus. Nevertheless, the absolute incidence of NAM may well be similar among various racial groups [21]. Most tumors are located on the thumbs, index fingers, and big toes. The mean age at diagnosis is 60 to 70 years. Acrolentiginous melanoma is the most frequent type; superficial-spreading melanomas and nodular melanomas are encountered less frequently. A delay in the diagnosis of NAM is common and is associated with poor prognosis. Delays can be attributable to the patient and to the medical staff. Nail plate pigmentation, usually an LM, is the first manifestation of NAM in 38% to 76% of the cases (Fig. 11) but only one third of patients consult a physician at this stage [20,22]. Medical misdiagnosis occurs in 52% of the cases
Benign melanocytic hyperplasia without nests (Fig. 1), also called lentigo, is observed in 9% of the adult cases and 30% of the pediatric cases of single-biopsied LM [6,18]. Nevi Nevi can be congenital or acquired. They represent 12% of LM in adults but almost 50% of LM in children. The nevi prevail on fingers, mainly the thumb. Their width measures 3 mm or more in half of the cases. A brown-black coloration is observed in two thirds of the cases (Fig. 10) and a periungual pigmentation (benign pseudoHutchinson sign) in one third. It should be remembered, however, that nail matrix nevi also can present as scarcely pigmented bands [6,7,18,19].
Fig. 11. In situ melanoma in a 28-year-old woman. Rapid enlargement of the band from 2 to 7 mm in 6 months’ time.
334
ANDRE´ & LATEUR
and is responsible for an 18-month median delay [23]. This misdiagnosis is true particularly for amelanotic melanoma, which represents at least 20% of NAM [20]. (Amelanotic melanoma is not considered in this article devoted to nail pigmentation.) In LM, the problem is probably different because most physicians are aware that LM can be the sign of a melanoma. The problem is knowing when it is necessary to biopsy the lesion and how to perform the sampling. When examining a white patient with a single digit LM, the threshold for biopsy should be low, especially when the LM is located in the thumb, index finger, or big toenail, in a patient more than 60 years of age, or in a patient who has a history of melanoma. LM that is large, dark, heterogeneous, and has blurred borders, or an LM accompanied by periungual pigmentation (Fig. 12), nail dystrophy, subungual tumor, or ulceration necessitates prompt biopsy. The ABCDEF rule to improve early clinical detection of subungual melanoma may be of use [24]. Rarely, subungual melanoma may be present as a brown to black spot in the matrix or nail bed [7]. It may be homogeneous or irregular. Hutchinson sign, an extension of brown-black pigmentation from the matrix and nail bed onto the surrounding tissues, represents the radial growth phase of subungual melanoma. Its presence dictates removal of the entire affected part of the nail without prior incisional biopsy. This course of action is important for the correct diagnosis of NAM by the pathologist and to avoid dissemination of the tumor. Clinicians must proceed with caution, however, because the possibility of a pseudo-Hutchinson sign must be
Fig. 12. Nail apparatus melanoma with Hutchinson sign in an 80-year-old woman. (Courtesy of P. Bruderer, MD, Brussels, Belgium.)
considered and other signs evocative of melanoma should be assessed [4,5]. A delay in diagnosis is believed to be the main reason that NAM has a worse prognosis than cutaneous melanoma. At the Sydney Melanoma Unit, the mean Breslow thickness of NAM at diagnosis is 3.05 mm compared with a mean of less than 1.0 mm for cutaneous melanoma, and significantly fewer patients present with local disease without metastasis [20]. In a British study of 105 patients who had NAM, the mean Breslow thickness was 4.8 mm. The five-year survival rate was 88% for a Breslow thickness of 2.5 mm or less and only 40% for a thickness greater than 2.5 mm [25]. It should be mentioned that ungual melanoma is extremely rare in children but does exist [7,26,27].
