Dermatol Clin 24 (2006) ixx

Preface

Nail Disorders and their Management

Aditya K. Gupta, MD, PhD, FRCP(C) Robert Baran, MD Guest Editors

Nail diseases are of particular concern to patients, inasmuch as they have both functional and aesthetic importance. Characteristics of the nail, such as color and texture, can be indicative of a wide range of medical conditions. Nail abnormalities can be due to external trauma to the nail, adverse eects of certain drugs, infections (fungal and bacterial), or they can result from an underlying systemic or skin disease. Disease of the nail often poses diagnostic and therapeutic problems. This issue of the Dermatologic Clinics discusses the management of nail disorders, with emphasis on diagnostic methods and treatmentdin particular, the diagnosis and treatment of onychomycosis, common nail tumors, nail changes caused by skin disorders such as psoriasis and lichen planus, and drug-induced nail manifestations. The initial articles in this edition focus on the treatment options for various disorders of the nail unit. An important treatment in these cases is nail

surgery. Included is an in-depth explanation of the nail anatomy, the types of anesthetics appropriate for nail surgery, and various techniques for nail surgery, nail biopsy, and imaging of the nail unit. This knowledge will help reduce patient pain, while reducing the probability of complications. The diagnosis of nail disease is fundamental to treatment because it allows for timely treatment of the disorder and more optimal appropriation of services and costs. The correct diagnosis of onychomycosis is essential because many nail disorders can present with abnormalities that are similar to onychomycosis. In addition, the accurate identication of the causative organism provides guidance in proper treatment. Nail histomycology is a sensitive procedure for the diagnosis of onychomycosis because it allows for the visualization of the location of the invasive fungus inside the nail. This procedure can be combined with culture of the putative organism to aid in the diagnosis of onychomycosis.

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PREFACE

There are three systemic treatments approved by the US Food and Drug Administration: terbinane, itraconazole, and griseofulvin. Other options are topical nail lacquer, mechanical or chemical treatments, or a combination of one or more of these modalities. Terbinane is the most eective oral agent for the treatment of dermatophyte onychomycosis, but combination therapy with ciclopirox nail lacquer is being evaluated. Combination therapy with other oral antimycotics, and the concept of booster therapy have been discussed. Because of the high recurrence rate of onychomycosis, patient education about proper foot care is essential for preventing reinfection. The nal article in this issue provides an interesting look at the potential diseases and problems associated with the nail cosmetic industry. Topics such as nail cosmetology, hazards in the workplace, and nail cosmetics in the health care setting are discussed. We hope that this issue of the Dermatologic Clinics, which is designed to familiarize the reader

with various nail disorders and their associated diagnositic and treatment options, will provide practitioners with a useful and interesting reference. Aditya K. Gupta, MD, PhD, FRCP(C) Division of Dermatology Department of Medicine Sunnybrook and Womens College Health Science Centre (Sunnybrook Site) University of Toronto 2075 Bayview Avenue Toronto, ON M4N 3M5, Canada Mediprobe Research, Inc. 645 Windermere Road London, ON N5X 2P1, Canada E-mail address: agupta@execulink.com Robert Baran, MD Nail Disease Centre 42 Rue des Serbes 06400 Cannes, France E-mail address: baran.r@club-internet.fr

Dermatol Clin 24 (2006) 291296

Surgical Anatomy of the Nail Apparatus

Eckart Haneke, MD, PhDa,b,*
b

Dermatology Clinic, Schlippenhof 5, 79110 Freiburg, Germany Department of Dermatology, St. Radboud University Medical Center, Rene Descartesdreef 1, 6525 GL Nijmegen, Netherlands

The nail organ is an integral part of the digital tip; it is both our most versatile tool and one of the most important sensory organs. It consists of four dierent components: the matrix, nail bed, nail plate, and nail folds (Fig. 1). The nail also is intimately associated with the distal interphalangeal joint and its capsule, ligaments, and tendons. A rich arterial supply and a dense innervation provide various sensory and autonomic functions. The matrix, which produces the nail plate, is mostly located under the proximal nail fold (PNF). The distal end of the matrix is visible as the whitish lunula (Fig. 2). The PNF is a crescentic sheet of tissue covered on its dorsal and undersurface with epidermis. Its sharp and angled free margin produces the cuticle. The nail bed is rmly attached to the nail plate. Distally, between nail bed and pulp epidermis, the hyponychium marks the end of the epithelial nail organ. Nail surgery is an integral part of dermatologic surgery [1]. It requires an in-depth knowledge of the anatomy, biology, physiology, and gross pathology of the entire nail organ. A particular knowledge of nail histopathology is necessary to perform diagnostic nail biopsies correctly. Good anesthetic technique, surgical skills, a sterile surgical setting, excellent light conditions, and often a head magnier lens or surgical microscope are necessary [2,3]. Anatomy of the tip of the digit Almost all tissue components found elsewhere in the body also can be found in the tip of the digit:
* Dermatology Clinic, Schlippenhof 5, 79110 Freiburg, Germany. E-mail address: haneke@gmx.net

skin, bone, joint, synovial membrane, ligaments, tendons, tendon sheaths, arteries, veins, lymphatic vessels, nerves, and specialized nervous end organs. The nail bed and matrix also are rich in glomus bodies, the function of which is thermoregulation of the nger tips. The matrix, which forms the nail plate, begins development in the ninth embryonal week from the nail anlage, an invagination of the primitive skin. By week 16, the morphogenesis is almost complete and a fetal nail can be discerned clearly [4,5]. The matrix is a convex band of highly proliferative epithelium. Approximately 80% of the nail plate is produced by the proximal half of the matrix [6]. Its proliferation activity is higher in its proximal portion than distally so that more nail substance is formed proximally and the nail plate achieves a natural convex curvature from proximal to distal. The proximal-to-distal growth of the matrix is the reason to perform matrix biopsies always with the long axis of the biopsy in the transverse direction to avoid a longitudinal scar that would not produce nail substance and cause a split in the nail. The matrix is sensitive to traumadaccidental and surgical. Any defect wider than 3 mm leads to permanent nail dystrophy that is dicult to repair [7,8]. With age, its proliferation rate gradually decreases [9]. The matrix, whether on ngers or toes, has lateral matrix horns that reach further proximally than the central part of the matrix. This is important when taking a lateral longitudinal nail biopsy or performing a wedge excision for an ingrown toenail. The lateral matrix horns are attached by a dorsal expansion of the lateral ligament of the distal interphalangeal joint [10]. The nail plate, commonly called the nail, is a mechanically and chemically resistant sheet of
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PNF L M

LNF

NB

Fig. 1. Sagittal section through nail apparatus. L, lunula; LNF, lateral nail wall; M, matrix; NB, nail bed.

compacted keratinized cells. It is semi-transparent and has a smooth, shiny surface. The surface becomes ridged and less shiny with age. The proximal matrix is responsible for the nail shine, and surgical or traumatic damage to it may result in a dull or rough surface. The nail plate is curved longitudinally and transversely; the curvature shows great interindividual variations, particularly on the toes. Persons who have relatively at big toenails have a much lesser chance of developing an ingrown nail than persons who have a pronounced transverse curvature. The nail bed is the distal continuation of the matrix. It does not produce nail plate substanced hence the term sterile matrixdbut a thin layer of keratin, which assures a rm attachment with the nail plate and permits it to slide over the nail bed despite this attachment [11]. It has a unique architecture of its rete ridges that run parallel and longitudinally. This corrugated pattern is macroscopically visible on the nail bed and at the nail plates undersurface after nail avulsion, clearly delimited from the smooth matrix epithelium. After nail avulsion, the visible ridges disappear. In the connective tissue papillae that

correspond to these rete ridges, the capillaries run parallel to each other and to the surface of the nail in a longitudinal direction with up to four to ve layers, one above the other. This unique microanatomy explains why fusiform nail bed biopsies always should be performed in a longitudinal direction (although the case for an oblique biopsy for matrix plus nail bed may be argued) and why splinter hemorrhages are oriented longitudinally. Polarization microscopy shows that the keratin bers run from the matrix and nail bed slightly obliquely up to the nail plate, which explains why the proximal nail avulsion technique is the least traumatic. The onychodermal band is an ill-dened transverse band of a deeper pink, approximately 1 to 1.5 mm in width, that marks the transition of the nail bed to the hyponychium (Fig. 3) [12]. Its integrity is important for the health of the nail bed [13]. The hyponychium is the structure that seals the hypothetical subungual space. It forms a tough keratin layer that, under certain conditions, may pose a veritable obstacle to penetration by a blunt surgical instrument, such as an elevator. The integrity of the hyponychium is important for a healthy nail bednail plate adhesion. It protects against the penetration of foreign bodies and dirt and the invasion of pathogens that cannot digest keratin. The adjacent pulp skin is rich in nervous end organs, such as Meissners and Vater-Pacini bodies. The nail folds (two lateral folds and one proximal) direct the nail growth in the correct position. The PNF is a crescentic sheet of tissue with a sharp angle at its free margin. Here, the cuticle is formed and seals the so-called nail pocket; it is formed predominantly by the horny

ODB
FM
L M M L

DG

Fig. 2. Relation in size and shape of nger and toenail. L, lunula; M, matrix.

Fig. 3. Hyponychium and onychodermal band. DG, distal groove; FM, free nail margin; ODB, onychodermal band.

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NP

Fig. 4. Formation of the cuticle. The cuticle is produced in part by the free margin of the proximal nail fold, but the bulk derives from the horny layer of the eponychium (undersurface of the PNF).

layer of the epidermis of the PNFs undersurface, which is attached to the dorsal surface of the nail plate. With the growth of the latter, the keratin is pulled out from under the PNF and detaches partly from the nail plate to form most of the cuticle (Fig. 4), which is why the cuticle disappears spontaneously when the PNFnail plate attachment gets lost, nail growth stops, or the free margin of the PNF thickens and rounds up. A distal nail fold forms only when the overlying nail plate is lacking. It is commonly seen after avulsion of the big toenail, but it is usually pushed down again by the regrowing nail plate. When present for a long time, however, it may become brotic and xed and does not recede. It becomes an obstacle for the outward growth of the nail plate. Under these circumstances, the distal nail fold must be removed by either taping or a crescentic wedge excision from the pulp of the digit (Fig. 5). The nail organ has a rich blood supply (Fig. 6). Two proper digital arteries, the small dorsal and the bigger volar arteries, bring oxygenated blood to each side of the nail. At approximately the level

Fig. 6. Blood supply of the nail apparatus. The palmar artery supplies most of the blood to the nail apparatus but anastomoses with the thinner dorsal artery. Three arcades connect the corresponding arteries of the two sides of the distal phalanx and give rise to longitudinally running ne vessels for the PNF, matrix, and nail bed.

of the distal interphalangeal joint, the volar and dorsal arteries form anastomoses. More distally, the dorsal branches anastomose with those of the other side of the digit to form arcades at the level of the PNF and the matrix and in the nail bed. These vessels give rise to capillaries, which mainly run obliquely in the matrix and proximal nail fold and parallel to the surface in the nail bed [14,15]. It is suggested that the direction of the papillary capillaries is responsible for the growth direction of the epithelial cells and the nail plate, the cuticle and the PNF, including the most proximal parts of the lateral nail foldsda possible explanation for the appearance of hang nails with their almost parallel direction to the skin surface [16]. Small, muscular arteries connect with the glomus bodies that function in thermoregulation. When

Fig. 5. Distal nail wall formation. When the nail is too short, the soft tissue of the pulp is gradually dislocated dorsally to form a distal nail wall. If this cannot be removed conservatively, surgery is necessary.

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thumb

middle finger

dorsal digital nerve

fifth finger

palmar digital nerve

Fig. 7. Innervation of the ngers shows the dierences between the single ngers.

they contract at low temperature, more blood is forced through the capillaries, which improves the supply with warm blood. The venous blood eux is less precise. The blood is collected into a deep and a supercial system that drains into few larger veins that run subcutaneously on the dorsal and volar aspect of the digits [1517]. Little is known about the lymphatic vessels of the digits. The innervation is variable between the dierent digits (Fig. 7). The nails of the long ngers are innervated by the volar proper digital nerves, which divide distally into three branches to the PNF, the matrix, and the nail bed, whereas the thumb and little nger nails are said to be innervated by the dorsal proper digital nerves. The former is the rationale to perform the transthecal anesthesia of the long ngers for nail surgery [18], because the volar nerves run in close proximity to the exor digitorum tendon; however, transthecal anesthesia also was found to be eective in the little nger and big toe (Fig. 8) (Funk J, personal communication, 2003). The distal three branches also can be anesthetized by a distal wing block (Fig. 9). The distal interphalangeal joint is in close anatomic relation with the matrix. In the central part of the matrix, a thin layer of connective tissue between the matrix epithelium and the extensor tendon feathers into the joint capsule and bone. We measured 0.8 mm of matrix connective tissue. Sometimes, the connective tissue of the PNF undergoes mucinous degeneration to form a myxoid

Fig. 8. Transthecal anesthesia. The injection needle is inserted through the metacarpophalangeal articular crease into the tendon sheath of the exor digitorum longus until a resistance is felt. Approximately 2 to 4 mL of 2% lidocaine or another local anesthetic agent is injected. The close anatomic relation of the exor sheath and the neurovascular bundle allows the local anesthetic to diuse to numb the volar proper digital nerve responsible for the innervation of the distal one third to half of the index to ring ngers.

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Fig. 10. Color-enhanced MRI of a glomus tumor of the thumb.

Fig. 9. Distal wing block anesthetizes the three branches of the palmar proper digital nerve.

pseudocyst, which in more than 80% of the cases later develops a connecting stalk with the distal interphalangeal joint. Submatrical localization of this lesion can be observed. The lateral ligaments of the big toe give a branch to the lateral matrix horns [10]. A hypertrophy of the distal dorsal extension of the lateral ligament was supposed to be responsible for congenital malalignment of the big toenail. The interosseous ligament spans between the palmar aspect of the base of the distal phalanx and the protuberant volar plate, which forms a shield for the palmar arterial arch beneath the maximal padding of the nger pulp. The tendons of the exor and extensor digitorum muscles feather out to form part of the joint capsules and reinforce it. The bone of the distal phalanx not only is responsible for the size and shape of the nail, which is evidenced by the altered nail shape in various syndactyly syndromes or when dorsal osteophytes cause transverse overcurvature of nger nails in degenerative osteoarthritis of the distal interphalangeal joints or medial and lateral osteophytes at the base of the distal phalanx of toes produce pincer toenails, but also is a prerequisite for nail formation during embryogenesis [19].

require any sophisticated technical facilities. Inspection and diascopy give information about the circulation; palpation provides information about possible tumors and their consistency; probing can locate painful or soft lesions; and transillumination (diaphanoscopy) shows cystic or opaque lesions. A magnier lens and a drop of oil on the nail plate to make it more transparent help dierentiate between blood, melanin, and other dark pigments. The vascularization can be examined further by observing the nails in a relaxed state of the digit in physiologic exion, under forced extension, and while pressing the pulp of the digit to a hard base. Epi-illumination microscopy and macrophotography give higher magnications and allow the more exact determination of color changes and minute structures. High-frequency ultrasound has been used mainly as a research tool and rarely in clinical practice [20,21]. Doppler sonography may be used to investigate the blood ow to the nail. Normal radiographic techniques are usually disappointing, but ultrasoft techniques as used for mammography (eg, xeroradiography or more modern digital techniques) are helpful for showing bone alterations and allowing the nail shadow to be discerned and nail abnormalities to be related to the underlying bone [2,3]. MRI, particularly high-frequency MRI, is the ultimate diagnostic tool for the localization of tumors (Fig. 10) [2225].

Summary Presurgical examination of the nail organ Inspection, palpation, probing, transillumination, and diascopy are simple methods that do not Although generally thought to be delicate or even dicult, nail surgery is logical when one has the appropriate knowledge of nail anatomy.

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References
[1] Zook EG, Baran R, Haneke E, et al. Nail surgery and traumatic abnormalities. In: Baran R, Dawber RPR, de Berker DAR, et al, editors. Diseases of the nails and their management. Oxford: Blackwell; 2001. p. 425514. [2] Haneke E. Nail surgery. Eur J Dermatol 2000;10: 23741. [3] Krull E, Baran R, Zook E, et al. Nail surgery: a text and atlas. Philadelphia: Lippincott Williams & Wilkins; 2001. [4] Lewis BL. Microscopic studies of fetal and mature nail and surrounding tissue. Arch Dermatol Syphilol 1954;70:73244. [5] Zaias N. Embryology of the human nail. Arch Dermatol 1963;87:3753. [6] de Berker DAR, Mawhinney B, Sviland L. Quantication of regional matrix nail production. Br J Dermatol 1996;134:10836. [7] Pessa JE, Tsai TM, Li Y, et al. The repair of nail deformities with the non-vascularized nail bed graft: indications and results. J Hand Surg [Am] 1990; 15A:46670. [8] Nakayama Y, Iino T, Uchida A, et al. Vascularized free nail grafts nourished by arterial inow from the venous system. Plast Reconstr Surg 1990;85:23945. [9] Raguz JM, Haneke E. Analyse der Proliferationsaktivita t der Nagelmatrixzellen mit der AgNORmethode. Hautarzt 1997;48(Suppl 1):S62. ro S, Guichard S, Fraitag SR. Ligamentary [10] Gue structure at the base of the nail. Surg Radiol Anat 1994;16:4752. [11] de Berker DAR, Angus B. Proliferative compartments in the normal nail unit. Br J Dermatol 1996; 135:5559. [12] Terry RB. The onychodermal band in health and disease. Lancet 1955;I:17981.

[13] Sonnex TS, Grith WAD, Nicol WJ. The nature and signicance of the transverse white band of human nails. Semin Dermatol 1991;10: 126. [14] Smith DO, Oura C, Kimura C, et al. Artery anatomy and tortuosity in the distal nger. J Hand Surg [Am] 1991;16A:297302. [15] Wolfram-Gabel R, Sick H. Vascular networks of the periphery of the ngernail. J Hand Surg [Br] 1995; 20B:48892. [16] Alkiewicz J, Pster R. Atlas der Nagelkrankheiten: Pathohistologie, Klinik und Dierentialdiagnose. Stuttgart: Schattauer; 1976. [17] Smith DO, Oura C, Kimura C, et al. The distal venous anatomy of the nger. J Hand Surg [Am] 1991;16A:3037. [18] Chiu DTW. Transthecal digital block: exor tendon sheath used for anesthetic infusion. J Hand Surg [Am] 1990;15A:4713. [19] Baran R, Juhlin L. Bone-dependent nail formation. Br J Dermatol 1986;114:3715. [20] Fornage BD. Glomus tumors in the ngers: diagnosis with US. Radiology 1988;167:1835. [21] Hirai T, Fumiiri M. Ultrasonic observation of the nail matrix. Dermatol Surg 1995;21:15861. [22] Jablon M, Horowitz A, Bernstein DA. Magnetic resonance imaging of a glomus tumor of the nger tip. J Hand Surg [Am] 1990;15A:5079. [23] Holzberg M. Glomus tumor of the hand. Arch Dermatol 1992;128:1602. JL, Idy-Peretti I, et al. Mag[24] Goettmann S, Drape netic resonance imaging: a new tool in the diagnosis of tumours of the nail apparatus. Br J Dermatol 1994;130:70110. JL, Idy-Peretti I, Goettmann S, et al. Stan[25] Drape dard and high-resolution MRI in glomus tumors of toes and ngertips. J Am Acad Dermatol 1996; 35:5505.

Dermatol Clin 24 (2006) 297311

Common Nail Tumors

Robert Baran, MDa,*, Bertrand Richert, MD, PhDb
b

Nail Disease Center, 42 rue des Serbes 06400, Cannes, France Department of Dermatology, University Hospital, 45 Quai Kurth 4020, Liege, Belgium

Nail abnormalities are varied and numerous. They include warts, keratoacanthomas, onychomatricomas, brokeratomas, osteochondromas, tumors (ie, glomus, giant cell, Koenens, and others), and Bowens disease. Although the gravity of these conditions may vary, prompt diagnosis and treatment is of the utmost importance. This article discusses the most common defects associated with the nail unit and its surrounding tissue, as well as the dierential diagnosis and treatment of these conditions. Warts Common warts are caused by human papilloma viruses (HPV) of dierent DNA types. They are benign, weakly contagious, broepithelial tumors with a rough keratotic surface. Most frequently, they are located on the lateral aspect of the proximal nail fold and spread across the dorsum of the entire fold (Fig. 1). Tender nodules beneath the proximal nail fold are infrequent [14] and rarely result in longitudinal grooving. Subungual warts initially aect the hyponychium, growing slowly toward the nail bed and nally elevating the nail plate, which often is not aected although surface ridging may occur. Subungual warts are painful and may mimic a glomus tumor. Biting, picking, and tearing of the nail and nail walls are common habits in persons who have periungual warts. This type of trauma probably is responsible for the spread of the warts and their resistance to treatment.