Differential diagnosis Black nail Hematoma is the main differential diagnosis of black nail [1,28]. The patient is not always aware of a prior trauma, because it may have been minor and chronic (eg, rubbing in a sports shoe). In most cases it grows out with the nail plate, exhibiting a proximal border that reproduces the shape of the lunula. On occasion, a hematoma does not migrate because of repeated daily trauma. An extended, non-migrating hematoma should be considered suspicious, however. Trauma has been evoked in the pathogenesis of melanoma, and a hematoma could hide an underlying melanoma. Dermoscopic examination is characterized by blood spots with well-limited, rounded proximal edges and a purple to brown color [29]. A hole punched in the nail plate (Fig. 13) allows for the visualization of the underlying nail bed and confirmation of the nature of the coloration. Pseudomonas and Proteus species have been reported to cause black nails [7]. Systemic medication, such as clofazimine, tetracycline, gold salts, and antimalarials, can provoke a dark nail dyschromia not related to stimulation of melanin synthesis [17]. As in internal causes, discoloration follows the shape of the lunula. Exogenous discoloration can be caused by topical applications, such as potassium permanganate and silver nitrate. In this case, discoloration follows the shape of the proximal nail fold. It usually can be scraped off the nail surface. In subungual linear keratotic melanonychia, the pigmented band consisting of a subungual
PIGMENTED NAIL DISORDERS
335
History It is important to know the age, occupation, and hobbies of the patient. The duration of the evolution of the band, the intake or application of drugs, the history of melanoma, and dysplastic nevus syndrome should be recorded. It is essential to question the patient about any recent changes appearing in the band. Clinical examination
Fig. 13. Hematoma.
keratinized epithelial ridge originates in the nail bed. The origin of the melanin pigment is linked to its synthesis within the acanthoma. The lesions are reminiscent of pigmented seborrheic keratoses [2]. Pseudo-Hutchinson signs Hutchinson sign is an important presumptive clue to the diagnosis of subungual melanoma. There are, however, exceptions to consider when evaluating a patient suspected of having a subungual melanoma. The possibility of pseudoHutchinson variants must be kept in mind to avoid overdiagnosing a malignancy. These conditions can be subdivided into benign, nonmelanoma, and illusory categories [5]. Benign conditions can be associated with pigmentation of the tissues surrounding the nail plate. This pigmentation can be seen in racial melanonychia (Fig. 2), Lauzier-Hunziker and Peutz-Jeghers syndromes, radiation therapy, malnutrition, minocycline-induced dyschromia, patients who have AIDS, and congenital nevus. Benign pseudo-Hutchinson sign can be induced by chronic trauma. Malignant nonmelanoma tumors, such as Bowen disease, also can be responsible for periungual hyperpigmentation. Pseudo-Hutchinson sign can be illusory: pigmentation confined to the nail bed and matrix can shine through the transparency of the cuticle. Very rarely, blood from a subungual hematoma can spread to the nail folds and hyponychium.
Clinical examination should focus on patient phototype and the number and location of the affected nails. The following aspects of LM should be recorded: color; width; homogeneity; aspect of the lateral borders; and presence of a periungual pigmentation, nail plate dystrophy, subungual tumor, or ulceration. Dermatoscopy Both histologic types of LM, namely melanocytic activation and melanocytic hyperplasia, also can be identified by dermatoscopy [29]. In melanocytic activation, a grayish background color is observed, frequently associated with regular thin gray lines, whereas prominent melanocytic hyperplasia is characterized by a brown coloration of the background and longitudinal brown-black lines. LM color, thickness, and spacing, along with parallelism, should be recorded carefully. Nevi are characterized by regular parallel lines, whereas in melanoma the lines are irregular with some disruption of parallelism. Dermatoscopy also has been used to distinguish benign and malignant Hutchinson sign [30]. Nail plate sampling In cases in which there is a doubt about the nature of the pigment, nail plate samples should be taken, either with nail clippers or a punch. Samples can be submitted for direct microscopy, culture, and histology. Direct microscopy and culture mainly are used to exclude onychomycosis. Histology can confirm melanic pigmentation (positive Fontana staining) (Fig. 14) and location within the nail plate. The difference between ferric and melanin pigment is seen easily by ultrastructural techniques [31].
Management
Biopsy
Confronted with a single-digit LM, the diagnosis of melanoma should always be kept in mind. Clinicians should consider the following:
It is important to emphasize that the precise nature of the lesion responsible for LM can be confirmed only by matrix biopsy. Clinicians
336
ANDRE´ & LATEUR
Fig. 14. Melanin in the nail plate (Fontana staining).
should be aware that partial biopsy can lead to a delayed diagnosis [28]. Partial biopsies should be restricted and considered on a case-by-case basis only. Partial biopsies may be necessary when clinical follow-up is difficult or to reassure an anxious patient with a stable, wide, black LM, for example. In these cases, a 3-mm punch biopsy can be performed at the origin of the darkest part of the band. Histologic diagnosis of atypical melanocytic hyperplasia necessitates the complete removal of the lesion, without exception. Glat and colleagues [32] characterized three clinical categories of LM and discussed distinct management algorithms. The categories are single digit in whites, single digit in nonwhites, and multiple digits. For single digit in whites, the policy is to biopsy every lesion with excisional biopsy if possible. For single digit in nonwhites, Glat and colleagues advocate to biopsy evolving LM, LM broader than 6 mm, LM that are brownish with variegated shades or homogeneously black, and LM accompanied by periungual pigmentation. LM in multiple digits usually are benign. Nonetheless, the threshold for biopsy should remain low, and any nails with suspicious features should undergo histologic evaluation. LM in children rarely represents NAM. Their management can be more conservative [33].