Bone erosion from verruca vulgaris also has been observed [3]. Some of these cases may be keratoacanthomas [4], however, because the latter as well as epidermoid carcinoma are sometimes clinically indistinguishable from verruca vulgaris. Therefore, in longstanding warts in the nail area, histologic examination may be necessary to dierentiate extensive periungual warts from verrucous Bowens disease. Dierential diagnosis includes onychophosis aecting a lateral fold of the toenails, subungual lamentous tumor, subungual vegetations of amyloidosis, subungual corn (heloma), verrucous epidermal nevus, inammatory linear verrucous epidermal nevus, and multicentric reticulohistiocytosis. When mucinous syringometaplasia involves the distal nail bed, the clinical resemblance to warts is striking. Treatment Treatment of periungual warts is often frustrating. Imiquimod was used successfully in widespread recalcitrant HPV-42 periungual warts in a patient who had AIDS [5] and may well be one of the best local treatments in children despite its cost. The multiple-puncture technique under local anesthesia with a bifurcated vaccination needle to introduce bleomycin sulfate (1 mg/mL in a sterile saline solution) into warts has been advocated by Shelley and Shelley [6], who eliminated 92% of a random series of 258 warts after a single treatment. Vasospastic eects such as permanent Raynauds phenomenon resulting from intralesional bleomycin therapy may occur, however, even when a reduced dose is used [7]. Liquid nitrogen is painful and causes blistering. Surgical treatment should be avoided. Pulsed-dye laser has been used
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* Corresponding author. E-mail addresses: baran.r@club-internet.fr or BARAN.R@wanadoo.fr (R. Baran).

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Fig. 2. Keratoacanthoma of the proximal nail fold. Fig. 1. Periungual wart in a child.

successfully for intractable warts [8]. Finally many lay and medical people may have good tricks for attempting to cure warts.

Distal digital keratoacanthoma Subungual and periungual keratoacanthoma may occur as solitary or multiple tumors [9,10]. They are rare, benign but rapidly growing, and seemingly aggressive, tumors usually situated below the edge of the nail plate or in the most distal portion of the nail bed. Multiple subungual keratoacanthomas without keratoacanthomas on other sites are exceptional [11]. The distal phalanx of the toe was aected in three cases. Spontaneous resolution is rare [12]. The lesion may start as a small and painful keratotic nodule visible beneath the free edge, growing rapidly to a 1- to 2-cm lesion within 4 to 8 weeks. Its typical gross appearance, as a domeshaped nodule with a central plug of horny material lling the crater, is not often seen subungually, although histology of an adequate biopsy specimen will clearly show the characteristic pattern. Less frequently the tumor grows out from under the proximal nail fold, which becomes inamed, and may cover or surround the proximal fold with a cushion of swollen tissue (Fig. 2). The tumor soon erodes the bone, and this erosion may be demonstrated radiographically as a fairly well-dened, crescent-shaped lytic defect of tuft adjacent to the overlying nail bed. Reconstitution of the bony defect can be expected. MRI may help depict a deep inltrating lesion of the distal nail bed. MRI is superior to radiographic studies in detecting an erosion of the distal phalanx. Images show a large nodule with a homogeneous signal (intermediate signal on T1-weighted

images and high signal on T2-weighted images). Intravenous injection of gadolinium provides strong peripheral enhancement. A central area of low signal indicates the central plug of horny material lling the crater. The limits may be ill dened by edema in the surrounding tissues [13]. The diagnosis of distal digital keratoacanthoma depends on rapid growth with bone erosion and characteristic histology. Its clinical dierentiation from squamous cell carcinoma is, nevertheless, dicult, and the tumor frequently is diagnosed histologically as a squamous cell carcinoma, keratoacanthoma type. The histopathology of subungual keratoacanthoma diers slightly from keratoacanthoma of the skin. In this particular location, the tumor is narrower but deeply inltrating. It shows a marked shoulder with an epidermal lip and a central crater lled with keratin; the tumor cells are large and pale and often develop keratohyalin granules. Treatment Management of subungual keratoacanthoma ranges from conservative local excision to amputation, but aggressive ablative surgery as the initial intervention for this benign condition has probably occurred because of either misdiagnosis or misinterpretation of the nature of the pathology. The treatment of choice is removal of the entire tumor with histologic control of the resection margins [2]. The patient should be followed for an adequate period of time to rule out a recurrence, because subungual keratoacanthoma has been reported to recur as late as 22 months [14]. A review of 18 cases reported in the literature revealed that 86% of the lesions treated by curettage were cured by eventual conservative amputation; this nding is strong evidence that curettage is not adequate therapy for subungual keratoacanthoma [15].

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Furthermore, a recurrence ought not to require curettage or amputation of the distal phalanx, depending on the destruction of bone destruction and function [16]. Retinoids may be benecial in the treatment of keratoacanthoma [17] and sometimes are used in combination with surgical removal [18]. Eruptive keratoacanthomas have responded to oral etretinate, 1 mg/kg/d, with complete resolution. Recurrence can occur after cessation of treatment, requiring maintenance therapy (10 mg on alternate days), but this mode of treatment is more eective as prophylaxis in multiple keratoacanthoma. 5-Fluorouracil also has been used, either injected into the lesion or applied as a 20% ointment three times daily for 3 to 4 weeks [19]. Intralesional bleomycin, as well as methotrexate [20], may be applied in the distal nail area [21].

Fig. 3. Onychomatricoma showing the matrix tumor and the holes involving the proximal nail extremity.

from the nail plate. Histologic examination establishes the diagnosis [30]. In some cases, the tumor has been associated with onychomycosis and longitudinal melanonychia [31]. MR images are typical [32]. Sagittal images highlight the tumoral core in the matrix area and the invagination of the lesion into the funnel-shaped nail plate. The center shows a low signal on all images with a peripheral rim with a signal identical to that of normal epidermis. The distal lamentous extensions present a higher signal on T2-weighted images because of a mucoid stroma with high water content. Axial slices accurately show the holes in the substance of the nail plate, lled with the digitations. This broepithelial tumor consists of two anatomic zones; there are three histologic criteria for each zone [25]. The proximal zone is located beneath the proximal nail fold with a proximal border starting at the root of the nail and a distal border corresponding to the cuticle. It is characterized by (1) deep epithelial invaginations lled with a thick V-shaped keratogenous zone; (2) a thickened nail plate without cavitation but with an undulating inferior border ending in ungual spurs; (3) a brillar stroma clearly demarcated from the undersurface. Two histologic dierential diagnoses should be discussed [30]. First, in the longitudinal sections, the structure is reminiscent of a brokeratoma. A diagnosis of brokeratoma of the nail matrix can be excluded by the multiplicity of broepithelial digitations, the absence of a horny corn, and the presence of cavitation lled with serous uid at the distal border of the thickened nail plate. Second, the stroma of the lunular segment of the onychomatricoma can suggest a broma. A broma can be ruled out by the hyperplastic and

Onychomatricoma Onychomatricoma, a condition described 25 years ago [22,23], has been reported in several countries [2428]. Three main clinical signs are striking enough to make the diagnosis or at least to arouse suspicion of this condition: 1. There is a yellow longitudinal band of variable width, leaving a single or double portion of normal pink nail on either side. Splinter hemorrhages may be seen in the yellow area involving the proximal nail region in a characteristic manner. Longitudinal ridging is prominent in the aected nail. 2. There is a tendency toward transverse overcurvature of the aected nail portion, which becomes more pronounced as the yellow color is more extended. 3. Nail avulsion exposes a villous tumor emerging from the matrix, and the nail appears as a thickened funnel, storing lamentous digitations of matrix tting into the holes of the proximal nail extremity (Fig. 3). The villous projections in the nail plate can be so pronounced that nail cutting may produce bleeding [29]. In some cases, however, the clinical presentation may be confusing, because longitudinal melanonychia may hide the yellow hue, and the proximal nail fold may be swollen at its junction with the lateral nail fold. This swelling gives the aected nail the texture of a cutaneous horn. In some cases, this horn is completely separated

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onychogenic nature of the epithelium. Histologically, an ungual broma compresses the matrix epithelium, which results clinically in thinning of the nail plate in the form of a longitudinal groove. Immunohistochemistry using the proliferation marker Ki-67 (MIB-1) shows only a low proliferation rate [33]. Examination by electron microscopy [34] demonstrates that basal cells have a decreased number of desmosomes, and their evolution is not uniform. The tumor may be considered the result of disturbed dierentiation of nail matrix cells. Treatment When the tumor is small, simple retraction of the proximal nail fold allows supercial removal of the tumor from the matrix without suturing. If the root of the tumor is not clearly exposed, the proximal nail fold should be pulled back.

Fig. 4. Koenens tumors appearing from beneath the proximal nail fold and associated with dermatophyte onychomycosis.

Koenens tumors Koenens periungual bromas develop in about 50% of the cases of tuberous sclerosis (epiloia or Bourneville-Pringle disease), which is a dominantly inherited multisystem disease aecting the central nervous system, eyes, skin, cutaneous appendages, kidneys, heart, blood vessels, and bones. Two major gene loci have been identied where mutations can cause the tuberous sclerosis complex with apparently indistinguishable phenotypes: TSC1 at 9q34 and TSC2 at 16p13.3 [35]. The periungual bromas usually appear between the ages of 12 and 14 years and increase progressively in size and number with age. They are more frequent on toes than on ngers. Rarely are Koenens tumors the only evidence of tuberous sclerosis [36]. Individual tumors are small, round, eshcolored, and asymptomatic, with a smooth surface (Fig. 4). The tip of the tumor may be slightly hyperkeratotic, resembling a brokeratoma. They grow out of the nail fold, eventually overgrowing the nail bed and destroying the nail plate. Depending on their location, they may cause longitudinal depressions in the nail plate. They sometimes also grow in the nail plate, similar to a dissecting brokeratoma or onychomatricoma [37]. Even tiny hyperkeratotic lesions in the cuticle area may produce identical longitudinal nail grooves and have the same signicance as Koenens tumors [38]. A single ungual brokeratoma

apparently is not a sign of a minor expression of tuberous sclerosis [39]. Excessively large tumors often are painful and should be excised at their base. Bone cysts may occur in tuberous sclerosis, although those in the distal phalanx are excessively rare [40] and must be dierentiated from a number of other osseous lesions causing cystic defects in the distal phalanx. In the Koenens tumors the authors have examined [41], two portions could be distinguished: a small distal segment with loose collagen and many blood vessels and a larger proximal part built up of dense collagen bundles and fewer capillaries. It thus seems that Koenens tumor can be considered as a particular type of brokeratoma that can be subdivided according to its clinical appearance, its location, and its origin into two groups. Fibrokeratomas originating from the dermal connective tissue are posttraumatic or appear spontaneously and usually are located on the ngers (acquired digital brokeratoma). Fibrokeratomas originating from the proximal nail fold or the surrounding connective tissue are located in the nail fold and can be hereditary (tuberous sclerosis) or acquired (eg, garlic-clove broma).

Treatment Koenens tumors are cured by simple excision. Usually, no suture is necessary. Tumors growing out from under the proximal nail fold are removed after reecting the proximal nail fold back by making lateral incisions down each margin in the axis of the lateral nail grooves. Subungual bromas are removed after avulsion of the corresponding part of the nail plate.

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Acquired ungual brokeratoma Acquired ungual brokeratoma probably is a variant of acquired digital brokeratoma [42] and garlic clove broma [43]. Classically, they are acquired, benign, spontaneously developing, asymptomatic nodules with a hyperkeratotic tip and a narrow base. They occur mostly in the periungual area or elsewhere on the ngers. They may double or even triple and may reach a considerable size. Most ungual brokeratomas emerge from beneath the proximal nail fold, growing on the dorsum of the nail where they cause a sharp longitudinal depression (Fig. 5). Some of these lesions originate from within the matrix and thus grow in the nail plate, eventually to emerge in the middle of the nail. These intraungual brokeratomas are also called dissecting ungual brokeratoma because they divide the nail plate [44]. Subungual brokeratomas arising from the nail bed are rare. MRI accurately depicts the component emerging from the proximal nail fold in the split of the nail plate [45]. Overall, MR images highlight the deep implantation close to the nail root. The signal of the tumor depends on the dierent histologic types: very low signal on all sequences for the dense and numerous collagen bundle type and high signal on T2-weighted images for mucoid stroma. Intralesional septa and the acanthotic epidermal coverage show regular limits and a signal identical to that of normal epidermis. MRI also is able to depict a tumor involving the ventral aspect of the proximal nail fold with an epithelial invagination. Trauma is thought to be a major factor in the initiation of acquired periungual brokeratoma. Biopsy is mandatory for the diagnosis of nail tumors because pseudobrokeratoma should be considered a clue for Bowens disease [46].

Histologic examination of 50 cases of acquired digital brokeratoma disclosed three histologic variants of these lesions [47]: 1. A tumor composed of thick, dense, and closely packed collagen bundles 2. A variant with an increased number of broblasts in the cutis 3. A type with an edematous and poorly cellular structure The acquired digital brokeratoma is thought to result from new collagen formation by broblasts. The acanthosis of the epidermis probably is secondary to the dermal alteration. Immunohistochemistry shows that the broblasts are vimentin positive, and many of them stain with HHF 35, a monoclonal antibody said to be specic for muscle actin. The dierential diagnosis of acquired periungual broma includes broma, keloid, Koenens tumor, recurring digital brous tumors of childhood, dermatobrosarcoma, brosarcoma, cutaneous horn, eccrine poroma, pyogenic granuloma, verruca vulgaris, and exostosis. Treatment Surgical treatment is the same as for Koenens tumors and depends on the size and location of the broma. Usually, the tumor is incised around its base and dissected from the bone. Supercial removal would result in a recurrence. Exostosis and osteochondroma Subungual exostoses are not true tumors but rather are outgrowths of normal bone or calcied cartilaginous remains. Whether or not subungual osteochondroma [48] is a dierent entity is still not clear [49]. Subungual exostoses are rarely reported. There were only 60 subungual exostoses in a series of 6034 benign osseous lesions [50]; however, they may be considerably underdiagnosed and underreported. Exostoses are bony growths that are painful on pressure and may elevate the nail (Fig. 6). They are particularly frequent in young people and are located mostly in the dorso-medial aspect of the tip of the great toe, although subungual exostoses may also occur in lesser toes or, less commonly, thumb, or index ngers [51]. They start as small elevations of the dorsal aspect of the distal phalanx and may eventually emerge from under the nail edge or destroy the nail plate. If the nail is lost, the surface becomes eroded and secondarily infected, sometimes

Fig. 5. Acquired ungual brokeratoma on the (left) lateral and the (right) median portion of the nail plate.

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Fig. 6. Subungual exostosis.

mimicking an ingrown toenail or even a melanoma, but solitary subungual exostoses have never been observed to undergo malignant degeneration. Walking may be painful. Some authors claim that a history of trauma is found only occasionally in subungual exostosis [52]. The triad of pain (the leading symptom), nail deformation, and radiographic features is usually diagnostic. The exostosis is an ill-dened trabeculated osseous growth with an expanded distal portion covered with radiolucent brocartilage. Osteochondroma, commonly evoking the same symptoms as subungual exostosis, is said to have a male predominance. Its onset is usually between the ages of 10 and 25 years. There often is a history of trauma [48]. Its growth rate is slow. Radiographic studies show a well-dened, circumscribed, pedunculated or sessile bone growth projecting from the dorsum of the distal phalanx near the epiphyseal line. Therefore, nail dystrophy may be pronounced [53]. Histology shows a bony tumor with a hyaline cartilage cap. On the basis of the histopathologic pattern, however, de Palma and colleagues [49] claim that, independent of their location at the distal phalanx, most subungual bone masses exhibit the features of conventional osteochondromas and not of subungual exostoses. Osteochondroma must be dierentiated from primary subungual calcication (particularly seen in elderly women), secondary subungual calcication caused by trauma and psoriasis [54], and primary osteoma cutis [55]. The dierential diagnosis of subungual exostosis and osteochondroma includes malignant melanoma, epithelioma, keratoacanthoma, glomus tumor, pyogenic granuloma, implantation cyst, and wart. Treatment Therapy of subungual exostosis and osteochondroma consists of local curettage or excision

of the excess bone under aseptic conditions. Conservative and thorough treatment of this pathology can be achieved using the appropriate tools in a dermatology outpatient setting [56]. If the tumor is located in the nail bed, the nail plate is partially removed, and a longitudinal incision is made in the nail bed. Whenever possible, it is preferable to remove the tumor by an L-shaped or a sh-mouth incision to avoid avulsion of the nail plate. The osseous growth with its cartilaginous cap is dissected carefully using ne skin hooks to avoid damage to the fragile nail bed, and the tumor is removed with a ne chisel. Most subungual exostoses are located in the medial aspect of the hyponychial area of the hallux elevating the distal margin of the plate. The overlying skin usually is extremely overstretched and must be removed by a fusiform excision that also facilitates removal of the exostosis by a ne chisel or bone rongeur [57].

Pyogenic granuloma Pyogenic granuloma is a benign, eruptive hemangioma resulting from minor, penetrating skin injury. It starts around the nail as a minute, red papule that rapidly grows to the size of a pea or even a cherry. Its surface may become eroded by necrosis of the overlying epidermis. Crusting may mimic a malignant melanoma, although the typical collarette can usually be seen. Pyogenic granuloma commonly is located at the proximal nail fold but may develop distally in the hyponychium region (Fig. 7) or in the nail bed, especially associated with onycholysis of the toe [58], where it often results from prolonged frictional trauma. The matrix may also be the site of this tumor after a penetrating wound of the nail plate. Tenderness and a tendency to bleed are characteristic features. Extensive tissue granulation caused by an ingrown toenail may mimic a periungual

Fig. 7. Pyogenic granuloma of the proximal nail fold.

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pyogenic granuloma; it also has been observed in patients treated with aromatic retinoids [59], indinar [60], cyclosporine [61], and all the new anticancer agents that act by inhibiting the epidermal growth factor receptor or its transduction, including cetuximab (C225) [62] and getinib [63,64]. Dierential diagnosis includes also cavernous angioma, pseudo-pyogenic granuloma, hemangiosarcoma, and, above all, amelanotic melanoma. Histologic investigation of the specimen is essential. Treatment Therapy should be as simple as possible to avoid disguring scars or nail deformity. Pyogenic granuloma may be removed by excision at its base [65] followed by electrodesiccation or application of Monsels or aluminum chloride solution. The use of argon, CO2, and 585-nm ashlamp-pumped pulsed dye lasers also is curative [66].

Fig. 8. Glomus tumor presenting with longitudinal erythronychia and distal splitting.

Glomus tumor Approximately 75% of glomus tumors occur in the hand, especially in the ngertips and in particular in the subungual area. One percent to 2% of all hand tumors are glomus tumors [67]. The age of patients at the time of diagnosis ranges from 30 to 50 years. Men are less frequently affected than women. Seven cases of subungual glomus tumors have been reported in von Recklinghausens neurobromatosis [68]. The glomus tumor is characterized by intense, often pulsating pain that may be spontaneous or provoked by the slightest trauma and exacerbation (eg, by placing an ice cube on the nail). Changes in temperature, especially from warm to cold, may trigger pain radiating up to the shoulder. Sometimes the pain is worse at night. A tourniquet placed at the base of the digit stops the pain; a blood pressure cu inated to 300 mm Hg before or immediately after minor trauma also abolishes the pain response [69]. The tumor is seen through the nail plate as a small bluish to reddish-blue spot several millimeters in diameter, rarely exceeding 1 cm in diameter. An erythematous focus that does not blanch totally with pressure and is associated with sharp pain commonly indicates a glomus tumor. Longitudinal erythronychia that may be associated with a distal ssure is a classical presentation (Fig. 8). A slight rise in surface temperature

detected by thermography may result; dynamic telethermography shows the lesion about three times its actual size [70]. One half of the tumors cause minor nail deformities, ridging and ssuring being the most common. Subungual hyperkeratosis with onycholysis is rare. About 50% cause a depression on the dorsal aspect of the distal phalangeal bone or possibly a cyst, visible on radiographic study [71]. Intraosseous location is unusual. Probing and transillumination may help localize the tumor if it is not clearly visible through the nail. Arteriography would reveal a star-shaped telangiectasic zone useful for diagnosis and localization of the tumor if it cannot be localized clinically or radiologically; however, this procedure is no longer performed. MRI may be preferable because it oers the highest sensitivity and a better assessment of the extent of the lesion [72]. Many patients report a history of trauma. The most common misdiagnoses are neuroma, causalgia, gout, and arthritis. The dierential diagnosis includes other painful lesions, such as subungual warts, keratoacanthoma, subungual exostoses, enchondroma, and leiomyoma, as well as inammatory processes, such as paronychia, osteitis, subungual whitlow, and dierent causes of longitudinal erythronychia. Histology shows a highly dierentiated, organoid tumor. It consists of an aerent arteriole and vascular channels lined with endothelium and surrounded by irregularly arranged cuboidal cells with round dark nuclei and pale cytoplasm. Immunohistochemistry of glomus tumors [73] showed the glomus cells positive for vimentin, a 42-kD muscle actin (with HHF 35), a smooth muscle actin (CGA 7), and myosin, but negative for desmin, factor VIII-related antigen, and several neural markers; however, nerve bers contain

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protein S-100, Leu-7 antigen (HNK-I, 110kD), neuron-specic enolase, and neurolaments. Treatment The only treatment for a glomus tumor is surgical removal [74]. Small tumors may be removed by punching a 6-mm hole into the nail plate, incising the nail bed longitudinally or the distal matrix transversely, and enucleating the lesion. The small nail disc is put back in its original position as a physiologic dressing. Larger tumors may be treated after lifting of the proximal half of the nail plate, allowing access to the tumor. The matrix is carefully incised parallel to the lunula border, and the lesion is dissected. The lifted nail plate is laid back and sutured to the lateral nail sulcus. An H-shaped incision or cruciate incision is necessary only with very large lesions. Glomus tumors in lateral positions are removed by an L-shaped incision parallel to and 4 to 6 mm on the volar side of the lateral nail fold. The nail bed is dissected carefully from the bone until the tumor is reached and extirpated. Excision usually is curative, although the pain may take several weeks to disappear. Recurrences occur in 10% to 20% of cases [75] and may represent incomplete excision, an overlooked tumor at the initial operation, or newly developed tumors. Amputation of the distal phalanx is an unnecessary mutilation.

Fig. 9. Giant cell tumor mimicking myxoid cyst.

Giant cell tumor Giant cell tumor is a neoplasm derived from the tendon sheath or the joint synovium. It is the second most common subcutaneous tumor of the hand. It is more frequent in females than in males. On the digits, it usually occurs on the dorsum of the distal interphalangeal joint and appears as a solitary, often lobulated, slow-growing, skin colored, and smooth-surfaced nodule that tends to feel rm and rubbery (Fig. 9). The tumor may enlarge to the size of a cherry and may cause pain on exion by virtue of its dimensions. Only rarely does the tumor interfere with the nail unit in the region of the lateral nail fold. Periodic inammation and drainage may occur. In contrast to malignant synovioma, no calcication is demonstrable on radiographic studies [76]. A giant cell tumor in a subungual location is unusual [77]. A cystic-appearing lesion adjacent to the nail may cause a wide longitudinal groove in the nail plate [78]. A giant cell tumor involving the lateral

nail fold and nail bed can interfere with nail growth [79]. MRI may suggest the diagnosis [80] with a nodule close to the distal insertion of the exor or extensor digitorum tendon or to the synovium of the distal interphalangeal joint. In typical cases, hemosiderin deposits lead to typical signal void artifacts on all MR images. An intermediate-to-low signal of a part of the tumor is common and must evoke the diagnosis. Histopathology shows a cellular tumor composed of histiocytic and broblastic cells with a variable number of giant cells and some foam cells in a hyalin stroma. Siderophages may give the tumor a brown appearance. The dierential diagnosis includes a ganglion (which tends to feel more cystic [aspiration or transillumination]), broma of the tendon sheath [81,82], implantation epidermal cyst, brokeratoma, rheumatoid nodule, multicentric reticulohistiocytosis, metastatic tumor, tendinous xanthoma, chondro- or osteosarcoma, and reticulohistiocytoma (the histology of which may be identical to that of giant cell tumor). Granuloma annulare and erythema elevatum diutinum also should be ruled out. Treatment Treatment is by careful surgical removal. An oblique incision along the greatest axis of the tumor enables the multilobulated lesion to be exposed. The tumor may penetrate the extensor tendon. Complete removal is necessary to prevent recurrences.

Bowens disease Bowens disease, the rst recognized example of carcinoma in situ, is a nonaggressive malignant

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condition that has attracted interest for several reasons: 1. There is increased awareness of its frequency because of numerous recent reports in the literature. 2. New clinical patterns have been identied. 3. The process is potentially polydactylous with the passage of time. 4. A proven link with the HPV sheds new light on the etiology of this type of cancer. Bowens disease of the nail apparatus is a distinctive type of squamous cell carcinoma that diers from other variants. Some authors prefer to avoid the use of the term Bowens disease for in situ epidermoid carcinoma occurring beneath the nail plate, because it is not always easy to distinguish invasive from in situ carcinoma. A biopsy specimen showing Bowens disease does not exclude the possibility of invasive carcinoma in another area of the lesion. The malignant process may develop in the epithelium of the periungual area as well as in the subungual tissues and most commonly originates in the nail folds or grooves. Classic clinical patterns Classic patterns of periungual involvement include hyperkeratotic or papillomatous and even warty proliferation, erosions or scaling of the nail fold, whitish cuticle [84], periungual swelling from deep tumor proliferation, a paronychia with erythema caused by inammation resulting from infection, and ssure or ulceration of the lateral nail groove, sometimes crusted with granulation-like tissue beneath the scab. Subungual involvement is the most common nding. It was consistent in the 12 cases reported by Guitart and colleagues [85]. It may present with onycholysis, and clipping away of the nonadherent portion of the nail plate shows partial or extensive hyperkeratosis of the nail bed (Fig. 10). Onycholysis associated with oozing erosion or ulceration of a sometimes crusty nail bed can be observed. Localized pain may be noted (eg, when the patient uses a keyboard). Sometimes the nail plate becomes dystrophic or ingrown. The presence of ulceration, bleeding, or nodule formation indicates that the carcinoma has become invasive. One of the most important clinical features of Bowens disease of the subungual tissues is associated with partial or total nail loss. Bone involvement is seen in fewer than
Fig. 10. Bowens disease of the nail bed with partial nail destruction.

20% of patients. Metastases have been reported in patients who have hereditary ectodermal dysplasia but also in patients who do not. The rate of metastasis seems to be low, however. Nodal involvement is reported in only 2% of reported patients who have subungual squamous cell carcinoma [86]. The key to diagnosis is the histologic examination. The picture is identical to that of Bowens disease in other skin areas. The most important feature is the intact basement membrane. Bowens disease has been reported in individuals between the ages of 13 and 90 years, with the highest incidence in patients aged 50 to 69 years. The tumor grows slowly, and the duration of signs and symptoms from onset to the time of diagnosis has varied from several months to 30 years. The diagnostic biopsy often is delayed because of the patients reluctance, technical diculties, or the physicians failure to suspect the disease. The toes are aected signicantly less frequently than the digits of the hands [87]. The thumb probably is the most commonly involved area, although some publications indicate that the second, third, and fourth ngers are diseased most frequently [88]. New clinical patterns Identication of longitudinal melanonychia, with a classic band pattern [89,90] that may be isolated [91] or present with an irregular appearance of the dark streak [9294], is a recent clinical nding conrmed by numerous authors. Lifting of the nail plate by subungual pseudobrokeratoma is an uncommon pattern [95]. The pseudobrokeratoma may be pigmented, appearing as a longitudinal melanonychia [96,97]. Pseudo-Hutchinsons sign is particularly misleading, because it is similar to melanoma when it aects only one digit [98], but several digits may be simultaneously involved.

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The authors also have seen longitudinal erythronychia in two cases of subungual Bowens disease [99]. Bowens disease of the ngernail structures always should be regarded as a potentially polydactylous process [100,101] with possible concomitant involvement of the hand and foot [102]. Adequate follow-up observation of uninvolved nails of all the digits, with prompt evaluation and treatment of suspicious changes, is mandatory. Dierential diagnosis Bowens disease often appears as a clinically misleading benign lesion [83103], which delays diagnosis [104]. The lesions often are mistaken for chronic inammatory conditions, including bacterial infections. Because of the rapidly enlarging growth of the proximal nail fold [105,106], squamous cell carcinoma must be considered in the differential diagnosis of nail fold neoplasm. An immunocompromised condition such as HIV/ AIDS may predispose a patient to malignant degeneration of lesions caused by infection with HPV. The dierential diagnosis includes pyogenic granuloma, verruca vulgaris, onychomycosis, subungual exostosis, melanoma, glomus tumor, epidermoid cyst, subungual keratoacanthoma (which may make diagnosis dicult radiologically and histopathologically), and even in acquired ungual brokeratoma [9597]. Pigmented onychomatricoma may be dicult to rule out without the histologic malignant patterns [24]. Metastatic squamous cell carcinoma of the nail bed as a presenting sign of lung cancer is rare [107,108]. It may be impossible to dierentiate radiologically between necrotic bone caused by infection and neoplastic bone caused by malignancy, but early radiographic examination may be useful to determine whether the squamous cell carcinoma is a primary lesion or a secondary complication of chronic infection. Etiology The etiology of subungual epidermoid carcinoma remains unclear. Arsenic, for example, cannot be excluded in older psoriatic patients. Trauma, infection, chronic paronychia [84,110], and, above all, exposure to x-ray (eg, in physicians, dentists, and patients) have been cited as etiologic factors. Exposure to x-ray may be

followed by radiodermatitis [111], which, together with HPV infection, is the most common factor for the development of squamous cell carcinoma [85]. HPV 16, 34 [112], and 35 [113] have been detected in situ and invasive epidermoid carcinoma. The HPV genome was found in 8 of 10 periungual lesions by dot-blot analysis of frozen tissue; 6 of these lesions were related to HPV 16 [114]. Using polymerase chain reaction to detect HPV in formalin-xed, paran-embedded specimens of periungual squamous cell carcinoma, Ashino and colleagues [115] found that ve of seven periungual lesions contained HPV 16. In situ hybridization failed to identify HPV in any of these patients tumors. At least 50 cases of ungual Bowens disease have proved to be associated with HPV 16 [94,100,116120]. This nding prompts speculation as to whether genital-digital transmission of the virus occurs. In the case reported by Ru dlinger and colleagues [113], Bowens disease of the nail apparatus and the bowenoid papulosis of the anogenital area revealed an identical HPV 35 infection. Because the patient suered from long-lasting pruritus of the anogenital area, scratching may have resulted in autoinoculation. Similarly, HPV 16 genome from digital Bowens disease in two women was identical with HPV DNA from archival samples of their genital dysplasia [98]. A review of HPV-associated digital squamous cell carcinoma also suggests the possibility of genital-digital spread as a mechanism of tumor genesis [119]. HPV associated with digital squamous cell carcinoma is more likely to recur after surgical treatment than previously reported. This rate of recurrence greatly exceeds that for cutaneous squamous cell carcinoma in general and may be caused by residual postsurgical HPV [119]. In the case of Bowens disease reported by Ostrow and colleagues [120], the HPV 16 DNA was discovered in a solitary subungual warty lesion, and the integration of the HPV 16 DNA at present seems to be closely associated with progression from a premalignant lesion to a malignant one. Cytophotometric analysis of a case of bilateral subungual Bowens disease with HPV 16 suggested a lack of HPV 16 genome integration into the host DNA of squamous cell carcinoma [116]. There is no reason to assume that benign viral warts undergo malignant transformation. HPV 18 associated with HPV 16 was identied twice [109,121]. HPV type 56 DNA [122] appearing as longitudinal melanonychia was detected recently [123]. Some cases were HPV type 73 [124] and 26.

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Box. 1. New therapeutic perspectives for Bowens disease 1. Imiquimod: Imiquimod topical treatment has been used with good results in genital or extragenital Bowens disease in immunocompetent or immunocompromised patients. It therefore was logical to use imiquimod to manage the digits of patients affected by Bowens disease. Lafte and Saurat [129] treated a patient presenting with recurrences. A cure was obtained after 4 months. One year later the patient was still disease free. 2. 5-Aminolevulinic acid: There has been some success using photodynamic therapy [130,131]. 3. Intra-arterial infusion with methotrexate: Intra-arterial infusion of chemotherapy [132] can be considered as a simple and eective alternative method for squamous cell carcinoma of the big toe with preservation of organ and function. 4. Radiation therapy: Radiation therapy should be considered as a treatment option for nail bed squamous cell carcinoma before suggesting amputation and perhaps for all unresectable lesions [133].

3. Electrosurgery is a therapeutic alternative in a few specic cases. 4. Liquid nitrogen may give good results in experienced hands. Neither electrosurgery nor liquid nitrogen allows adequate histologic control of tumor margins, however. 5. Bone involvement requires amputation of the distal phalanx. A perionychial squamous cell carcinoma without bone involvement requires complete removal with margins of 0.5 to 1 cm and usually requires coverage with a skin graft. If there is bone involvement or extensive soft tissue involvement, amputation of the distal interphalangeal joint or a more proximal amputation should be considered. Lymph node dissection is indicated if palpable lymph nodes do not disappear within 3 to 4 weeks after amputation or excision, because many lymph node enlargements are caused by chronic inammation [127]. A multidisciplinary approach to resection and reconstruction is mandatory [128]. New therapeutic perspectives for Bowens disease are given in Box 1. References
[1] Holland TT, Weber CB, James WD. Tender periungual nodules. Arch Dermatol 1992;128:10510. [2] Lauchli S, Eichmann A, Baran R. Swelling of the proximal nail fold caused by underlying warts. Dermatol 2001;202:3289. [3] Kumar B, Sharma SC, Kaur S. Phalangeal erosions with subungual warts. Indian J Dermatol Venereol 1980;46:1668. [4] Plewig G, Christophers E, Braun-Falco O. Mutilierende subunguale Warzen: Abheilung durch Methotrexat. Hautarzt 1973;24:33841. [5] Hengge UR, Esser S, Schultewolter T, et al. Selfadministered topical 5% imiquimod for the treatment of common warts and mollusca contagiosa. In: Abstracts of the 5th Congress of the GermanJapanese Society of Dermatology. Marburg (Germany): German-Japanese Society of Dermatology; 1999. p. 18. [6] Shelley WB, Shelley ED. Intralesional bleomycin sulfate therapy for warts: a novel bifurcated needle puncture technique. Arch Dermatol 1991;127: 2346. [7] Epstein E. Intralesional bleomycin and Raynauds phenomenon. J Am Acad Dermatol 1991;24:7856. [8] Ross BS, Levine VJ, Nehal K, et al. Pulsed dye laser treatment for warts: an update. Dermatol Surg 1999;25:27780. [9] Baran R, Goettmann S. Distal digital keratoacanthoma: a report of 12 cases and review of the literature. Br J Dermatol 1998;139:5125.

Classic treatment The need for complete removal of the lesion cannot be overemphasized. 1. The best treatment is Mohs micrographic surgery allowing adequate excision with maximal preservation of normal tissue and function [86,125,126]. This surgery can be performed with routine instrumentation as well as with the CO2 laser in a focusedbeam incisional mode, which avoids bleeding and ensures minimal postoperative discomfort for the patient. 2. Excisional surgery may be used in some cases or for complete removal of the nail apparatus, with healing by secondary intention, grafting, or repair with a bridge ap.

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[10] Baran R, Mikhail G, Costini B, et al. Distal digital keratoacanthoma. Two cases with a review of the literature. Dermatol Surg 2001;27:5759. [11] Haneke E. Multiple subungual keratoacanthomas. XII International Congress of Dermatologic Surgeons, Munich, Germany. Zbl Haut-Geschl Kr 1991. p. 159, 3378. [12] Sinha A, Marsh R, Langtry J. Spontaneous regression of subungual keratoacanthoma with reossication of underlying distal lytic phalanx. Clin Exp Dermatol 2005;30:202. JL, Goettmann S, Chevrot A, et al. Ultra[13] Drape sonography and magnetic resonance imaging of the perionychium. In: Baran R, Dawber RPR, Haneke E, et al, editors. A text atlas of nail disorders. London: Martin Dunitz; 2003. p. 2017. [14] Scarini P, Ghigi G, Bertarelli C, et al. Subungual keratoacanthoma. A variant of verrucous squamous cell carcinoma of the skin. Appl Pathol 1983;1:33942. [15] Pellegrini VD, Tompkins A. Management of subungual keratoacanthoma. J Hand Surg 1986;11A: 71824. [16] Patel MR, Desai SS. Subungual keratoacanthoma in the hand. J Hand Surg 1989;14A:13942. [17] Yoshikawa K, Hirano S, Kato T. A case of eruptive keratoacanthoma treated by oral etretinate. Br J Dermatol 1985;112:57983. [18] Voigtla nder V, Baum C. Destruierendes subunguales Keratoakanthom: Erhaltung der Endphalanx durch kombinierte operative und medikamento se Therapie. Z Hautkr 1990;66(Suppl 3):1101. [19] Bennet R, Epstein E, Goette D. Current management of keratoacanthoma using 5-FU. Cutis 1985; 36:21836. [20] Melton JL, Nelson BR, Stough DB, et al. Treatment of keratoacanthomas with intralesional methotrexate. J Am Acad Dermatol 1991;25: 101723. [21] Sayama S, Tagami H. Treatment of keratoacanthoma with intralesional bleomycin. Br J Dermatol 1983;109:44952. [22] Baran R, Kint A. Surgical treatment of a lamentous tufted tumour in the matrix of a funnelshaped nailda new entity. Z Haut Geschlechtskr 1991;159:337. [23] Baran R, Kint A. Onychomatricoma. Filamentous tufted tumour in the matrix of a funnelshaped nail: a new entity. Br J Dermatol 1992; 126:5105. [24] Van Holder C, Dumontier C, Abimelec P. Onychomatricoma. J Hand Surg 1999;24B:1201. [25] Fraga GR, Patterson JW, McHargue CA. Onychomatricoma. Report of a case and its comparison with brokeratoma of the nail bed. Am J Dermatopathol 2001;23:3640. [26] Nagamatsu S, Tozawa A, Nakuoka H, et al. A case of onychomatricoma. Japanese Journal of Plastic Reconstructive Surgery 2002;45:87580.

[27] Laxmisha C, Thappa DM, Karthikeyan K, et al. Onychomatricoma. Indian J Dermatol 2003;48: 945. [28] Ko CJ, Shi L, Barr RJ, et al. Ungioblastoma and unguioblastic bromadan expanded spectrum of onychomatricoma. J Cutan Pathol 2004;31:20711. [29] Raison-Peyron N, Alirezai M, Meunier L, et al. Onychomatricoma: an unusual cause of nail bleeding. Clin Exp Dermatol 1998;23:138. [30] Perrin C, Goettmann S, Baran R. Onychomatricoma: clinical and histopathologic ndings in 12 cases. J Am Acad Dermatol 1998;39:5604. [31] Fayol J, Baran R, Perrin C, et al. Onychomatricoma with misleading features. Acta Derm Venereol 2000;80:3702. JL, Baran R, et al. Onycho[32] Goettmann S, Drape re sonance matricome: 3 nouveaux cas, inte t de la re tique nucle aire. Ann Dermatol Venereol magne 1994;121:S145. [33] Haneke E, Fra nken J. Onychomatricoma. Dermatol Surg 1995;21:9847. [34] Kint A, Baran R, Geerts ML. The onychomatricoma: an electron microscopic study. J Cutan Pathol 1997;24:1838. [35] Sampson JR, Harris PC. The molecular genetics of tuberous sclerosis. Hum Mol Genet 1994;3: 147780. [36] Webb DW, Clarke A, Fryer A, et al. The cutaneous features of tuberous sclerosis: a population study. Br J Dermatol 1996;135:15. [37] Haneke E. Intraoperative dierential diagnosis of onychomatricoma, Koenens tumours, and hyperplastic Bowens disease. 7th Congress of the European Academy of Dermatology and Venereology European Nail Society, Nice, 1998. J Eur Acad Dermatol Venereol 1998;13(Suppl S):119. sions des [38] Colomb D, Racouchot J, Jeune R. Les le rose tube reuse de Bourneville ongles dans la scle es ou associe es aux tumeurs de Koenen. Ann isole Dermatol Syphilgr (Paris) 1976;103:4317. [39] Zeller J, Friedmann D, Clerici T, et al. The signicance of a single periungual broma: report of seven cases. Arch Dermatol 1995;131:14656. [40] Pontious J, Labovitz JM. Periungual bromas associated with tuberous sclerosis. Int J Low Extrem Wounds 1997;4:1923. [41] Kint A, Baran R. Histopathologic study of Koenen tumours. J Am Acad Dermatol 1988;18:36972. [42] Bart RS, Andrade R, Kopf AW, et al. Acquired digital brokeratomas. Arch Dermatol 1968;97: 1209. [43] Steel HH. Garlic-clove broma. JAMA 1965;191: 10823. [44] Haneke E. Intraoperative dierential diagnosis of onychomatricoma, Koenens tumours, and hyperplastic Bowens disease. J Eur Acad Dermatol Venereol 1998;11:S119. JL. Imaging of tumors of the nail unit. In: [45] Drape Krull E, Zook E, Baran R, et al, editors. Nail

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[66] Poetke M, Berlien HP. Treatment of a subungual hemangioma with ashlamp- pumped pulsed-dye laser. J Am Acad Dermatol 2000;43:11356. [67] Rettig AC, Strickland JW. Glomus tumor of the digits. J Hand Surg 1977;2:2615. [68] Sawada S, Honda M, Kamide R, et al. Three cases of subungual glomus tumors with von Recklinghausen neurobromatosis. J Am Acad Dermatol 1995;32:2778. [69] Hildreth DH. The ischemia test for glomus tumor: a new diagnostic test. Rev Surg 1970;27:1478. [70] Corrado EM, Passareti U, Messore L, et al. Thermographic diagnosis of glomus tumour. Hand 1982;14:214. [71] Van Geertruyden J, Lorea P, Goldschmidt D, et al. Glomus tumours of the hand. A retrospective study of 51 cases. J Hand Surg 1996;21(2):25760. [72] Van Ruyssevelt CE, Vranckx P. Subungual glomus tumoral emphasis of MR angiography. AJR Am J Roentgenol 2004;182:2634. [73] Daugaard S, Jensen ME, Fisher S. Glomus tumours. An immunohistochemical study. APMIS 1990;98:98390. [74] Moon SE, Won JH, Kwon DS, et al. Subungual glomus tumor: clinical manifestations and outcome of surgical treatment. J Dermatol 2004;31:9937. [75] Foucher G, Le Viet D, Dalliana Z, et al. Les gion ungue ale. A propos tumeurs glomiques de la re rie de 55 patients. Revue de chirurgie dune se orthopedique 1999;85:3626. [76] Wright CJE. Benign giant-cell synovioma. An investigation of 85 cases. Br J Surg 1951;38:25771. [77] Abimelec P, Cambiaghi S, Thioly D, et al. Subungual giant cell tumor of the tendon sheath. Cutis 1996;58:2735. [78] Batta K, Tan CY, Colloby P. Giant cell tumour of the tendon sheath producing a groove deformity of the nail plate and mimicking a myxoid cyst. Br J Dermatol 1999;140:72081. J. Latero-subungual giant cell [79] Richert B, Andre tumor of the tendon sheath: an unusual location. J Am Acad Dermatol 1999;41:3478. JL, Goettmann S, Chevrot A, et al. Ultra[80] Drape sonography and magnetic resonance imaging of the parionychium. In: Baran R, Dawber RPR, Haneke E, et al, editors. A text atlas of nail disorders. London: Martin Dunitz; 2003. p. 20116. [81] Humphreys S, McKee PH, Fletcher DM. Fibroma of tendon sheath, a clinicopathologic study. J Cutan Pathol 1986;13:3318. [82] Norton LA. Tumors. In: Scher RK, Daniel CR, editors. Nails, therapy, diagnosis, surgery. Philadelphia: W.B. Saunders; 1990. p. 20213. [83] Ongenae K, Van De Kerckhove M, Naeyaert JM. Bowens disease of the nail. Dermatol 2002;204: 34850. [84] Zaias N. The nail in health and disease. 2nd edition. Norwalk (CT): Appleton & Lange; 1990.