The two largest histologic studies dealing with LM were published by Tosti [6] and Goettmann [18]. Tosti and her coauthors [6] considered 100 isolated LM in patients aged 1 to 72 years. A nevus was observed in all 11 pediatric cases. Among adult patients, melanocyte activation was recorded in 73% of the cases, benign melanocytic hyperplasia (lentigo) in 9%, nail matrix nevus in 12%, and melanoma in 6%. Goettmann and colleagues [18] considered 40 cases of longitudinal or total melanonychia in children aged 2 to 16 years. They found melanocytic activation in 22.5%, lentigo in 30%, and nevus in 47.5%. There was no melanoma. In both studies the vast majority of ungual nevi were junctional: 19 of 22 for Tosti and 17 of 19 for Goettmann (Fig. 15). In practice, histologic diagnosis of melanocytic tumors can be difficult for several reasons. To start, a poor-quality biopsy may not be representative of the tumors. The biopsy can be too small or too superficial, jagged, or infected [34]. It may have been taken from the wrong location, for example, in the nail bed and not in the matrix. The orientation also is important. The pathologist must be informed about the type of biopsy performed so that it is oriented correctly. Longitudinal multiple sections are essential. Eventually, there are also interpretation problems. Immunostaining with HMB 45 and Melan A often is necessary to determine whether there is genuine melanocytic hyperplasia or simple hyperpigmentation. Melanocytic intraepithelial lesions showing some nuclear atypia and discrete pagetoid spread in the most superficial layers
Pathology On histologic examination, LM can reveal Melanocytic activation (melanin hyperpigmentation without any increase in the number of melanocytes) Benign melanocytic hyperplasia represented by lentigo and nevus Atypical intraepithelial melanocytic hyperplasia (see later discussion) In situ or invasive melanoma
Fig. 15. Junctional nail matrix nevus.
PIGMENTED NAIL DISORDERS
frequently are described as atypical intraepithelial melanocytic hyperplasia; the process by which these lesions progress remains unclear. Because they can represent very early signs of a melanoma these lesions should be excised completely. Histology, as with clinical assessment, is not an infallible science. Histologic diagnosis is one of the possible reasons for the late diagnosis so frequently observed in NAM. The most accurate diagnosis requires examination of the entire lesion, serial sections, immunostaining, and proper clinical assessment. When there is a discrepancy between the clinical observation and the histologic diagnosis, the clinician must not hesitate to contact the pathologist. The telephone and now E-mail messages and images are, along with the microscope, the pathologist’s best friends. Performing the biopsy To perform a biopsy it is necessary to remove the nail plate to visualize the pigmented area responsible for the LM. It usually is restricted to the matrix area but can extend toward the nail bed and up to the hyponychium in benign nevi and melanoma. Only LM that is very light in appearance defies this rule. No single biopsy method meets the needs of all patients. The chosen procedure depends on (1) the likelihood of NAM, (2) the need to minimize the risk for postoperative dystrophy, (3) the location of the band (median or lateral), (4) the band’s width, and (5) the matrix origin. Patients should be made aware of the cosmetic outcome. If the lateral third of the nail plate is involved, hemi–nail plate avulsion is performed, followed by lateral longitudinal excision of the pigmented lesion. This technique removes the matrix, the proximal nail fold, the cuticle, the portion of the lateral nail fold adjacent to the proximal nail fold, and the nail bed. The patient is left with a narrowed nail. If the midportion of the nail plate is involved, relaxing incisions are made in the proximal nail fold and the proximal nail plate is removed. In light-colored bands, however, the precise origin may be difficult to ascertain after removal of the nail plate (see later discussion). If the band is 2 mm or less and originates in the distal two thirds of the matrix, the origin of the band can be removed by a 3-mm punch excision. For pale-colored LM it is preferable that the punch be performed directly through the nail plate. The proximal part of the nail plate can
337
then be removed, allowing inspection of the surrounding matrix and nail bed. Last, the cylinder of tissue is removed by cutting it off down to the bone. Postoperative dystrophy usually is minimal. If the band is 2 mm or less, but originates in the proximal third of the matrix, the 3-mm punch technique also can be used. The proximal nail fold must be reflected back completely to ensure full exposure of the band. An attempt can be made to minimize the defect by partial approximation (rather than complete closure) with a 6-0 absorbable suture. The risk for postoperative dystrophy is substantial [4]. If the band is between 3 and 6 mm wide and originates in the distal two thirds of the matrix, transverse elliptic incision is indicated. Because the proximal matrix remains intact, a thinned nail plate regenerates postoperatively, limiting the cosmetic damage. For a 3- to 6-mm wide band originating in the proximal one third of the matrix, the releasing flap method of Schernberg and Amiel is advised. This procedure leaves a severe postsurgical dystrophy (longitudinal nail splitting). A partial biopsy can be discussed. For bands wider than 6 mm, or if the full thickness of the nail is pigmented, the underlying disease process is unlikely to be benign. Depending on the clinical circumstances, a biopsy could be proposed or the entire portion of the involved nail apparatus can be excised en bloc. When the risk for postoperative scarring is high, as for bands located in the proximal matrix or bands larger than 6 mm, the shave biopsy technique suggested by Haneke is an interesting alternative [35]. Treatment of NAM Treatment of NAM is not the focus of this article. It must be remembered, however, that the diagnosis of melanoma should lead to further surgical procedures [25,36]. With in situ melanoma, total excision of the entire nail apparatus remains the norm of treatment. Mohs surgery can be used for more limited excision, however [37]. In invasive melanoma, amputation of the distal phalanx usually is recommended, but there is a legitimate move toward less radical therapy for NAM of low Breslow thickness [38]. A recent article suggests that nonamputative local excision with micrographically controlled margin using the Mohs surgical technique is a reasonable
338
ANDRE´ & LATEUR
option in the management of melanoma of the nail apparatus [39]. Adjuvant therapy should be considered for NAM with a poor prognosis [25]. The technique of sentinel node biopsy is increasingly used for NAM with a depth greater than 1 mm and for thinner, ulcerated melanoma, the detection of micrometastasis being one of the most important prognostic factors [40]. Controlled, prospective clinical trials on cutaneous melanoma are ongoing; their results will certainly influence the future evidence-based management of NAM.
Summary LM can be the first sign of a subungual melanoma. Confronted with an isolated LM, the threshold for biopsy should be low. It is important to know when and how to perform biopsy to improve the poor prognosis usually associated with NAM. References [1] Baran R, Haneke E, Drape´ JL, et al. Tumours of the nail apparatus and adjacent tissues. In: Baran R, Dawber RPR, de Berker DAR, et al, editors. Diseases of the nails and their management. 3rd edition. Oxford: Blackwell Science Ltd; 2001. p. 607–30. [2] Baran R, Perrin C. Linear melanonychia due to subungual keratosis of the nail bed: report of two cases. Br J Dermatol 1999;140:730–3. [3] Perrin C, Michiels JF, Pisani A, et al. Anatomic distribution of melanocytes in normal nail unit: an immunohistochemical investigation. Am J Dermatopathol 1997;19(5):462–7. [4] Baran R, Kechijian P. Longitudinal melanonychia (melanonychia striata): diagnosis and management. J Am Acad Dermatol 1989;21:1165–75. [5] Baran R, Kechijian P. Hutchinson’s sign: a reappraisal. J Am Acad Dermatol 1996;34(6):87–90. [6] Tosti A, Baran R, Piraccini BM, et al. Nail matrix nevi: a clinical and histopathological study of twenty-two patients. J Am Acad Dermatol 1996; 34(5):765–71. [7] Lateur N, Andre´ J. Melanonychia: diagnosis and treatment. Dermatol Ther 2002;15:131–41. [8] Aratari E, Regesta G, Rebora A. Carpal tunnel syndrome appearing with prominent skin symptoms. Arch Dermatol 1984;120:517–9. [9] Skowron F, Combemale P, Faisant M, et al. Functional melanonychia due to involvement of the nail matrix in systemic lupus erythematosus. J Am Acad Dermatol 2002;47:S187–8. [10] Baran R. Longitudinal melanonychia in localized scleroderma: report of four cases. J Am Acad Dermatol 2004;50(3):E5.