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[85] Guitart J, Bergfeld WF, Tuthull RJ, et al. Squamous cell carcinoma of the nail bed: a clinicopathological study of 12 cases. Br J Dermatol 1990;123: 21522. [86] Zaiac MN, Weiss E. Mohs micrographic surgery of the nail unit and squamous cell carcinoma. Dermatol Surg 2001;27:24651. [87] Nasca MR, Innocenzi D, Micali G. Subungual squamous cell carcinoma of the toe: report on three cases. Dermatol Surg 2004;30:3458. [88] Zabawski EJ, Washak RV, Cohen JB, et al. Squamous cell carcinoma of the nail bed: Is nger predominance another clue to etiology? A report of 5 cases. Cutis 2001;67:5964. [89] Saijo S, Kato T, Tagami H. Pigmented nail streak associated with Bowens disease of the nail matrix. Dermatologica 1990;181:1568. [90] Lemont H, Haas R. Subungual pigmented Bowens disease in a nineteen-year-old black female. J Am Podiatr Med Assoc 1994;84:3940. [91] Henry M, Renaut JJ, Baran R, et al. Bande pig e ungue ale acquise, re ve latrice dun carcimente pidermo de du lit de longle. Nouvelles nome e Dermatalogiques 2003;22(Suppl 2):1920. [92] Baran R, Simon C. Longitudinal melanonychia: a symptom of Bowens disease. J Am Acad Dermatol 1988;18:135960. [93] Baran R, Eichmann A. Longitudinal melanonychia associated with Bowen disease. Dermatology 1993; 186:15960. J, Stene JJ, et al. Longitudinal mela[94] Sass U, Andre nonychia revealing an intraepidermal carcinoma of the nail apparatus: detection of integrated HPV-16 DNA. J Am Acad Dermatol 1998;39:4903. [95] Haneke E. Epidermoid carcinoma (Bowens disease) of the simulating acquired ungual brokeratoma. Skin Cancer 1991;6:21721. [96] Baran R, Perrin C. Pseudo-brokeratoma of the nail apparatus: a new clue for Bowen disease. Arch Dermatol 1987;74:44950. [97] Dominguez-Cherit J, Garcia C, Vega-Memije ME, et al. Pseudo-brokeratoma: an unusual presentation of subungual squamous cell carcinoma in a young girl. Dermatol Surg 2003;29:7889. [98] Sau P, McMarlin SL, Sperling LC, et al. Bowens disease of the nail bed and periungual area. A clinicopathologic analysis of seven cases. Arch Dermatol 1994;130:2049. [99] Baran R, Perrin C. Longitudinal erythronychia with distal subungual keratosis: onychopapilloma of the nail bed and Bowens disease. Br J Dermatol 2000;143:1325. [100] Baran R, Gormley D. Polydactylous Bowens disease of the nail. J Am Acad Dermatol 1987;17: 2014. [101] Goodman G, Mason G, OBrien T. Polydactylous Bowens disease of the nail bed. Austr J Dermatol 1995;36:1645.

[102] Koch A, Scho nlebe J, Haroske G, et al. Polydactylous Bowens disease. J Eur Acad Dermatol Venereol 2003;17:2135. [103] Virgili A, Zampino MR, Bacilieri S, et al. Squamous cell carcinoma of the nail bed: A rare disease or only misdiagnosed? Acta Derm Venereol 2001; 81:3067. [104] Hale LR, Dawber RPR. Subungual squamous cell carcinoma presenting with minimal nail changes: a factor in delayed diagnosis? Austr J Dermatol 1998;39:868. [105] High WA, Tyring SK, Taylor RS. Rapidly enlarging growth of the proximal nail fold. Dermatol Surg 2003;29:9846. [106] Baran R, Perrin C. Bowens disease clinically simulating an onychomatricoma. J Am Acad Dermatol 2002;47:9479. [107] Chang SE, Choi JH, Sung KJ, et al. Metastatic squamous cell carcinoma of the nail bed: a presenting sign of lung cancer [letter]. Br J Dermatol 1999; 141(5):93940. J, et al. Me [108] Vanhooteghem O, Dumont M, Andre ales bilate rales de carcinome tastases sous-ungue ` ge diagnostique! spino-cellulaire pulmonaire: un pie Revue de medicine de Liege 1999;54(8):6534. [109] Nasca MR, Innocenzi D, Micali G. Subungual squamous cell carcinoma of the toe: report on three cases. Dermatol Surg 2004;30:3458. [110] Faila JM. Subungual lipoma, squamous carcinoma of the nail bed, and secondary chronic infection. J Hand Surg 1996;21A:5124. [111] De Dulanto F, Camacho F. Radiodermatitis. Acta Dermato Silitica 1979;70:6794. [112] Kawashima M, Jablonska S, Favre M, et al. Characterization of a new type of human papillomavirus found in a lesion of Bowens disease of the skin. J Virol 1986;57:68892. [113] Ru dlinger R, Grob R, Yu XY, et al. Human papillomavirus-35 positive bowenoid papulosis of the anogenital area and concurrent with bowenoid dysplasia of the periungual area. Arch Dermatol 1989; 125:6559. [114] Moy RL, Eliezri Y, Nuovo GJ, et al. Human papillomavirus type 16 DNA in periungual squamous cell carcinomas. JAMA 1989;261:266973. [115] Ashino R, Junli J, Jacobson M, et al. Detection of HPV DNA in squamous cell carcinoma of the nail bed and nger determined by polymerase chain reaction. Arch Dermatol 1991;127:18138. J, Laporte M, et al. Human [116] DeDobbeleer G, Andre papillomavirus type 6/11 and 16 in periungual squamous carcinoma in situ. Eur J Dermatol 1993;3:124. [117] Tosti A, La Placa A, Fanti PA. Human papillomavirus type 16-associated periungual squamous cell carcinoma in a patient with acquired immunodeciency syndrome. Acta Derm Venereol 1994;74: 4789.

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[118] Kapranos N, Aronis E, Braziotis A, et al. HPV-16assoziierter Morbus Bowen des Nagelbetts un der periungual-region beider Daumen. Z Hautkr 1996;71:4850. [119] Forslund O, Nordin P, Andersson K, et al. DANN analysis indicates patient-specic human papillomavirus type 16 strains in Bowens disease of ngers and in archival samples from genital dysplasia. Br J Dermatol 1997;136:67882. [120] Ostrow RS, Shaver MA, Turnquist S, et al. Human papillomavirus-16 DNA in a cutaneous invasive cancer. Arch Dermatol 1989;125:6669. [121] Alam M, Caldwell JB, Eliezri YD. Human papillomavirus-associated digital squamous cell carcinoma: literature review and report of 21 new cases. J Am Acad Dermatol 2003;48:38593. [122] Uezato H, Hagiwara K, Ramuzi ST, et al. Detection of human papilloma virus Type 56 in extragenital Bowens disease. Acta Derm Venereol 1999;79: 3113. [123] Matthew C, Lambiase MC, Gardner TL, et al. Bowen disease of the nail bed presenting as longitudinal melanonychia: detection of human papillomavirus type 56 DNA. Cutis 2003;72:3059. [124] Mitsuishi T, Sata T, Matsukura T, et al. The presence of mucosal HPV in Bowens disease of the hands. Cancer 1997;79:19117. [125] Mikhail GR. Bowen disease and squamous cell carcinoma of the nail bed. Arch Dermatol 1974;110: 26770.

[126] De Berker DAR, Dahl MGC, Malcolm AJ, et al. Micrographic surgery for subungual squamous cell carcinoma. Br J Plast Surg 1996;49:4149. [127] Zook E. Tumours of the nail apparatus. In: Baran & Dawbers diseases of the nails and their management. 3rd edition. Oxford (UK): Blackwell Science; 2001. p. 543. [128] Peterson SR, Layton EG, Joseph AK. Squamous cell carcinoma of the nail unit with evidence of bony involvement: a multidisciplinary approach to resection and reconstruction. Dermatol Surg 2004;30:21821. ale [129] Latte E, Saurat JH. Maladie de Bowen ungue cidivante: traitement par imiquimod topique re (Aldara). Ann Dermatol Venereol 2003;130:2113. [130] Wong TW, Sheu HM, Lee YY, et al. Photodynamic therapy for Bowens disease (squamous cell carcinoma in situ) of the digit. Dermatol Surg 2001;27:4526. [131] Tan B, Sinclair R, Foley P. Photodynamic therapy for subungual Bowens disease. Australas J Dermatol 2004;45:1724. [132] Sheen YS, Sheen MC, Sheu HM. Squamous cell carcinoma of the big toe successfully treated by intra-arterial infusion with methotrexate. Dermatol Surg 2003;29:9823. [133] Yaparpalvi R, Mahadevia PS, Gorla GR, et al. Radiation therapy for the salvage of unresectable subungual squamous cell carcinoma. Dermatol Surg 2003;29:2946.

Dermatol Clin 24 (2006) 313322

Basic Nail Surgery

Bertrand Richert, MD, PhD
Department of Dermatology, University of Lie`ge, Quai Kurth 45 B-4020, Lie`ge, Belgium

Anesthesia Premedication Premediction may be useful in anxious patients. Short-action molecules, such as hydroxyzine or diazepines, orally or sublingually, are preferable. The combination of hydroxyzine, 25 mg the night before operation, and lorazepam sublingually 1 hour before surgery is eective. The use of the eutectic mixture of lidocaine 2.5% and prilocaine 2.5% under an occlusive dressing before surgery will alleviate the pain caused by needle insertion but not the pain resulting from the deposition of the local anesthetic or the subsequent dilatation [1]. Materials Because all types of anesthesia used for nail unit surgical procedures are high-resistance injections because of weak dilatation of tissues, the use of a Luer-Lock syringe is mandatory. The rationale for the use of very thin needles (30-gauge for ngers, 27-gauge for toes, and 30-gauge for children in all locations) is twofold: pain from the needle puncture is reduced, and anesthetic ow is controlled better so there is a very gradual swelling of the soft tissues. It is common for the physician to spend more time administering the anesthetic than performing the surgical procedure. Anesthetic products Several products are available for regional blocks. Lidocaine (1% or 2%) is the reference local anesthetic with a duration of action of 60 minutes. Lidocaine is acid. Its alkalinization reduces pain during infusion [2]. The addition of too
E-mail address: Bertrand.richert@skynet.be

much sodium bicarbonate results in a cloudy solution because of occulation and may impair the ow through the needle, which can become obstructed. The simple procedure of warming the anesthetic to 37 C also reduces the pain associated with its infusion [3]. Many textbooks discourage the use of epinephrine in the extremities because of the theoretical risk of ischemia. Multiple studies involving thousands of patients support the premise that the use of lidocaine with epinephrine is safe in the digits [4]. The use of lidocaine with epinephrine has clear advantages, such as quicker onset, need for fewer reinforcement doses, less need for special bleeding maneuvers, and better total time of postoperative analgesia [5]. It is, however, recommended that epinephrine not be used in patients who have vasospastic, thrombotic, or extreme medical conditions. Prolonged ischemia may be reversed with nitroglycerin ointment or phentolamine injection [6]. Because most surgical nail procedures last less than 30 minutes, reinforcement doses are not required to prolong anesthesia. To achieve a bloodless eld as needed (ie, in phenolization and in matricial surgery), a tourniquet should be placed at the base of the digit. For these reasons, the use of lidocaine with epinephrine is of little interest in surgery of the nail apparatus. Bupivacaine 0.5% is eective after 45 minutes for up to 480 minutes [7]. It may be added to lidocaine to lengthen the postoperative analgesia. An alternative is to inject 0.5 mL to 1 mL of bupivacaine immediately after surgery as a lateral wing block. It will act as a chemical tourniquet preventing further bleeding. Rovipacaine is used in several surgical elds (eg, breast surgery, eye surgery, dentistry, brachial block) with favorable results: it has the same
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0733-8635/06/$ - see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2006.03.006

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quick onset as lidocaine, it provides better postoperative pain relief (up to 9 hours) [811], and it is less cardiotoxic than bupivacaine [12]. Pain at inltration depends on concentration and occurs with concentrations over 5 mg/mL. The onset of anesthesia is approximately 2 minutes and varies according to the concentration. The mean time to regain full sensation is more than 7 hours for 2 mg/mL rovipacaine and increases with more concentrated solutions [13]. Ropivacaine seems to produce vasoconstriction at low dosages [14]. For all these reasons, the routine use of rovipacaine, 2 mg/mL, provides comfortable anesthesia and postoperative outcome for patients undergoing nail surgery. Techniques It is best to have the patient in a reclined position during the administration of anesthesia in the event of a vasovagal episode. It is also best to inform the patient when the needle stick is about to occur to avoid a dangerous reex jerk [15]. Regional anesthesia of a single nger commonly is achieved by the proximal block (ring block). This technique has several drawbacks, however. The anesthetic eect requires up to 20 minutes to develop, and there is a potential hazard of compression and trauma to neurovascular bundles with subsequent postoperative edema that causes long-lasting pain [16]. Thus, this regional anesthesia is no longer recommended. The distal wing block is the technique of choice in nail surgery. The injection site is the point about 5 to 8 mm proximal and lateral to the junction of the proximal nail fold (PNF) and the lateral nail fold. By introducing the needle at a 45 angle directed distally down to the bone (Fig. 1), slow injection of 0.3 mL to 0.5 mL of anesthetic

will distend and blanch both folds and anaesthetize the terminal, transverse, and descending branches of the dorsal nerve. As the folds distend distally and medially from the local injection point, a winglike appearance is noted [15]. Resistance to injection suggests that the needle tip has penetrated the periosteum. Careful withdrawal of the needle will result in a free ow. Blanching of the lateral part of the lunula is often noted. It always is necessary to complete the procedure by an injection into the lateral nail fold up to the hyponychium to ensure complete anesthesia. The needle may be bent at 120 , reinserted at the initial puncture site, and pushed distally to the distal extremity of the lateral nail fold. Approximately 0.3 mL to 0.5 mL of anesthetic is deposited into the lateral nail fold in a retrograde motion. This injection provides anesthesia for half of the nail apparatus. For complete anesthesia, the procedure should be repeated on the opposite side with the PNF inltrated along its entire width. Anesthesia takes eect immediately. If more advanced surgery (ie, aps) is planned, anesthesia of the ventral root is necessary. The needle is inserted at the initial puncture site and pushed downwards skimming the lateral aspect of the phalanx, and 0.5 mL is injected into the pulp to anaesthetize the ventral nerve roots. Tools Basic nail surgery requires few but specic instruments. The classic tray should include an elevator to detach the nail plate from its attachments (eg, Freer elevator, dental spatula), a nail splitter (eg, English nail splitter), hemostats (straight), ne Iris or Stevens scissors that are curved or straight, 15 or 15C surgical blade, netoothed Addison pick-ups for handling tissue, 3-mm and 6-mm punches, a ne needle holder, and 3/0 and 4/0 nonabsorbable sutures. Biopsy techniques There are ve main techniques to biopsy nail tissue. The methods chosen depend on the location of the pathologic process. Keratin biopsy As onychomycosis many present in many guises that can puzzle even an experienced clinician, keratin biopsy is always mandatory to rule out a fungal infection. Moreover, this noninvasive technique allows melanic pigmentation to be

Fig. 1. Digital wing block.

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distinguished from hemosiderin deposit when there is a black/brown discoloration of the nail [17]. The techniques of sampling the nail plate in the case of onychomycosis are described in the article by Gupta and Ricci found elsewhere in this issue. Nail bed biopsy Indications for nail bed biopsies are the diseases of the nail bed presenting as an onycholysis, a subungual hyperkeratosis, or a tumor of the nail bed. Technique of biopsy will vary according to the clinical presentation:  In case of onycholysis, partial avulsion of the detached nail plate allows punch biopsy of the exposed nail bed. It is mandatory to push the punch until bone contact. The best information will be obtained at the proximal junction of the onycholysis. Elliptical biopsy of the nail bed is indicated to remove larger specimen (ie, small tumors). The elliptical excision should be oriented in a longitudinal axis. It is said that defect over 4 mm should be sutured in order to avoid secondary oncholysis. The nail bed is very fragile, however, and reapproximation of the margins may be dicult. It is amazing to note that a very large defect of the nail bed (ie, after Mohs surgery for Bowens disease) may regenerate totally by secondary intention (Fig. 2).  If the nail plate still adheres to its bed, the two-punch set technique is the most convenient [18]. Soaking the digit in lukewarm water for 10 to 15 minutes softens the nail plate and facilitates the passage of the punch through the nail. Another method to thin a nail plate is to use a hand-held electric burr. A 6-mm punch is made through the nail plate only (Fig. 3A); the circle of nail

plate is removed with the tip of a #11 blade, and a smaller punch of 4 mm is performed through the nail bed down to the underlying bone (Fig. 3B). The enlarged hole in the nail plate allows easier access to the biopsy material. Harvesting the specimen from the bone is facilitated by using ne-curved Stevens scissors or, preferably, the double-curved La Grange scissors. The piece of removed nail plate can be replaced and secured with adhesive strips as part of the dressing (Fig. 3C).

Matricial biopsy Matricial biopsies are most interesting in longitudinal melanonychias. Dystrophic sequelae almost never occur if the pigment is located within the distal matrix, which is fortunately the circumstance in about 95% of all cases [19]. Because the distal matrix synthesizes the ventral part of the nail plate, the only concern should be a nail plate thinned from below. If the pigment source is located within the proximal matrix, a nail plate dystrophy will occur in all instances, mainly presenting as a longitudinal ssure, because this part of the matrix generates the upper third of the nail plate. Several techniques are available, depending on the width of the band (easily and precisely measured using a dermatoscope). If the band is less than 3 mm wide, the punch biopsy technique is indicated. Using an elevator, the PNF is detached from the nail plate. Two lateral incisions at 45 permit its reclination. Thus, the nail plate is totally exposed, and the origin of the band is visualized (Fig. 4A). The punch is pushed at the base of the pigmented band down to the bone. Avulsion of the proximal third of the nail plate allows easy harvesting of the biopsy specimen. Punching before avulsing is useful when dealing with light-pigmented bands;

Fig. 2. (A) Defect after Mohs surgery for a Bowens disease of the nail bed. (B) Result after secondary intention healing.

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Fig. 3. (AC) Two-punch set technique.

in some instances, the source of pigment is supercial, and proximal avulsion detaches the supercial pigmented upper layers of the matrix epithelium, rending the origin of the band hardly visible. Avulsion also allows visual conrmation that the pigmented source has been removed completely (Fig. 4B). If it has not, further excision with a blade is mandatory, with possible suturing of the matrix with resorbable 5/0 or 6/0 sutures. The proximal portion of the nail is put back in place and sutured to the lateral nail fold. The PNF is returned to its original position, and the lateral incisions are sutured [20]. Histologic examination of the specimen guides the therapeutic attitude.

For a pigmented streak located in the lateral third of the nail plate, the technique of the lateral longitudinal biopsy, as described later, is highly suitable. If the longitudinal melanonychia is more than 3 mm in width, the surgical procedure is more delicate and requires a skilled surgeon. Recently, Haneke proposed a new, enticing technique for large, pigmented bands that formerly were an indication for total ablation of the nail plate (Haneke, personal communication, 2004). This shave biopsy removes the upper layers of the matricial epidermis of the entire pigmented surface allowing the pathologist to view the entire lesion. If the lesion is benign, the postoperative dystrophy is minimal; if the lesion is

Fig. 4. (A) Visualization of the origin of the band after reclination of the PNF. Note that the band is quite proximal, which is unusual. (B) Proximal avulsion of the nail plate reveals that the pigment extends distally.

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malignant, the excision of the whole nail apparatus is mandatory. This technique avoids mutilating surgery in cases of benign, large longitudinal melanonychias. Proximal nail fold biopsy Biopsy sampling of the PNF may be needed in some instances. Depending on the reason, there are three techniques for a biopsy of this area:  When the indication is similar to that for a biopsy elsewhere on the skin, a punch biopsy (not exceeding 3 mm) may be taken on the PNF, taking care that its distal margin is preserved.  The shave biopsy technique also is adequate in this area. Hemostasis is obtained from Monsels solution or aluminum chloride.  When more tissue is required, as in collagen diseases, a crescent-shaped excision, 2 to 3 mm wide is performed from one side of the nail to the other. If the surgeon is concerned about harming the underlying matrix, a Freer elevator may be inserted under the PNF to protect the matrix from inadvertent damage from the scalpel. This amount of tissue allows histology, immunohistology, and electron microscopy to be performed [21]. Healing by secondary intention is rapid (less than 4 weeks), and no dystrophy results. The same method may be applied to recalcitrant chronic paronychia, which is discussed later.

Lateral longitudinal biopsy Lateral longitudinal biopsy allows the study of the whole nail apparatus: PNF, matrix, nail bed, nail plate, and hyponychium. It is the most interesting biopsy technique for the pathologist when disease of the proximal part of the nail apparatus presents as alterations in the surface of the nail plate. It is mandatory that at least one nail exhibit a lateral involvement with marked clinical signs to denote pertinent histologic alterations. The patient must be informed that this type of biopsy will narrow the nail permanently because of the partial amputation of the lateral horn of the matrix. The specimen should not exceed 3 mm in width to avoid any postoperative lateral deviation [22]. The incision begins half way between the cuticle and the crease of the distal interphalangeal joint and runs distally through the PNF, the nail plate, and its bed to the hyponychium. A second incision performed in the lateral nail fold parallels the rst incision and joins it at the tip of the nger. Proximally, the incision curves laterally about 5 mm on the lateral side of the nger to remove the lateral horn of the matrix (Fig. 5A) [20,23]. This removal is especially mandatory with the great toenail. The specimen is detached carefully from the bone with ne scissors. At the proximal tip of the biopsy, the matrix must be preserved, and particular care must be taken to avoid raising the scissors too soon and foreshortening the specimen (Fig. 5B). The defect is reapproximated with

Fig. 5. (AC) Lateral longitudinal biopsy.

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horizontal mattress stitches to recreate a lateral nail fold (Fig. 5C). This technique may be applied to all tumors or longitudinal melanonychias of the lateral third of the nail plate (Fig. 6). Basic surgical procedures Nail avulsion Nail avulsion is a useful technique in nail surgery. It allows clinicians to see what is happening under the nail plate, and it is an adjuvant treatment in onychomycosis because it reduces the fungal mass. Total surgical removal of the nail plate should be discouraged because the distal nail bed may shrink and become distorted dorsally. In addition, the loss of counterpressure induced by the disappearance of the nail plate allows dorsal expansion of the distal pulp, promoting distal embedding. Partial nail avulsion should always be preferred. In some instances (ie, prominent dystrophic total onychomycosis), total avulsion is necessary. Total surgical nail avulsion Total surgical nail avulsion may be performed using either a distal or a proximal approach. Distal approach. A Freer elevator is used to detach the nail plate from its attachments. The elevator is slid gently under the PNF in a backand-forth motion from until the PNF is freed from the nail plate. Then the elevator is pushed under the nail plate until it gives way (ie, it has reached the matrix area to which the nail plate is loosely attached). This anterior-posterior movement is repeated several times from one side of the nail plate to the other to avoid injuring the fragile longitudinal nail bed ridges. Caution must be taken to detach the lateral horns of the nail plate fully by rmly pushing the instrument in the posterolateral angles. Then, one lateral portion of the nail plate is grasped with a sturdy hemostat

and the nail plate is avulsed with an upward, rotating motion [24]. Proximal approach. The proximal approach is advised when the distal subungual area adheres strongly to the nail plate and the hyponychium might be injured by the introduction of the elevator. The PNF is detached as described previously. Then, the elevator is used to reect the PNF and is inserted delicately under the base of the nail plate (loose adherence of the plate to the matrix) and pushed distally up to the hyponychium. This procedure is repeated several times along the entire width of the nail bed. When the nail plate is freed completely, avulsion is unproblematic [24]. Partial surgical nail avulsion The considerable advantage of partial surgical nail avulsion is that a large portion of the normal nail plate (which still exerts a pressure on the underlying soft tissues) remains, reducing the risk of distal embedding. Partial avulsion is absolutely required in the treatment of some types of onychomycosis (ie, longitudinal streaks, lateral disease, dermatophytoma, onycholysis, and onychomycosis caused by molds) [25]. Furthermore, partial nail avulsion is a part of many surgical procedures such as phenolization, treatment of acute paronychia, surgical exploration of the nail bed, and nail matrix tumor. It is performed in the same manner as the distal approach of total surgical nail avulsion, but it is restricted to a portion of the nail plate (Fig. 7). Acute paronychia Surgical treatment of acute paronychia should be considered as a nail emergency because of the pain generated from the condition and because long-standing pressure from the collection onto the matrix may impair the normal regrowth of the nail plate. Incision of the PNF is discouraged,

Fig. 6. (A, B) Excision of a laterally located pigmented band in the way of the lateral longitudinal biopsy.

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appear a bit longer because of a small retraction of the PNF [27]. Fibrokeratoma resection After a distal wing block, the PNF is freed from the underlying nail plate and is reected following two oblique incisions. This procedure exposes the cul-de-sac and the inferior part of the PNF. In most instances, the brokeratoma originates from the most proximal part of the ventral PNF. The tumor should be dissected delicately using ne Iris scissors to its base, where it must be sectioned. It is impossible to damage the matrix, because the nail plate is still in place. The PNF then is laid back and secured with 5/0 stitches or adhesive strips. The nail will regrow without any residual nail plate dystrophy. Incomplete resection leads to recurrence. Phenolization for ingrowing toenails Phenolic ablation is easy to learn and is eective (!3% recurrence). Moreover, phenolization has a low morbidity [28]. The therapeutic aim of this procedure is selective cautery of the lateral horns of the matrix to obtain a permanently narrowed

Fig. 7. (A, B) Partial nail avulsion of yellow mycotic streaks.

because it may result in a deformed eponychium. If the abscess is collected under the PNF or around the base of the nail (runaround), avulsion of the proximal third of the nail plate allows drainage of the pus (Fig. 8). If the collection is in the lateral nail fold, partial avulsion of a lateral strip of nail plate should be performed. Systemic antibiotics are prescribed empirically and adapted according to the culture of the material [26]. Chronic paronychia When medical treatment of chronic paronychia (corticosteroid ointment twice a day for several weeks, as well as intralesional injections of triamcilone acetonide) fails, surgical treatment is required. A Freer elevator is inserted into the proximal nail groove under the PNF to protect the matrix and the extensor tendon. A 15 or 15C surgical blade is used to excise en bloc a crescentshaped full-thickness piece of skin, 4 mm at its greatest width, extending from one lateral nail fold to the other. A bevel incision at 45 prevents the excision of the nail-producing tissues of the PNF responsible for the normal shine of the nail plate (Fig. 9A and B). Complete healing by secondary intention restores the PNF with its cuticle in less than 5 weeks (Fig. 9C). The nail plate will

Fig. 8. (A, B) Partial nail avulsion in acute paronychia.

Fig. 9. (A) Chronic paronychia, before surgery. (B) Excision of the PNF in a crescent shape. (C) Results at 7 months. (Courtesy of Nilton Di Chiacchio, MD, PhD, Sau Paulo, Brazil.)

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nail plate that will eliminate the nail platelateral nail fold conict. This technique may be performed on both sides of pincer nails and immediately suppresses the pincer eect of the lateral edge of the nail plate on the underlying soft tissues [29]. After a distal wing block, the lateral part of the PNF is detached from the underlying nail plate using an elevator. The lateral fth of the nail plate is freed from its underlying attachments using the same elevator, which is slid under the nail plate until it gives way (Fig. 10A). The detached part of the nail plate is split along its length with a nail splitter or a nail nipper down to the base of the nail under the PNF (Fig. 10B). Then, the lateral strip of nail plate is grasped with a sturdy hemostat and, with an upward rotating motion, the nail plate is avulsed (Fig. 10C). If the nail resists removal, failure to free the corners of the horns from the PNF or the nail bed should be suspected. In this case, the elevator should be reinserted beneath the nail plate to focus the eort on freeing the nail plate from the underlying horns of the matrix. For the same reason, the instrument is pushed between the nail folds and the underlying horns of the nail plate [30]. This partial nail avulsion exposes the lateral horns of the matrix at the bottom of

the cavity. The phenolic cauterization of the lateral horns of the matrix is performed with a cottontipped applicator dipped into 88% phenol, which is pushed into the cavity with a rolling motion and is rubbed with back-and-forth movements onto the matrix for 1 minute (Fig. 10D). This procedure is repeated three times with a freshly soaked, cotton-tipped applicator. Particular care is taken to work the phenol into the pocket of the lateral matrix. To assure the eect of the phenol, it is mandatory to work in a bloodless eld [31] using a tourniquet or manual pressure on the lateral side of the toe. Rovipacaine, 2 mg/mL, has a slight vasoconstrictor eect that allows work in a bloodless eld without a tourniquet. Spilling phenol on the periungual tissues should be avoided, because it causes unnecessary burn; any overow should be mopped up promptly with gauze. For beginners, a greasy ointment applied to the perionychium before phenolization may act as a protective device. It is useless to neutralize the phenol with alcohol, because phenol induces coagulation of proteins of the matricial epithelium. Once coagulated, the epithelium becomes impermeable to any liquid. The postoperative course is comfortable for the patient, because phenol has

Fig. 10. (A) Detachment of the lateral part of the nail plate. (B) Splitting of the nail plate. (C) Avulsion of the freed lateral strip of nail plate. (D) Phenolic cauterization of the lateral horns of the matrix.

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a necrotizing eect in addition to the anesthetic effect caused by the phenolic nerve damage at the site of surgery. This anesthetic eect may persist up to 4 months, with the median time being 2 months. The major drawback of this technique is the prolonged oozing from the phenolic burn. This oozing may last up to 6 weeks, although daily soakings and povidone iodine may shorten the period. The ooze should not be mistaken for infection. Dressings are detailed in the next section. Postoperative care Dressing should include a large amount of antibiotic ointment covered with petrolatum gauze to avoid adhesion to the wound and facilitate the removal of the dressing, nonadherent gauze, two to three ne mesh gauzes, and either a tubular elastic net or elastic bands. A narrow bandage (4 cm) is a more exible form of dressing and may apply more precise pressure over the wound. The entire dressing is secured with adhesive tape in a U-shaped fashion to avoid any possibility of its acting as a tourniquet. The dressing should aord light compression that does not compromise blood ow. This bulky dressing will absorb postoperative bleeding and will provide some protection against trauma. The limb should be kept elevated for 48 hours to ease throbbing and to facilitate healing. The patient should wear a sling if the surgery involves a nger; the foot should be elevated for a few days after toe surgery. Therefore the patient should not plan to drive him/herself home [23]. Painkillers should be prescribed for the patient for the next 3 days. Paracetamol usually is adequate, but nonsteroidal anti-inammatory agents such as ibuprofen or naproxen are sometimes more eective. Most patients usually need analgesia for the rst day only. There is almost always some bleeding and soaking into the dressing, so removal may be required on day 2. Sometimes early removal is necessary after 24 hours if bleeding is severe, because the impregnated gauze of the bulky dressing dries and become sti and may cause unpleasant or painful compression. Further care includes application of povidone iodine twice a day. The wound should be covered by a plaster until healing is complete. References
[1] Morgan Serour F, Ben-Yehuda Y, Boaz M. EMLA cream prior to digital nerve block for ingrown

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16] [17] [18]

toenail surgery does not reduce pain at injection of anesthetic solution. Acta Anaesthesiol Scand 2002; 46:2036. Cornelius P, Kendall J, Meek S, et al. Alkalinisation of lignocaine to reduce the pain of digital nerve blockade. J Accid Emerg Med 1996;13:33940. Davidson JA, Boom SJ. Warming lidocaine to reduce pain associated with injection. BMJ 1992;305: 6178. Krunic AL, Wang LC, Soltani K, et al. Digital anesthesia with epinephrine: an old myth revisited. J Am Acad Dermatol 2004;51:7559. Andrades PR, Olguin FA, Calderon W. Digital blocks with or without epinephrine. Plast Reconstr Surg 2003;111:176970. Denkler K. A comprehensive review of epinephrine in the nger: to do or not to do. Plast Reconstr Surg 2001;108:11424. Reichl M, Quinton D. Comparison of 1% lignocaine with 0.5% bupivacaine in digital ring blocks. J Hand Surg 1987;12:3756. Casati A, Vinciguerra F, Scarioni M, et al. Lidocaine versus rovipacaine for continuous interscalene brachial plexus block after open shoulder surgery. Acta Anaesthesiol Scand 2003;47:35560. Lo Martire N, Savastano S, Rossini L, et al. Topical anaesthesia for cataract surgery with photoemulsication: lidocaine 2% versus rovipacaine 1%, preliminary results. Minerva Anaesthesiol 2002;68: 52935. Enrberg M, Kopp S. Rovipacaine for dental anaesthesia: a dose nding study. J Oral Maxillofac Surg 2002;60:100410. Peng PW, Coleman MM, McCartney CJ, et al. Comparison of anaesthetic eect between 0.375% rovipacaine versus 0.5% lidocaine in forearm intravenous regional anaesthesia. Reg Anesth Pain Med 2002;27:5959. Fayman M, Beeton A, Potgieter E, et al. Comparative analysis of bupivacaine and rovipacaine for inltration analgesia for bilateral breast surgery. Aesthetic Plast Surg 2003;27:1003. Mot DL, de Berker DAR, Kennedy CTK, et al. Assessment of rovipacaine as a local anaesthetic for skin inltration in skin surgery. Dermatol Surg 2001;27:43740. Gherardini G, Samuelson U, Jernbeck J, et al. Comparison of vascular eect of rovipacaine and lidocaine on isolated rings of human arteries. Acta Anaesthesiol Scand 1995;39:7658. Salashe S. Surgery. In: Scher RK, Daniel CD, editors. Nails: therapy, diagnosis and surgery. Philadelphia: WB Saunders; 1990. p. 25880. Flarity-Reed K. Methods of digital block. J Emerg Nurs 2002;28:3514. J, Achten G. Techniques de biopsie de longle. Andre Ann Dermatol Venereol 1987;114:88992. Siegle RJ, Swanson NA. Nail surgery: a review. J Dermatol Surg Oncol 1982;8:65966.

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[19] Baran R, Kechijian P. Longitudinal melanonychia (melanonychia striata): diagnosis and treatment. J Am Acad Dermatol 1989;21:116575. [20] Krull E. Biopsy techniques. In: Krull EA, Zook EG, Baran R, et al, editors. Nail surgery: a text and atlas. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 5581. [21] Schnitzler L, Baran R, Civatte J, et al. Biopsy of the proximal nail fold in collagen diseases. J Dermatol Surg Oncol 1976;2:3135. [22] de Berker DAR, Baran R. Acquired malalignment: a complication of lateral longitudinal biopsy. Acta Derm Venereol 1998;78:46870. [23] De Berker DAR. Lateral longitudinal biopsy. Australas J Dermatol 2001;42:1424. [24] Baran R, Hay R, Haneke E, et al. Review of the current antifungal therapy. In: Baran R, Hay R, Haneke E, et al, editors. Onychomycosis: the current approach to diagnosis and treatment. London: Martin Dunitz; 1999. p. 4459.

[25] Baran R, Richert B. Traitement des onychomycoses. Ann Dermatol Venereol 2003;130:126071. [26] Keyser JJ, Littler JW, Eaton RG. Surgical treatment of infections and lesions of the perionychium. Hand Clin 1990;6:13753. [27] Baran R, Bureau H. Surgical treatment of recalcitrant chronic paronychia of the ngers. J Dermatol Surg Oncol 1892;7:1067. [28] De Berker DAR. Phenolic ablation of the nail matrix. Australas J Dermatol 2001;42:5961. [29] Richert B. Dystrophies non-traumatiques: longle . In: Dumontier C, editor. Longle. Monoincarne te Franc graphie de la Socie aise de la Chirurgie de la Main. Paris: Elsevier; 2000. p. 18994. [30] Krull EA. Nail removal. In: Krull EA, Zook EG, Baran R, et al, editors. Nails surgery. a text and atlas. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 3948. [31] Baran R, Haneke E. Matricectomy and nail ablation. Hand Clin 2002;18:6936.

Dermatol Clin 24 (2006) 323328

Ultrasound Imaging of Nails

Ximena Wortsman, MDa, Gregor B.E. Jemec, MD, DMScb,*
b

Imaging Department, Hospital del Professor, Alameda 4860, Santiago, Chile Department of Dermatology, University of Copenhagen, Roskilde Hospital, Kgevej, DK-4000 Roskilde, Denmark

Nails have functional and aesthetic importance to patients [1]. Today, nail diseases are diagnosed mainly based on clinical examination, although biopsies and scrapings also can provide clinically signicant information. Biopsies are not perceived positively by most patients, however, and may have negative cosmetic consequences because of scarring. There is an interest in noninvasive methods to supplement clinical examination of the nails. Traditionally, magnetic resonance (MR) scanning has been used for this, but because this requires specialized equipment it is not broadly available [2]. Ultrasound may provide an appropriate and more widely available alternative. The nail apparatus consists of well-dened tissue of dierent densities and as such is well suited for studies with ultrasonography. This technique may provide a wealth of dynamic new information about nail physiology without the need for biopsies. Previous studies used ultrasound to measure nail plate thickness, nail plate volume, and to describe normal nail anatomy [35]. It also has been shown to be useful for examination of various nail diseases, such as nail abnormalities in systemic lupus erythematosus, systemic sclerosis, and psoriasis, and in patients with subungual tumors [6]. Ultrasound measurement of the distance between the nail and the underlying bone also has been suggested as a possible method for quantication of disease severity in psoriasis [7]. Most studies have been done with traditional high-frequency ultrasound, developed in the 1980s, for the study of human skin. This method has a particularly clear trade-o between penetration

and resolution; the resolution of the images poses a limitation of this technique. New techniques have become available, however, that allow instantaneous integration of several overlapping ultrasound scans taken at dierent angles to produce a compound image with better information content. This technique is called real-time spatial compound imaging. This method reduces artifacts and provides a sharper image [8]. In addition to noninvasive imaging, it also should be remembered that compound ultrasound images only provide an abstract picture of reality. Ultrasound imaging contains dierent information than ordinary imaging with light; therefore all images are abstractions to some degree. These abstractions do allow us to speculate about the physical properties of the tissue and the tissue dynamics and to follow changes over time, which is something that has not been achieved previously in the study of nails.

Principles and normal ultrasound anatomy Ultrasound imaging is based on the time delay that occurs when ultrasound beams are reected from dierent tissues. The clarity of the image depends on the structure of the tissue, its echogenicity, and several technical factors. Modern diagnostics usually are performed with the new generation of high-resolution ultrasound machines that can process data over 9216 channels per image frame with dynamic ranges of 170 db, and with the appearance of highfrequency compact linear transducers that can reach frequencies of 15 MHz, with the capability for detecting several dierent parameters. The composition compound technology, which electronically combines images recorded from dierent
derm.theclinics.com

* Corresponding author. E-mail address: rsgrj@ra.dk (G.B.E. Jemec).