[11] Fayol J, Baran R, Perrin C, et al. Onychomatricoma with misleading features. Acta Derm Venereol 2000; 80:370–2. [12] Sass U, Andre´ J, Stene JJ, et al. Longitudinal melanonychia revealing an intraepidermal carcinoma of the nail apparatus: detection of integrated HPV-16 DNA. J Am Acad Dermatol 1998;39(3):490–3. [13] Cribier B, Leiva Mena M, Rey D, et al. Nail changes in patients infected with human immunodeficiency virus. Arch Dermatol 1998;134:1216–20. [14] Quinlan KE, Janiga JJ, Baran R, et al. Transverse melanonychia secondary to total skin electron beam therapy: a report of 3 cases. J Am Acad Dermatol 2005;53(2):S112–4. [15] Kar HK. Longitudinal melanonychia associated with fluconazole therapy. Int J Dermatol 1998;37: 719–20. [16] O’Branski EE, Russel EW, Prose NS, et al. Skin and nail changes in children with sickle cell anemia receiving hydroxyurea therapy. J Am Acad Dermatol 2001;44(5):859–61. [17] Piraccini BM, Tosti A. Drug-induced nail disorders. Incidence, management and prognosis. Drug Saf 1999;21(3):187–201. [18] Goettmann-Bonvallot S, Andre´ J, Belaich S. Longitudinal melanonychia in children: a clinical and histopathologic study of 40 cases. J Am Acad Dermatol 1999;41(1):17–22. [19] Le´aute-Labre`ze C, Bioulac-Sage P, Taı¨ eb A. Longitudinal melanonychia in children: a study of 8 cases. Arch Dermatol 1996;132:167–9. [20] Thai KE, Young R, Sinclair RD. Nail apparatus melanoma. Australas J Dermatol 2001;42(2):71–81. [21] Stevens NG, Liff JM, Weiss NS. Plantar melanoma: is the incidence of melanoma of the sole of the foot really higher in blacks than whites? Int J Cancer 1990;45:691–3. [22] Kato T, Suetake T, Sugiyama Y, et al. Epidemiology and prognosis of subungual melanoma in 34 Japanese patients. Br J Dermatol 1996;134:383–7. [23] Metzger S, Ellwanger U, Stroebel W, et al. Extent and consequences of physician delay in the diagnosis of acral melanoma. Melanoma Res 1998;8:181–6. [24] Levit EK, Kagen MH, Scher RK, et al. The ABC rule for clinical detection of subungual melanoma. J Am Acad Dermatol 2000;42(2):269–74. [25] Banfield CC, Redburn JC, Dawber RPR. The incidence and prognosis of nail apparatus melanoma: a retrospective study of 105 patients in four English regions. Br J Dermatol 1998;139:276–9. [26] Takata M, Maruo K, Kageshita T, et al. Two cases of unusual acral melanocytic tumors: illustration of molecular cytogenetics as a diagnostic tool. Hum Pathol 2003;34(1):89–92. [27] Antonovich DD, Grin C, Grant-Kels JM. Childhood subungual melanoma in situ in diffuse nail melanosis beginning as expanding longitudinal melanonychia. Pediatr Dermatol 2005;22(3):210–2.
PIGMENTED NAIL DISORDERS
[28] Dawber RPR, Colver GB. The spectrum of malignant melanoma of the nail apparatus. Sem Dermatol 1991;10(1):82–7. [29] Ronger S, Touzet S, Ligeron C, et al. Dermoscopic examination of nail pigmentation. Arch Dermtol 2002;138:1327–33. [30] Kawabata Y, Ohara K, Hino H, et al. Two kinds of Hutchinson’s sign: benign and malignant. J Am Acad Dermatol 2001;44(2):305–7. [31] Achten G, Andre´ J, Laporte M. Nails in light and electron microscopy. Semin Dermatol 1991;10: 54–64. [32] Glat PM, Spector JA, Roses DF, et al. The management of pigmented lesions of the nail bed. Ann Plast Surg 1996;37(2):125–34. [33] Andre´ J, Goettmann-Bonvallot S. Longitudinal melanonychia. J Am Acad Dermatol 2003;49:776. [34] Blessing K, Kernohan NM, Park KGM. Subungual malignant melanoma: clinicopathological features of 100 cases. Histopathology 1991;19:425–9.
339
[35] Haneke E, Baran R. Longitudinal melanonychia. Dermatol Surg 2001;27(6):580–4. [36] Tseng JF, Tanabe KK, Gadd MA, et al. Surgical management of primary cutaneous melanomas of the hands and feet. Ann Surg 1997;25(5):544–53. [37] Banfield CC, Dawber RPR, Walker NK, et al. Mohs micrography surgery for the treatment of in situ nail apparatus melanoma: a case report. J Am Acad Dermatol 1999;40(1):98–9. [38] de Berker D. The Black Nail dTreatment. Proceedings of the European Nail Society. Amsterdam, September 19, 1999. [39] Brodland DG. The treatment of nail apparatus melanoma with Mohs micrographic surgery. Dermatol Surg 2001;27(3):269–73. [40] Gershenwald JE, Thompson W, Mansfield PF, et al. Muti-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I and II melanoma patients. J Clin Oncol 1999;17(3):976–83.