0733-8635/06/$ - see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2006.03.014

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Fig. 2. Normal ultrasound anatomy of the nail apparatus. Fig. 1. Ultrasound of the nail unit. Note the shape of the 157 MHz compact linear probe and the thickness of the pad of gel that permits the appropriate transmission to see the nail.

protective barrier at the distal end of the nail bed. All these structures can be visualized by ultrasound examination (Fig. 2). Normal ultrasound anatomy The nail ultrasonographic unit can be divided in three segments  the plate (dorsal and ventral)  the matrix  the nail bed The dorsal and ventral aspects of the nail plate are viewed as bilaminar, hyperechoic (white), parallel bands with a virtual hypoechoic (dark gray) space between them called the interplate space. The nail bed appears as the hypoechoic region under the plate, and the nail matrix is the echoic (soft gray) region at the proximal end of the nail bed [5,9]. The nail bed is an extremely vascular and longitudinally ridged structure; it receives vascularity from the ulnar and radial digital arteries. Branches of these vessels course around the distal phalanx and penetrate brous septae to form a proximal and distal anastomotic arcade with the basal layer of the nail bed. Multiple arteriovenous anastomoses and myoneural glomus units are present within the nail bed. Capillaries are abundant in the germinal matrix and an arcade of vessels in the distal nail bed communicates with a similar arcade from the palmar pulp vessels. Two large venous channels emerge from the lateral aspect of the nail bed and proceed dorsally to converge with the dorsal venous drainage system of the nger just distal to the distal interphalangeal joint. The lymphatic vessels follow the same route and have a similar network. The use of Color Doppler permits the live viewing of the vascularity of the nail bed,

angles of view, generally permits more sharpness, resolution, contrast, and extended eld of view. The presence of blood ow is studied with the use of Color Doppler and Power Angio, which allow for the detection of vessels and ow. Ultrasound can give information on the anatomy and pathologic processes in real time with the possibility to measure and calculate parameters of thickness and volume and blood ow, with an accuracy of approximately 100 mm (depending on the device used). In practical terms, the visualization of the nail structure requires the application of a pad of gel over the nail surface (Fig. 1). The ngernail unit consists of the nail plate, the proximal nail fold (eponychium), the lateral nail fold (perionychium), the distal nail fold (hyponychium), and the matrix. The nail plate is a multilayered, stacked sheet of cornied cells derived from anucleate onychocytes that arise from the germinal matrix epithelium of the nail bed. The eponychial fold covers the softer and less cornied proximal nail plate. The cells of this proximal plate are not completely anucleated; they project a white color because of the parakeratosis that occurs at the level of the germinal matrix. The sterile matrix epithelium does not undergo parakeratosis; therefore, the nail plate assumes its color from the underlying, wellvascularized nail bed. The hyponychium represents the junction of the terminal nail bed with the skin of the ngertip. The nail plate becomes nonadherent at this point and extends from a variable distance over the tip of the nger. The hyponychium serves as an important mechanical

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Fig. 3. Color Doppler image of the nail that shows the normal vessels in the nail bed.

Fig. 4. Glomus tumor. Between marks there is a solid hypoechoic nodule that erodes the bone margin of the distal phalanx.

specically arterial and venous vessels that may be as small as 12 mm in diameter. Additionally, with the use of power Doppler we can identify the characteristic spectral curves of ow for each vessel. Under the nail bed there is a regular hyperechoic line corresponding to the bone margin of the distal phalanx. In women with cosmetic acrylic nails there is no limitation for using ultrasound in the study of the nails, because the articial nail is distinguished easily from the normal nail plate. Bloodow (Color Doppler utility) Color Doppler identies the presence of ow, and is based on the determination of frequency shift of the ultrasonic beam. This method makes it possible to study the blood ow surrounding the nail apparatus (Fig. 3). Detection of objects in movement is important in the study of inammation and tumors. The Color Doppler, associated to the pulse Doppler, allows the identication of the nature of the ow: arterial, venous, or arteriovenous shunt. It also is possible to describe the presence of a dominant vessel in vascular lesions.

The Power Angio function, which is another vascular application of ultrasound, uses a color map for showing the power or amplitude of the Doppler signal. It reduces noise and permits a higher eective gain setting, thereby achieving more sensitive ow detection. A consequence of this function is that it does not allow for discrimination between arterial or venous vessels. Power Angio can, however, be useful in the identication of vascular lesions when reduced ow is detected. The use of ultrasound contrast medium in soft parts is being studied. These contrast media consist of lipid-coated microspheres lled with octauoropropane gas. The microspheres average approximately 1.13.3 mm (in vitro measurements) in size and are smaller than erythrocytes (68 mm). The microspheres are injected or infused into the body. When exposed to ultrasound waves the microspheres resonate and create a strong echo. The dierence in density between the gas-lled bubbles and the blood around them creates an increased level of contrast visible in the resulting ultrasound image. Activated contrast enhances images of the inner edges of the vessels or the entire lumen of the vessels, producing an improved

Fig. 5. Glomus tumor with Color Doppler. This is the same tumor as Fig. 4. The solid nodule has visible vascularity.

Fig. 6. Mucous cyst at the base of the nail. Anechoic cystic lesion present at the dorsum of the nger.

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Fig. 7. Subungual inammation. Left (abnormal) to right (normal) comparison of enlargement of the nail bed secondary to a dog bite. Note the plate irregularity at the dorsal plate at the site of the lesion. Other causes of inammation show a similar picture.

image that may enable physicians to better diagnose diseases.

Glomus tumors Ultrasound can identify a glomus tumor as a solid hypoechoic region at the nail bed. The tumor commonly produces a localized defect or erosion at the hyperechoic bone margin of the distal phalanx [6]. The use of Color Doppler and Power Angio can demonstrate the presence of a localized, enlarged vessel inside the tumor, which usually represent arterial low-resistance neovasculature (Figs. 4 and 5). In normal nails, vascularity also can be seen in Color Doppler studies and therefore must be dierentiated from tumor vascularity. Imaging of the vasculature can be enhanced by using ultrasound contrast media (Fig. 6). Pseudoerosions of the bone margin of the distal phalanx, however, also are seen in some normal anatomic variants, and in these cases left-to-right comparative studies are useful. As a general principle in ultrasound examination, left-to-right comparisons are useful in the study of neoplasms, unilateral trauma, or infection.

Nail pathology Tumors Ultrasound is well suited to the identication of tumors with characteristic changes of density, unique ow, or a cystic component. The subungual hematoma or abscess also is detected as a uid anechoic (black) region at the nail bed, and may contain echoes or septations inside. On occasion, uid collection dissects the planes of the tumor and extends to the rest of the distal nger, often beginning at the lateral borders of the nail bed and producing a generalized edema of the distal nger that can mask the organized uid collection of the tumor during a conventional clinical examination. Unfortunately, ultrasound has not proved useful in the identication of solid malignant tumors, such as carcinoma or melanoma, which usually appear as nonspecic hypoechoic areas. Alternative methods are therefore recommended for the diagnosis of these growths.

Fig. 8. Focal dystrophy in psoriasis. Psoriatic hyperkeratotic plaque only partially aects the deep plate.

Fig. 9. Extensive dystrophy in psoriasis Absence of definition of the ventral plate in a psoriatic patient. Note also subungual edema.

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Fig. 11. Lost fragment of a nail plate causing inammation.

Fig. 10. Candidiasis of the nail with a loss of plate architecture and extensive subungual inammation.

The vascular component may be made more clearly visible by the use of contrast media. Mucous cyst This cyst appears as an anechoic (black) area of the ultrasound picture; it appears connected to the base of the nail. The mucin occasionally can be heterogenous in its echostructure and therefore may contain smaller echoes. No vascularity is seen inside the cyst normally, which can help dierentiate it from the glomus tumors. The main dierential diagnosis is other cystic lesions, such as synovial cyst, that can be either connected to the distal interphalangeal joint or located around the extensor tendon sheath. Another dierential diagnosis is solid lesions (eg, giant cell tumor) that frequently are located around the tendons. Inammatory changes The detection of inammation at the nail can be seen as enlargement of the nail bed with a decrease in echogenicity (Fig. 7). In a leftto-right comparison, the operator often can detect subclinical inammatory changes. The use of Doppler and Power Angio permits visualization of a diusely increased vascularity (not localized as the glomus tumor) and an absence of erosions of the bone margin of the distal phalanx. Inammation also may increase the convex shape of the bilaminar hyperechoic plates as a result of the extrinsic compression by the swollen tissue. Nail psoriasis The use of ultrasound as a noninvasive method for psoriatic nail study oers an advantage over clinical examination. Clinically imperceptible

changes can be found in early disease, particularly in studies of the ventral nail plate. The hyperechoic deposits seen at the plate correlate with the subungual hyperkeratosis, and in the advanced stages of the disease the involvement of both plates is visible. With advanced disease there is an enlargement of the nail bed compared with healthy control individuals. There are four types of morphologic changes described in the psoriatic nails, from minor to major: focal hyperechoic involvement of the ventral phalanx without involvement of the dorsal plate (Fig. 8), loosening of the borders of the ventral plate, the appearance of wavy plates, and the loss of denition of both plates (Fig. 9). The use of ultrasound opens the possibility of monitoring disease progression or treatment [7,10].

Candidiasis and fungal infections Fungal involvement of the nail unit produces a signicant increase in the thickness of the nail bed greater than that observed with nail psoriasis; diuse thickening of the nail plate also occurs (Fig. 10). Just as in psoriasis, however, these can merge in one thick plate in ultrasound. More observations will have to be made in this eld in terms of detecting early changes that may be specic to fungal involvement.

Trauma Traumatic nail deformities, such as nail lacerations or subsequent scarring, can cause problems of continuity between the nail plate and the nail bed. Ultrasound can detect the exact site of laceration and its extension, and it can determine the position of dislocated nail plate fragments following trauma (Fig. 11). Associated damage of the insertion of the extensor tendon at the base of the distal phalanx also can be identied.

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Ultrasound can be particularly useful when general edema and pain complicate the clinical examination. Discussion The use of a noninvasive method for the study of human nails oers several advantages over existing research methodology: it allows for longitudinal studies, it provides information about subcutaneous processes, and it allows for quantication of blood ow. The use of ultrasound is particularly appropriate for the study of nail morphology because of the dierences in tissue density. Furthermore, the use of ultrasound is convenient because appropriate technology is readily available in most secondary and tertiary treatment centers. Characteristic nail plate morphology is well described. There is congruence between several studies and congruence between ultrasound imaging and known anatomy. The ability to study the nail in real time with no artifacts and with a high resolution of the nail unit and its surrounding structures is an advantage for the study of the nail pathology. Vascular applications and the capability to determine the nature of a lesion were not possible twenty years ago. Further studies including more diseases and a larger patient population are required to better determine specic morphologies of diseases aecting the nail unit. In particular, the use of contrast medium can provide us with specic diagnoses, consideration of washout curves with relation to contrast, and a better description of the vascular morphology of the lesions. Summary Based on the principle of reected sound waves, ultrasound imaging provides an abstract picture of tissue morphology that may be used to diagnose a wide range of diseases. The nail apparatus contains tissues of various echogenicities, and is thus well suited for ultrasound examination. Moreover, ultrasonography is widely available and is noninvasive, and may therefore be used

for longitudinal studies of tissues and diseases. There are methodological limitations in the resolution of ultrasound pictures, but on the other hand, the method allows assessment of functional parameters, such as blood ow. Characteristic ultrasound pictures can be seen in psoriasis, cysts, glomus tumors, and other nail diseases. Furthermore, ultrasound technology allows for the noninvasive examination of trauma and the identication of dislodged nail fragments. Imaging of vasculature may be enhanced by the use of contrast media developed for ultrasonography. Ultrasound examination can contribute significantly to noninvasive examination of the nail apparatus, and may be used to visualize and quantify morphologic and functional aspects of nail biology. References
[1] Rich P. Nail cosmetics and esthetics. Skin Pharmacol Appl Skin Physiol 1999;12:1445. [2] Goettmann S, Drape JL, Idy-Peretti I, et al. Magnetic resonance imaging: a new tool in the diagnosis of tumours of the nail apparatus. Br J Dermatol 1994;130:70110. [3] Finlay AY, Western B, Edwards C. Ultrasound velocity in human ngernail and eects of hydration: validation of in vivo nail thickness measurement techniques. Br J Dermatol 1990;123:36573. [4] Hirai T, Fumiiri M. Ultrasonic observation of the nail matrix. Dermatol Surg 1995;21:15861. [5] Jemec GB, Serup J. Ultrasound structure of the human nail plate. Arch Dermatol 1989;125:6436. [6] Ogino T, Ohnishi N. Ultrasonography of a subungual glomus tumour. J Hand Surg [Br] 1993;18: 7467. [7] Wortsman X, Holm EA, Jemec GB, et al. Fifteen MHz high resolution ultrasound of the psoriatic nail. Revista Chilena de Radiologia 2004;10(1):611. [8] Holm EA, Wortsman X, Gniadecka M, et al. Real time spatial compound imaging of skin and skin lesions. Skin Res Technol 2004;10:2331. [9] Wollina U, Berger M, Karte K. Calculation of nail plate and nail matrix parameters by 20 MHz ultrasound in healthy volunteers and patients with skin disease. Skin Res Technol 2001;7:604. [10] Jemec GBE, Gniadecka M. In vivo studies of normal and psoriatic nger nails using high frequency ultrasound. Turk J Derm Pathol 1999;8:15.

Dermatol Clin 24 (2006) 329339

Pigmented Nail Disorders

, MD*, Nadine Lateur, MD Josette Andre
Department of Dermatology, CHU Saint-Pierre, Brugmann, HUDERF, 129, Bd de Waterloo, B-1000 Brussels, Free University of Brussels, Belgium

Denition Nail pigmentation is dened 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 dierence 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 dier from melanocytes located elsewhere in the skin not

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 rst and second layers [3]. When melanocytes are activated, melanin-rich melanosomes are transferred by way of dendrites to dierentiating 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 24 mm), and sharp or blurred borders [4]. Extension of pigmentation to the skin adjacent to the nail plate involving the nail folds or the ngertip 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.
derm.theclinics.com

* Corresponding author. E-mail address: josette_andre@stpierre-bru.be ). (J. Andre

0733-8635/06/$ - see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2006.03.012

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than 50. Bands are more frequently located in the digits used for grasping (thumb, index nger, and middle nger), 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 classied 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 aected 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

A frequent cause of LM is chronic traumatism. Repeated trauma can be seen in the toenails of patients who have ill-tting shoes or overriding toes. It often is symmetric and aects the lateral and external part of the fourth or fth 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 inammatory 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 inammatory 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. 2. Racial melanonychia with pseudo-Hutchinson sign.

Fig. 3. Frictional LM and horn in a fourth toenail.

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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 diusible black pigment (Trichophyton rubrum var nigricans) (Fig. 5). In some cases presenting with paronychia (Candida spp) melanocytes are stimulated by inammation 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 brous histiocytoma, and verruca vulgaris are other examples [4].

Fig. 6. LM aligned with a myxoid pseudocyst.

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 aect ngernails and toenails. In

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 planustype 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 aected on the hands and the feet. In terms of drug intake, chemotherapeutic agents yield the rst place but other drugs have also been implicated (Box 1) [1517]. 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

Fig. 5. Black longitudinal dyschromia caused by Trichophyton rubrum var nigricans.

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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 Amorolne 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. 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 aects white adults and usually starts between 20 and 40 years of age. The most distinguishing clinical nding 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 ngers than the toes (Figs. 8 and 9). A pseudo-Hutchinson sign may be present. Mucosal pigmented macules are an important clue in the dierential 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. 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. 8. Laugier-Hunziker syndrome: multiple bands of melanonychia in a 50-year-old patient. (Courtesy of ` ge, Belgium.) B. Richert, MD, Lie

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Fig. 9. Laugier-Hunziker syndrome: pigmented macules on the tongue (patient shown in Fig. 8). (Courtesy of ` ge, Belgium.) B. Richert, MD, Lie

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 ngers, and big toes. The mean age at diagnosis is 60 to 70 years. Acrolentiginous melanoma is the most frequent type; supercial-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 sta. Nail plate pigmentation, usually an LM, is the rst 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

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 dened 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 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 ngers, 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.

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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 nger, 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 aected 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

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 ve-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].

Dierential diagnosis Black nail Hematoma is the main dierential 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 conrmation 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 o the nail surface. In subungual linear keratotic melanonychia, the pigmented band consisting of a subungual

Fig. 12. Nail apparatus melanoma with Hutchinson sign in an 80-year-old woman. (Courtesy of P. Bruderer, MD, Brussels, Belgium.)

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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 Clinical examination should focus on patient phototype and the number and location of the aected 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 identied 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 conrm melanic pigmentation (positive Fontana staining) (Fig. 14) and location within the nail plate. The dierence between ferric and melanin pigment is seen easily by ultrastructural techniques [31]. Biopsy It is important to emphasize that the precise nature of the lesion responsible for LM can be conrmed only by matrix biopsy. Clinicians

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 conned 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.

Management Confronted with a single-digit LM, the diagnosis of melanoma should always be kept in mind. Clinicians should consider the following:

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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 dicult 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]. 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

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 dicult for several reasons. To start, a poor-quality biopsy may not be representative of the tumors. The biopsy can be too small or too supercial, 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 supercial layers

Fig. 15. Junctional nail matrix nevus.

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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 pathologists 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 dees 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 bands 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, heminail 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 dicult 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

then be removed, allowing inspection of the surrounding matrix and nail bed. Last, the cylinder of tissue is removed by cutting it o 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 reected 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 ap 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

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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 inuence the future evidence-based management of NAM.

Summary LM can be the rst 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
JL, et al. Tumours of the [1] Baran R, Haneke E, Drape 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. 60730. [2] Baran R, Perrin C. Linear melanonychia due to subungual keratosis of the nail bed: report of two cases. Br J Dermatol 1999;140:7303. [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):4627. [4] Baran R, Kechijian P. Longitudinal melanonychia (melanonychia striata): diagnosis and management. J Am Acad Dermatol 1989;21:116575. [5] Baran R, Kechijian P. Hutchinsons sign: a reappraisal. J Am Acad Dermatol 1996;34(6):8790. [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):76571. J. Melanonychia: diagnosis and [7] Lateur N, Andre treatment. Dermatol Ther 2002;15:13141. [8] Aratari E, Regesta G, Rebora A. Carpal tunnel syndrome appearing with prominent skin symptoms. Arch Dermatol 1984;120:5179. [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:S1878. [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; 80:3702. J, Stene JJ, et al. Longitudinal mela[12] Sass U, Andre nonychia revealing an intraepidermal carcinoma of the nail apparatus: detection of integrated HPV-16 DNA. J Am Acad Dermatol 1998;39(3):4903. [13] Cribier B, Leiva Mena M, Rey D, et al. Nail changes in patients infected with human immunodeciency virus. Arch Dermatol 1998;134:121620. [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):S1124. [15] Kar HK. Longitudinal melanonychia associated with uconazole therapy. Int J Dermatol 1998;37: 71920. [16] OBranski 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):85961. [17] Piraccini BM, Tosti A. Drug-induced nail disorders. Incidence, management and prognosis. Drug Saf 1999;21(3):187201. J, Belaich S. Longi[18] Goettmann-Bonvallot S, Andre tudinal melanonychia in children: a clinical and histopathologic study of 40 cases. J Am Acad Dermatol 1999;41(1):1722. aute-Labre ` ze C, Bioulac-Sage P, Ta eb A. Longi[19] Le tudinal melanonychia in children: a study of 8 cases. Arch Dermatol 1996;132:1679. [20] Thai KE, Young R, Sinclair RD. Nail apparatus melanoma. Australas J Dermatol 2001;42(2):7181. [21] Stevens NG, Li 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;45:6913. [22] Kato T, Suetake T, Sugiyama Y, et al. Epidemiology and prognosis of subungual melanoma in 34 Japanese patients. Br J Dermatol 1996;134:3837. [23] Metzger S, Ellwanger U, Stroebel W, et al. Extent and consequences of physician delay in the diagnosis of acral melanoma. Melanoma Res 1998;8:1816. [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):26974. [25] Baneld 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;139:2769. [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):8992. [27] Antonovich DD, Grin C, Grant-Kels JM. Childhood subungual melanoma in situ in diuse nail melanosis beginning as expanding longitudinal melanonychia. Pediatr Dermatol 2005;22(3):2102.

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[28] Dawber RPR, Colver GB. The spectrum of malignant melanoma of the nail apparatus. Sem Dermatol 1991;10(1):827. [29] Ronger S, Touzet S, Ligeron C, et al. Dermoscopic examination of nail pigmentation. Arch Dermtol 2002;138:132733. [30] Kawabata Y, Ohara K, Hino H, et al. Two kinds of Hutchinsons sign: benign and malignant. J Am Acad Dermatol 2001;44(2):3057. J, Laporte M. Nails in light and [31] Achten G, Andre electron microscopy. Semin Dermatol 1991;10: 5464. [32] Glat PM, Spector JA, Roses DF, et al. The management of pigmented lesions of the nail bed. Ann Plast Surg 1996;37(2):12534. J, Goettmann-Bonvallot S. Longitudinal [33] Andre 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;19:4259.

[35] Haneke E, Baran R. Longitudinal melanonychia. Dermatol Surg 2001;27(6):5804. [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):54453. [37] Baneld 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):989. [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):26973. [40] Gershenwald JE, Thompson W, Manseld 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):97683.

Dermatol Clin 24 (2006) 341347

The Nail in Systemic Diseases

Antonella Tosti, MD*, Matilde Iorizzo, MD, Bianca Maria Piraccini, MD, PhD, Michela Starace, MD
Department of Dermatology, University of Bologna, Via Massarenti 140138, Bologna, Italy

Although abnormalities of the nails have been reported in dierent systemic disorders, most of these abnormalities are nonspecic. This article reports and discusses only a limited number of nail signs that may provide clues to clinicians for the diagnosis of systemic disorders. When evaluating nails for clues, it is important to examine all of the nails as well as the surrounding nail tissues. Diagnostic imaging work-up is often required to conrm the diagnosis. Forensic Medicine The slow growth rate of nails makes it possible to use nail clippings to detect prior exposure to drugs or toxins [1]. Compounds that can be measured in the nails are listed in Box 1. Some toxins, such as arsenic and thallium, can cause nail abnormalities that can be recognized easily by the physician (ie, transverse white lines of true leukonychia, called Mees lines, aecting most or all ngernails). Mees lines typically appear 2 to 6 weeks after an acute episode of arsenic or thallium poisoning. Multiple parallel lines reecting repetitive exposure to the poison are seen occasionally. Mees lines must be distinguished from striate true leukonychia caused by trauma and transverse apparent leukonychia. The lines of striate true leukonychia caused by trauma (frequently observed in ngernails of women secondary to manicure) are more evident in the central part of the nail plate, parallel the proximal nail fold edge, and often spare the lateral portion of the nail. Transverse apparent leukonychia (Muehrckes lines) diers from Mees lines in that the bands fade with compression of the nail plate.
* Corresponding author. E-mail address: tosti@med.unibo.it (A. Tosti).

The nail plate also can be used for genetic analysis (DNA extraction for genotyping) and for diagnostic and therapeutic purposes in general and environmental medicine. Defective hepatic metabolism of alcohol and drugs can be predicted by genotyping alcohol dehydrogenase in nail clippings. Moreover, nail clippings can be used for assessing the long-term control of blood glucose levels in diabetic patients. The presence of furosine and fructose-lysine in the nails indicates nonenzymatic glycosylation and therefore is indicative of episodes of diabetic hypoglycemia in the previous 3 to 5 months. The measurement of creatinine from the nail plate also can be used for dierentiating acute from chronic renal failure because the distal nail clippings would contain elevated levels of creatinine. Increased levels of porphyrins in ngernails have been detected in patients who have porphyria cutanea tarda. The DNA of the hepatitis B virus can be detected from nail clippings of patients positive for hepatitis B surface antigen. Koilonychia In koilonychia, the nail plate is at and spoonshaped because of the upward eversion of its lateral edges. Although koilonychia, which occurs frequently in the toenails of children, has been reported in association with a large number of systemic conditions, the only disorder that routinely should be ruled out in adults is severe iron deciency associated with anemia [2]. Clubbing Clubbing is caused by enlargement of the soft tissues of the distal digit. The nail plate is enlarged
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0733-8635/06/$ - see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2006.03.005

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Box 1. Substances that can be measured in the nails Alcohol dehydrogenase Amphetamine/methamphetamine Cannabinoids Chloroquine Cocaine/benzoylecgonine Creatinine Doping substances Fluconazole Furosine/fructose-lysine Hepatitis B virus/hepatitis B surface antigen Itraconazole Ketoconazole Morphine/dextromoramide Nickel Nicotine/cotinine Porphyrins Terbinane Trace elements (aluminum, arsenic, cadmium, chromium, copper, gold, iron, lead, manganese, mercury, selenium, silver, thallium, zinc)

Box 2. Systemic conditions associated with clubbing Bronchopulmonary diseases Bronchiectasis Chronic infections (abscesses of the lungs, tuberculosis) Neoplasms (primary or metastatic cancers, pleural tumors) Primary diseases: pulmonary brosis, cystic brosis, sarcoidosis Cardiovascular diseases Aortic aneurysm Bacterial endocarditis Congenital heart disease Congestive cardiac failure Gastrointestinal diseases Cancers Infestations (amoebiasis, ascariasis) Inammatory bowel disorders Liver disorders (chronic active hepatitis, cirrhosis) Infection Arterial graft sepsis (clubbing limited to perfused extremities) HIV infection Endocrine Hypertrophic osteoarthropathy Secondary thyroid disease (primarily hyperthyroidism)

and excessively curved (Fig. 1), with greater than 180 widening of the angle between the proximal nail fold and the nail plate (Lovibonds angle). In congenital heart diseases, clubbing is associated with cyanosis; the regional distribution of the clubbing may provide clues for diagnosing the specic disorder. Secondary clubbing can be unilateral or bilateral. Unilateral clubbing is more frequent with neurologic (hemiplegia) and vascular disorders. Bilateral clubbing has been associated with

Fig. 1. Finger clubbing.

pulmonary, cardiac, gastrointestinal, infectious, and endocrine diseases (Box 2). In Crohns disease and ulcerative colitis, the hyponychial angle can be signicantly correlated with disease activity. Finger clubbing in patients who have Crohns disease has been reported to regress after resection of macroscopic disease. Numerous hypotheses about the pathophysiology of clubbing have been proposed. Some authors hypothesize that clubbing is associated with increased blood ow in the local arteriovenous anastomoses [3]. This increased blood ow is provoked by alterations in vascular dynamics that allow blood to bypass capillaries. In actuality, the anastomoses are neurohumoral end organs that

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allow the autonomic nervous system to regulate the digital microcirculation. In clubbing associated with inammatory bowel disorders, the focal stimuli include mucosal inammatory changes and brosis mediated by the vagus nerve and possibly other autonomic pathways acting as the aerent arc of a nger-clubbing reex [4]. Clubbing usually develops over years but sometimes may develop subacutely, generating pain. In evaluating a patient who has new-onset clubbing, it is important rst to verify that the patient has true clubbing and not pseudoclubbing. Pseudoclubbing usually involves only a single digit and often results from the presence of a subungual mass. At rst glance, the digit may appear to be truly clubbed, but on closer inspection the prole angle probably will be normal.

Fig. 2. Terrys nail.

Parrots beak nails Parrots beak nails are observed in systemic sclerosis as a consequence of the atrophy of the ngertip. The free margin of the nail plate is overcurved, simulating the beak of a parrot, but if the patient trims the nail plate close to the line of separation from the nail bed, no abnormality is observed; soaking the nails in tepid water results in a similar appearance.

frequently seen in chronic congestive heart failure and adult-onset diabetes mellitus.  Muehrckes nails are seen in patients who have hypoalbuminemia (nephrotic syndrome: albumin !2.2 g/100 mL). The nail has multiple transverse whitish bands that are parallel to the lunula and disappear when the serum albumin level returns to normal. The bands most commonly are observed in the second, third, and fourth ngers. Muehrckes lines also are a common side eect of antineoplastic drugs and are seen especially in patients undergoing combined chemotherapy.  Half-and-half nails are detected in approximately 10% of patients who have chronic renal disease (uremic patients). The leukonychia aects the proximal half of the nail, and all nails are involved. Yellow nails Yellow nails are commonly observed with yellow nail syndrome, a chronic disorder usually involving all 20 nails and characterized by an arrest or a reduction in the nail growth (less than 0.2 mm/wk) resulting in nail thickening, hardening, and discoloration (Fig. 3) [6]. Nail color is variable from pale yellow to orange. Nails are also longitudinally overcurved with a disappearance of the cuticle. Secondary onycholysis leading to total nail plate detachment is frequent, as is onychomadesis. Colonization by Pseudomonas aeruginosa may produce a green-to-black discoloration of the nail plate. The slow growth rate that characterizes the yellow nail syndrome results in a proportional or increased nail thickness, but total nail production is not changed: a slowed growth produces an altered orientation of the nail plate cells. In typical nail syndrome, lymphedema and respiratory disturbances (sinusitis, bronchitis,

Leukonychia Leukonychia [5] means white nails, and it can be caused by the presence of parakeratotic cells within the ventral portion of the nail plate, as in true leukonychia, which is caused by diseases that disturb distal nail matrix keratinization. It also can be caused by abnormalities in the nail bed vascularization, as in apparent leukonychia, which does not move distally with nail growth and fades with pressure. Apparent leukonychia is commonly a sign of systemic disorders, although it is not specic because it can also occur in normal individuals, especially with aging. Depending on the clinical presentation, apparent leukonychia can be divided into three dierent types:  Terrys nails are as a common sign of liver cirrhosis, occurring in up to 82% of patients. The leukonychia aects the whole nail except for a 1- to 2-mm distal band (Fig. 2). All nails are uniformly involved. Terrys nails also are

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Fig. 3. Yellow nail syndrome. Fig. 4. Argyria.

bronchiectasis, pleural eusion) usually are associated with the nail abnormalities. Because the nail abnormalities are not always present, the presence of typical nail alterations should be considered an absolute indication of the diagnosis. The time between the development of the systemic manifestations and nail abnormalities may range from months to years. In patients who have paraneoplastic yellow nail syndrome, the nails often return to normal when the tumor regresses. The pathogenesis of yellow nail syndrome is still unknown, but a congenital abnormality of the lymphatic vessels may be involved. Functional defects in the lymphatics also have been detected by lymphangiography in aected patients, and this association explains why the nail abnormalities improve or regress when the respiratory disease is treated successfully. A relation between nail changes and abnormal lymphatic vessels also is suggested by the nail pathology that reveals ectatic lymphatics in the nail bed and matrix dermis. Yellow nail syndrome has also been reported in infancy, and a case of acquired idiopathic yellow nail syndrome has been observed in a pregnant woman who delivered a term female rstborn infant who had an unexplained nonimmune fetal hydrops and recurrent left chylothorax at 4 weeks of age.

silver salts to black metallic silver under the inuence of ultraviolet rays may explain the pathogenesis of pigmentation involving both skin and nails. Minocycline also is responsible for a blue-gray pigmentation of the nail plate. Antimalarial agents can cause a blue-brown pigmentation.

Splinter hemorrhages Splinter hemorrhages appear as dark red, thin, longitudinal lines; the shape is caused by the longitudinal orientation of nail bed capillaries. Splinter hemorrhages are possible indicators of systemic diseases when they appear simultaneously in most or all nails and are located in the proximal portion of the nail plate (Box 3) (Fig. 5). In bacterial endocarditis, splinters are generally painful. Their origin is not completely known, but they are probably caused by microemboli. They most frequently are localized in the distal

Box 3. Systemic disorders characterized by splinter hemorrhages Amyloidosis Arterial emboli Bacterial endocarditis Bergers disease Chronic mountain sickness Cyanotic congenital heart disease Oslers disease Periarteritis nodosa Scurvy Trichinosis Thrombocytopenia Vasculitis

Blue nail Blue discoloration of the nail plate has been described in Wilsons disease and argyria. In Wilsons disease the blue discoloration involves the lunula and fades proximally, being more intense at the distal margin of the lunula. In argyria, a slate-blue permanent pigmentation of the proximal nail bed is typical and is more evident in the lunula (Fig. 4). The reduction of

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Fig. 5. Proximal splinter hemorrhages.

Fig. 6. Carpal tunnel syndrome.

part of the nail plate and can be associated with Oslers nodes, tender red nodules localized around the nail unit, also possibly caused by septic microemboli. In trichinosis, 10% to 30% of patients develop splinters during the larval migrating phase of the infestation. These splinters are painful. In chronic mountain sickness and in cyanotic congenital heart disease, splinters involve the entire nail bed, probably because of raised hemoglobin levels. In alpinists, splinters are a common problem because of the high altitude combined with recurrent nger trauma. Drugs that impair the nail bed blood vessels also may damage the nail unit with splinter hemorrhages. Splinter hemorrhages are, in fact, possible side eects of antithrombotic agents and anticoagulants, cancer chemotherapeutic agents, tetracyclines, and ganciclovir.

this stage, atrophy of the thenar eminence is present and can be detected by observing the two palms close together. Neurologic examination and electromyography conrm the diagnosis. Digital metastases are rare and usually painless; metastases in the ngers most commonly are associated with pulmonary neoplasms and those in the toes with genitourinary neoplasms [7]. Digital metastases may be the rst sign of the malignancy and are associated with a very poor prognosis. A radiologic examination is mandatory to conrm the diagnosis.

Bazexs acrokeratosis Bazexs acrokeratosis is a rare paraneoplastic manifestation of malignant epitheliomas of the upper respiratory or digestive tracts, reported for the rst time by Bazex in 1965. It may appear several months before the rst signs of the malignancy with erythematous, keratotic, and irregular lesions symmetrically distributed in hands, feet, ears, and nose. The nails generally are involved early in the disease, becoming fragile and thin with a raised free edge from subungual hyperkeratosis. Skin manifestations disappear when the tumor is removed, but the nails do not always recover fully.

Pseudoinammatory nail changes In pseudoinammatory nail changes, the distal portion of the digit is greatly enlarged and red, simulating an acute paronychia, but the skin temperature is cold or normal. This presentation should suggest digital ischemia or metastases to the distal phalanges. In digital ischemia, the digit is cold and painful. The most common causes include arterial obstruction and peripheral neuropathies causing ischemia, such as carpal tunnel syndrome and diabetes. In carpal tunnel syndrome, the nail abnormalities usually are limited to the rst, second, and third ngers and are associated with ngertip paresthesia (Fig. 6). Depending on the severity of the nerve damage, nail changes vary from Beaus lines to onychomadesis and necrosis. At

Abnormalities in proximal nail fold capillaries Abnormalities in the proximal nail fold capillaries are seen frequently in autoimmune connective tissue disorders, because they occur in almost all patients. They may or may not be associated with other nail signs. Capillaroscopy is a simple technique that can be used to conrm the diagnosis (Fig. 7).

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Fig. 7. Proximal nail fold capillaries abnormalities. (Left) Lupus erythematosus. (Center) Normal individual. (Right) Scleroderma/dermatomyositis.

Roughness, hemorrhages, and necrosis of the cuticles are common in dermatomyositis and scleroderma in which capillaroscopy shows reduced capillary density and avascular areas alternating with dilated capillary loops. In scleroderma, the severity of the proximal nail fold changes may be an index of the degree of systemic involvement and may reect the status of the entire vascular system. Capillaroscopy may also be helpful in distinguishing early scleroderma from Raynauds disease, in which capillaries are normal. In systemic lupus erythematosus, capillaroscopy shows a normal capillary density with dilated tortuous capillaries. Pseudopyogenic granulomas Pseudopyogenic granuloma of the proximal nail fold of one digit may be a sign of mild and transitory peripheral nerve injury, especially if associated with onychomadesis (Fig. 8). It typically is seen in patients who have phalanx, metacarpal, or wrist bone fractures during or after cast immobilization. Patients often report a history

of pain or paresthesias of the hand during the period of immobilization. Pseudopyogenic granuloma resolves spontaneously over a few weeks [8]. Drugs, especially retinoids, cyclosporin, and indinavir, also can cause multiple pyogenic granulomas.

Periungual bromas (Koenens tumors) Periungual bromas should arouse the suspicion of tuberous sclerosis and require a complete dermatologic examination of the patient to detect other possible signs of the disease. Koenens tumors occur in 50% of patients who have tuberous sclerosis and usually develop after puberty. Fibromas may be single or multiple, and the number of the aected nails is variable. Periungual bromas usually originate from the proximal nail fold and appear as a pink or eshcolored growth. Compression of the nail matrix produces a longitudinal depression of the nail plate. Subungual liform lesions may occur.

Ventral pterygium Ventral pterygium (pterygium inversum unguis) is characterized by the adhesion of the distal nail plate to the hyponychium, resulting in pain during nail trimming. Ventral pterygium is a distinctive sign of scleroderma related to impaired peripheral perfusion [9]. References
[1] Daniel CR III, Piraccini BM, Tosti A. The nail and hair in forensic science. J Am Acad Dermatol 2004; 50(2):25861. [2] Zaiac MN, Daniel CR III. Nails in systemic disease. Dermatol Ther 2002;15(2):99106.

Fig. 8. Pseudopyogenic granuloma of the proximal nail fold after cast immobilization.

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[3] Spicknall KE, Zirwas MJ, English JC III. Clubbing: an update on diagnosis, dierential diagnosis, pathophysiology, and clinical relevance. J Am Acad Dermatol 2005;52(6):10208. [4] Kitis G, Thompson H, Allan RN. Finger clubbing in inammatory bowel disease: its prevalence and pathogenesis. BMJ 1979;2(6194):8258. [5] Zaun H. Leukonychias. Semin Dermatol 1991;10(1): 1720. [6] Tosti A, Piraccini BM, Iorizzo M. Systemic itraconazole in the yellow nail syndrome. Br J Dermatol 2002; 146(6):10647.

[7] Baran R, Tosti A. Metastatic bronchogenic carcinoma to the terminal phalanx of the big toe: report of two cases and review of the literature. J Am Acad Dermatol 1994;31(2Pt1):25963. [8] Tosti A, Piraccini BM, Camacho-Martinez F. Onychomadesis and pyogenic granuloma following cast immobilization. Arch Dermatol 2001;137(2): 2312. [9] Caputo R, Cappio F, Rigoni C, et al. Pterygium inversum unguis. Report of 19 cases and review of the literature. Arch Dermatol 1993;129(10): 13079.

Dermatol Clin 24 (2006) 349354

Common Nail Disorders

Mark Holzberg, MD*
Department of Dermatology, 5001 Woodru Memorial Building, Emory University School of Medicine, Atlanta, GA 30322, USA

Common skin diseases often present with nail changes. This article reviews nail manifestations associated with psoriasis, lichen planus, alopecia areata, and twenty-nail dystrophy. There is considerable overlap in the nail ndings in these cutaneous conditions, but nail changes distinct to these conditions do exist. Psoriasis Approximately 1% to 2% of the general population has psoriasis, and nail changes are found in approximately 12% of these patients [1]. Examination of the nail often is helpful in establishing the diagnosis of psoriasis. If, for example, the skin examination reveals a scaly, erythematous, patchy rash on the arms and legs, the presence of nail pitting might indicate psoriasis rather than eczema in that individual. Clinical presentation Psoriasis in the skin presents as white, scaly, erythematous plaques with a predilection for the elbows, knees, gluteal cleft, and scalp. The histology of psoriasis is an inammatory parakeratotic papule. This same inammatory hyperkeratotic papule occurs in the nails of psoriatic patients. The location of that papule determines the clinical presentation [2]. Psoriatic lesions can be seen in the cutaneous surface of the proximal nail fold, the undersurface of the proximal nail fold, the matrix, the nail bed, and the hyponychium. Erythematous scaly papules and plaques can be seen on the cutaneous surface of the proximal
* 710 Newnan Crossing Bypass, Newnan, GA 30263. E-mail address: Mark_Holzberg@hotmail.com

nail fold and hyponychium and appear similar to psoriasis in other areas of the skin. Psoriatic lesions in this location do not cause changes in the nail plate. The undersurface of the proximal nail fold contributes the horny cuticle to the nail. This cuticle allows the attachment of the proximal nail fold to the dorsal surface of the nail plate. A psoriatic lesion in the undersurface of the proximal nail fold produces an abnormal cuticle causing a separation of the proximal nail fold from the nail plate. This separation causes a paronychia characterized by an erythematous, inamed proximal nail fold and ragged or absent cuticle. Like any chronic paronychia, maceration and overgrowth of yeast under the proximal nail fold can perpetuate the abnormality. Lesions of psoriasis in the matrix may occur in the proximal or the distal matrix. Normally, the proximal matrix contributes orthokeratotic keratin to the dorsal nail plate; the distal matrix contributes orthokeratotic keratin to the ventral nail plate. In psoriasis, a cluster of abnormal parakeratotic cells is contributed to the horny nail plate. These parakeratotic cells are incorporated into the dorsal surface of the nail plate if this psoriatic lesion is present in the proximal matrix. These loosely arranged cells might travel with the nail plate for a short distance but are lost quickly, and a depression or pit marks the prior location of these cells. The pits formed are the hallmark of psoriatic nail disease. If the parakeratotic cells are in the central or distal portion of the matrix, these parakeratotic cells are trapped within the nail plate, and reected light gives the nail plate an opaque white appearance. Psoriatic lesions may occur in the nail bed. Early psoriasis may present with erythema only. A deeply erythematous macule may be seen in
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the nail bed through the translucent nail plate. In more advanced lesions, abnormal parakeratotic keratin disrupts the normal adhesion of the nail plate to the nail bed. Consequently, white subungual keratinaceous debris develops, associated with onycholysis. Psoriatic lesions produce glycoproteins that accumulate underneath the nail plate, presenting clinically as a yellowish nail bed macule known as the oil dropping sign. Splinter hemorrhages also may be seen in psoriatic nails because of disruption of the underlying nail bed vasculature. A constellation of the ndings described here is usually seen, depending on the location of the psoriatic lesions. A completely dystrophic nail characterized by mounds of keratinaceous debris can be seen if the psoriatic lesion is particularly large (Fig. 1), especially in pustular psoriasis or acrodermatitis continua of Hallopeau. The severity of nail disease can be correlated with more severe skin disease and more advanced psoriatic arthritis [3]. Intermittent inammation of the nail matrix can produce Beaus lines [4]. Other less common nail changes described in psoriasis are nail fold telangiectasias [5], red lunulae [6], punctate red spots in the lunula [7], transverse leukonychia [6,8,9], leukonychia punctata [10], half-and-half nail [7], koilonychia [7], and onychoschizia [11]. Dierential diagnosis Nail changes in psoriasis can be virtually indistinguishable from onychomycosis. Both fungal nail disease and psoriasis can produce a distal subungual onycholysis and subungual hyperkeratosis. In these cases, specic ndings help dierentiate between the two: (1) a positive potassium hydroxide (KOH) preparation or fungal culture often helps establish the diagnosis of

Fig. 1. Completely dystrophic nails of psoriasis.

onychomycosis; (2) other signs of fungal disease, such as tinea pedis, help to establish the diagnosis of onychomycosis; (3) nail pitting helps establish the diagnosis of psoriasis; (4) other signs of psoriasis on the cutaneous surface, such as the elbows, knees, gluteal cleft, and scalp, help establish the diagnosis of psoriasis; (5) a family history of psoriasis may also help sway the clinician toward the diagnosis of psoriasis. To complicate the picture further, psoriatic nails may harbor a secondary dermatophyte infection. One study found nail changes in 47% of 561 patients who had psoriasis, and 27% of the patients who had nail changes had KOH-positive onychomycosis [12]. Proximal subungual onychomycosis can be confused with proximal nail psoriasis. White-spot tinea unguium usually has a KOH-positive supercial whitening of the nail plate caused by dermatophytes on the nail surface. This presentation is unusual in psoriasis. Total dystrophic onychomycosis might appear clinically similar to completely dystrophic nail psoriasis. A biopsy with fungal periodic acid-Schi stain should be performed to help establish the diagnosis in challenging cases. Subungual hyperkeratosis can also be seen in pityriasis rubra pilaris [13] and may develop in patients who are HLA B27 positive [14]. Subungual hyperkeratosis may be an inherited isolated nding or found in association with hyperkeratosis of the palms and soles [8]. Nail plate pitting is considered a hallmark of psoriasis, but alopecia areata also can produce pitting. As a general rule, pitting in psoriasis is more irregular and broader based; pitting in alopecia areata is more regular, shallow, and geometric and produces ne pits. Deeper and more irregular pits, similar to those in psoriasis, can be seen in pityriasis rubra pilaris [15] and Reiters disease [7]. Such deep pits can also be helpful in building a case for psoriatic arthritis in the absence of other denitive markers [7]. Psoriasis-associated onycholysis often is accompanied by subungual debris; with primary onycholysis the nail bed often is unremarkable. Psoriasis can be conrmed by a punch biopsy of the nail bed. Other conditions should be considered when psoriasiform nail changes are observed in only one nail. Bowens disease, squamous cell carcinoma, and verruca vulgaris may appear as an isolated subungual or periungual scaly plaque. Nail plate destruction may accompany these changes. These isolated neoplasms often are

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resistant to topical or intralesional corticosteroids and may be resistant to repeated destructive methods such as liquid nitrogen cryotherapy or electrodesiccation and curettage. A biopsy should be performed to establish a denitive diagnosis. Treatment Treatment for psoriatic nail disease often is as frustrating for the clinician as it is for the patient. Psoriatic nail disease may improve with the use of methotrexate and has been reported to improve with immunomodulary biologic agents [16]. Topical therapies may prove frustrating if systemic medication is not an option. It is dicult to deliver medication to the aected location because the lesion in nail psoriasis is beneath the nail plate in the matrix or nail bed. Topical corticosteroids might be used but are most successful when the nail plate is fairly dystrophic, allowing better penetration of the therapeutic agent. Grenz ray and x-ray treatment might be helpful in isolated cases, especially if the nail is of normal thickness [17]. Tazarotene gel has been demonstrated to reduce onycholysis and pitting, especially if used under occlusion [18]. Determined patients often accept intralesional corticosteroids as the best therapy. Treatment is repeated monthly, and multiple treatments are necessary because the nail plate takes 3 to 4 months to grow out. Triamcinolone in dosages ranging from 3 to 10 mg/cm3 is injected into the deep aspect of the lateral nail folds either proximally or distally, depending on the location of the psoriatic lesion. Diusion allows the corticosteroid to reach the aected lesion.

Fig. 2. Onychorrhexis and nail plate splitting in lichen planus.

also produce trachyonychia, a rough sandpaper appearance to the surface of the nail plate. Trachyonychia is characterized by a gray opacity, and nails may be brittle and split. The nail plate may be thrown into folds (Fig. 3). Less commonly, lichen planus can produce complete atrophy of the nails. When the lichenoid inltrate enlarges to encompass the proximal nail fold, the matrix, and the nail bed, pterygium can occur. Pterygium is strongly associated with lichen planus and may present as the only manifestation. It occurs as a shortening of the cul-de-sac under the proximal nail fold with associated thinning of the nail plate until the proximal nail fold fuses to the matrix and proximal nail bed dividing the nail plate into two lateral sections [20]. Dierential diagnosis Onychorrhexis is a common nail nding, especially in older individuals, where it is referred to as senile nails. Onychorrhexis has a particularly strong association with rheumatoid arthritis [21], but it can be associated with other circulatory disorders and endocrine disorders and can be familial.

Lichen planus Lichen planus presents as pruritic papules on the volar wrists and extremities. Mucosal lesions in the mouth and genitalia are common. It may be associated with nail changes, but nail changes occur more often as an isolated nding [19]. Clinical presentation Lichen planus of the nails has a variety of clinical presentations depending on the location of the lichenoid inammatory inltrate. Most commonly, lichen planus aects the matrix and produces three distinct patterns [18]. Onychorrhexis presents as nail plate thinning with longitudinal ridging and ssuring caused by the lichenoid inltrate in the proximal portion of the matrix (Fig. 2). The lichenoid inltrate in the matrix might

Fig. 3. Lichen planus.

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Trachyonychia can be seen in alopecia areata and as a part of twenty-nail dystrophy of childhood. Alopecia areata can be dierentiated from lichen planus by associated cutaneous ndings and/or the association of ne pitting of the nail plates in alopecia areata. Twenty-nail dystrophy diers from nail lichen planus in its monomorphic appearance (longitudinal ridging aects the nail plate surface uniformly, and there is absence of ssuring and pterygium) [18]. Pterygium is almost pathognomonic for lichen planus of the nail. It can, however, be seen in nailpatella syndrome and in other destructive conditions such as trauma, peripheral vascular disease, Raynauds phenomenon, radiotherapy, infection, and immunobullous disease [8,2224]. Treatment Lichen planus of the nail, like cutaneous lichen planus, responds to systemic agents. Low-dose, alternate-day systemic corticosteroids and intramuscular corticosteroids have been reported to be successful but the condition may recur when therapy is discontinued [18]. Griseofulvin and systemic retinoids have been used with varying success in lichen planus and lichen planus of the nail [25,26].

[30]. Rough, gray, thin, sandpaper-appearing trachyonychia has been reported to occur in 3.65% of patients who have alopecia areata and in 15.4% of patients who have alopecia universalis [30]. On biopsy, most of these patients showed a lymphocytic inltrate with spongiosis in the proximal nail fold, matrix, nail bed, and hyponychium that was responsible for the changes seen clinically. Trachyonychia may occur before, concurrently with, or after the hair changes of alopecia areata. Alopecia areata may aect only the matrix. The spotty absence of the whiteness of the lunula, the so-called spotted lunula, is strongly associated with alopecia areata [31]. The acute onset of alopecia areata universalis has been associated with nail plate shedding (onychomadesis) [27]. Dierential diagnosis Pitting also may be observed in psoriasis, but in psoriasis the pitting is more often broad-based and irregular. Other cutaneous ndings of psoriasis may be helpful in dierentiating alopecia areata from psoriasis. Shallow and more regular pitting also can be seen in dermatitis [8]. In HLA B27 inheritance, pitting occurs in tight, longitudinal rows [14]. Pitting also is seen in diabetes [32] and occupational trauma [11]. Trachyonychia can be observed in lichen planus and twenty-nail dystrophy of childhood. Treatment Alopecia areata may respond to intralesional corticosteroids. Triamcinolone in concentrations of 3 to 10 mg/cm3 in the lateral nail fold lateral to the matrix may prove helpful. Treatment also may be as simple as concealing the nail changes with polish.

Alopecia areata Nail changes in alopecia areata may be more common than originally thought. If the nails in these patients are examined closely, nail ndings may be seen in up to half of alopecia areata patients; nail plate pitting is the most common observation [27]. Nail changes may be seen in patients who have alopecia areata of the scalp but are more common and more severe in alopecia universalis. Alopecia areata also may present as an isolated nding, present only in the nails. Clinical presentation Nail plate pitting and trachyonychia are characteristic of alopecia areata. Pitting is often ne and regularly distributed across the nail plate. The pitting may be so regular that suggests a geometric pattern. The pitting may be white (leukonychia punctata), associated with small foci of parakeratotic cells [28]. It may be an isolated nding in one nail, present in multiple nails, or present in all 20 nails [29]. Pitting reportedly has been observed in 21.9% of patients who have alopecia areata

Twenty-nail dystrophy Hazelrigg and colleagues [33] originally described twenty-nail dystrophy of childhood in children who had acquired trachyonychia of all 20 nails. This condition was observed in children from 18 months to 18 years of age in the absence of a skin condition or disease. Since the original description in children, twenty-nail dystrophy also has been observed in adults [34]. The nail changes usually resolve over several years, although a few cases have persisted into adulthood [7]. Twenty-nail dystrophy is a benign condition that never produces scarring [18].

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Clinical presentation The nail changes of twenty-nail dystrophy are characterized by rough nail plates, longitudinal ridging, and brittleness. The longitudinal ridging responsible for the sandpaper appearance is relatively monomorphic from nail to nail. The condition commonly occurs in all 20 nails, but it may be limited to one or several digits. Dierential diagnosis The dierential diagnosis of trachyonychia includes psoriasis, lichen planus, and alopecia areata [35]. Twenty-nail dystrophy often is the appropriate diagnosis in children when trachyonychia is the only nding. Trachyonychia of twenty-nail dystrophy appears more regular and monomorphic; in other conditions trachyonychia is less monomorphic. Pitting may occur in alopecia areata. Onycholysis, the yellow oil-dropping sign, and more severe dystrophy may sway the clinician toward the diagnosis of psoriasis; pterygium, ssuring, and/or more irregular onychorrhexis are characteristic of lichen planus. Cutaneous examination is also helpful in establishing the diagnosis. There seems to be a dierential diagnosis in the histology of this condition. There are two distinct biopsy ndings in this condition: a psoriasiform/ lichenoid inltrate and a spongiotic inltrate [35,36]. Some investigators found lichenoid histology in twenty-nail dystrophy and considered it a variant of lichen planus [34]. A biopsy of one child who had long-standing dystrophy of all 20 nails showed the presence of a lichenoid inammatory inltrate, and lichen planus was proven histologically [37]. One patient who had trachyonychia and both alopecia universalis and ichthyosis vulgaris showed a nail biopsy consistent with lichen planus [37]. An additional study of children who had trachyonychia found vacuolated cells with intercellular and intracellular edema in the nail bed epidermis and squamous cells of the matrix typical of lichen planus [11]. A second group of investigators found a spongiotic inammatory inltrate, histologically similar to the pathology seen in alopecia areata, when children who had twenty-nail dystrophy were biopsied [7,30]. One study of ve patients who had twenty-nail dystrophy showed spongiotic inammatory inltrates on pathology of all ve patients [38]. The authors suggest that these patients represent a subgroup of patients who have endogenous eczema who have a predilection for

involvement of the nail matrix. A second but less likely hypothesis suggests that these patients may exhibit an autoimmune response to the matrix. Another study of patients who had twentynail dystrophy substantiated these ndings, showing spongiotic histology in 19 of 23 patients examined [39]. Some authors point to the association of with ichthyosis vulgaris and atopy in these patients [40]. The historic evidence of atopy in these patients supports the possibility of an eczematous origin. Treatment Therapy aimed at decreasing the inammatory causative response may help ameliorate clinical ndings, but this condition often resolves spontaneously. Topical corticosteroid lotions and intramatrix corticosteroid injections have been used, but there is an associated risk of premature closure of the underlying epiphyseal bone plates [7]. Topical psoralen plus UVA has been used with excellent results in all ngernails but requires 90 treatments to clear the nails and aggressive maintenance treatment to prevent recurrence [41].

References
[1] Mallbris L, Larsson P, Bergqvist S, et al. Psoriasis phenotype at disease onset: clinical characterization of 400 adult cases. J Invest Dermatol 2005;124(3): 499504. [2] Zaias N. Psoriasis of the nail. Arch Dermatol 1969; 99:56779. [3] Williamson L, Dalbeth N, Dockerty JL, et al. Extended report: nail disease in psoriatic arthritisd clinically important, potentially treatable and often overlooked. Rheumatol 2004;43:7904. [4] Burkhart CG. Beaus lines: an association with pustular psoriasis and telogen euvium. Arch Dermatol 1980;116:11901. [5] Ohtsuka T, Yamakage A, Miyachi Y. Statistical denition of nailfold capillary pattern in patients with psoriasis. Int J Dermatol 1994;33:77982. [6] Baran R, Dawber RPR, editors. Diseases of the nails and their management. 1st edition. Oxford (UK): Blackwell Scientic; 1984. [7] Scher RK, Daniel CR. Nails: therapy, diagnosis, surgery. Philadelphia: W.B. Saunders; 1990. [8] Zaias N. The nail in health and disease. New York: Spectrum; 1980. [9] Marino MT. Mees lines. Arch Dermatol 1990;126: 8278. [10] De Nicola P, Morsiani M. Nail diseases in internal medicine. Springeld (IL): Charles C. Thomas; 1974.

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[11] Baran R, Dawber RPR, editors. Diseases of the nails and their management. 2nd edition. Oxford (UK): Blackwell Scientic; 1994. [12] Gupta AK, Lynde CW, Jain HC, et al. A higher prevalence of onychomycosis in abnormal-appearing nails in psoriatics compared to nonpsoriatics: a multicenter study. Br J Dermatol 1997;136(5):7869. [13] Sonnex TS, Dawber RP, Zachary CB, et al. The nails in adult-type I pityriasis rubra pilaris. J Am Acad Dermatol 1986;15:95660. [14] Pajarre R, Kemo M. Nail changes as the rst manifestation of HLA-B27 inheritance. Dermatologica 1977;154:3504. [15] Griths WAD. Pityriasis rubra pilarisdan historical approach. Clin Exp Dermatol 1976;1:3750. [16] Nandedkar-Thomas MA, Scher RK. An update on disorders of the nail. J Am Acad Dermatol 2005; 52:87787. [17] Lindelof B. Psoriasis of the nails treated with Grenz rays: a double-blind bilateral trial. Acta Derm Venereol 1989;69:802. [18] Scher RK, Stiller M, Zhu YI. Tazarotene 0.1% gel in the treatment of ngernail psoriasis: a double-blind, randomized, vehicle-controlled study. Cutis 2001; 68:3558. [19] Tosti A, Piraccini BM, Cambiaghi S, et al. Nail lichen planus in children. Arch Dermatol 2001;137: 102732. [20] Caputo R, Prandi G. Pterygium inversum unguis. Arch Dermatol 1973;108:8178. [21] Michel C, Cribier B, Sibilia J, et al. Nail abnormalities in rheumatoid arthritis. Br J Dermatol 1997;137: 95862. [22] Pierre M, editor. The nail. Edinburgh (UK): Churchill Livingstone; 1981. [23] Burge SM, Powell SM, Ryon TJ. Cicatricial pemphigoid with nail dystrophy. Clin Exp Dermatol 1985; 10:4725. [24] Shawan SS, Zaias N. The nail fold in pemphigus vulgaris. Arch Dermatol 1990;126:13745. [25] Kato N, Ueno H. Isolated lichen planus of the nails treated with etretinate. J Dermatol 1993;20(9): 57780. [26] Haldar B. Lichen planus with pterygium unguis treated by grisiofulvin. Indian J Dermatol 1976;21:53.

[27] Tosti A, Morelli R, Bardazzi F, et al. Prevalence of nail abnormalities in children with alopecia areata. Pediatr Dermatol 1994;11:1125. [28] Dotz WI, Lieber CD, Vogt PJ. Leukonychia punctata and pitted nails in alopecia areata. Arch Dermatol 1985;121:14524. [29] Horn RT, Odom RB. Twenty-nail dystrophy of alopecia areata. Arch Dermatol 1980;116:5734. [30] Tosti A, Fanti PA, Morelli R, et al. Trachyonychia associated with alopecia areata: a clinical and pathologic study. J Am Acad Dermatol 1991;25:26670. [31] Shelley WB. The spotted lunula. J Am Acad Dermatol 1980;2:3857. [32] Green RA, Scher RK. Nail changes associated with diabetes mellitus. J Am Acad Dermatol 1987;16: 101521. [33] Hazelrigg DE, Duncan WC, Jarrat M. Twenty-nail dystrophy of childhood. Arch Dermatol 1977;113: 735. [34] Scher RK, Fischbein R, Ackerman B. Twenty nail dystrophy, a variant of lichen planus. Arch Dermatol 1978;114:6123. [35] Baran R, Dawber R. Twenty-nail dystrophy of childhood: a misnamed syndrome. Cutis 1987;39: 4812. [36] Grover C, Khandpur S, Reddy BSN, et al. Longitudinal nail biopsy: utility in 20-nail dystrophy. Dermatol Surg 2003;29:11259. [37] Silverman RA, Rhodes AR. Twenty nail dystrophy of childhood: a sign of localized lichen planus. Pediatr Dermatol 1977;113:1613. [38] Jerasutus S, Suvanprakorn P, Kitchawengkul O. Twenty-nail dystrophy. A clinical manifestation of spongiotic inammation of the nail matrix. Arch Dermatol 1990;126:106870. [39] Tosti A, Bardazzi F, Piraccini BM, et al. Idiopathic trachyonychia (twenty-nail dystrophy): a pathological study of 23 patients. Br J Dermatol 1994;131: 86672. [40] Jam WD, Odom RB, Horn RT. Twenty-nail dystrophy and ichthyosis vulgaris. Arch Dermatol 1981; 117:316. [41] Halkier-Sorensen L, Cramers M, et al. Twenty nail dystrophy treated with topical PUVA. Acta Derm Venereol (Stockh) 1990;70:5101.

Dermatol Clin 24 (2006) 355363

Childhood Nail Diseases

David de Berker, BA, MBBS, MRCP
Bristol Dermatology Centre, Bristol Royal Inrmary, Bristol BS2 8HW, UK

What is normal? A large proportion of pediatric nail presentations involve parents bringing in their children with questions regarding nail appearance rather than the plain presentation of a disease or functional problem. Parents are concerned whether the nails are normal, if they are uncomfortable for the baby or child, if the nails will aect walking or other future function, or if the changes are of wider signicance and suggest more sinister medical problems than are yet apparent. To address these concerns, the clinician needs a good grasp of what is normal. Normal nails in childhood In the rst few years it is common for nails to be fragile, with transverse lamellar changes at the free edge. This condition is most noted on the big toes and thumbs, with thumb sucking being an exacerbating factor. Turano [1] observed that 92% of normal infants between 8 and 9 weeks of age had a single transverse depression (Beaus line) of the ngernails. This depression typically appeared at the proximal portion of the nail as early as 4 weeks of age and grew out to the distal edge by 14 weeks of age. A small degree of onycholysis, deviation from the midline, and distal thickening are transient features of the toenails usually lasting no more than 24 months. Distal ingrowing can be expected in the big toenails and is not of importance unless it is associated with inammation. When inammation occurs, swelling of the digit pulp may begin a cycle of further ingrowing that can be painful and recurrent. As children commence walking, the balance of forces

E-mail address: David.deberker@ubht.swest.nhs.uk

acting within the toes changes; many problems settle, but others can evolve. These are fewer normal variations in the ngernails in the rst 5 years. Deviation and distal thickening are seldom found, in contrast to the toes, and may carry more prognostic signicance. The periungual skin can peel without obvious eczema or inammation, which is less often seen on toes. In a school survey of 160 healthy children aged 5 to 7 years, the most common features were herringbone nails and nail biting in the ngers, and lamellar dystrophy, koilonychia, malalignment, and nail thickening in the toes [2]. Herringbone nails have also been referred to as chevron nails [3]; there is debate as to whether this condition is a pattern of the midline or one with a series of dierent central axes [4]. The feature is best viewed with oblique lighting and usually is subtle. It grows out in early adulthood and is of unclear signicance. It poses interesting questions concerning the interpretation of the patterns and dynamics of nail growth that are not yet resolved. It has no apparent association with atopy or other medical problems. Nail biting is usually recognized as such by the parent. A study in the United Kingdom revealed that 36% of children aged 5 years bite their nails, rising to 57% at age 12 years and falling to 31% by age 16 years [5]. There may be associated complications, such as paronychia (Fig. 1), in which the biting habit may extend to the skin, or the nail can be left with spurs that grow into the lateral nail fold. Distal ingrowing can also be a problem (Fig. 2) and, in addition, there are reports in the dental literature that nail biting may cause tooth root problems and gum disease from nail fragments embedded between teeth [6]. Many studies have attempted to determine whether nail
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Fig. 1. An acute paronychia in a 6-year-old child who bites his nails. Pus is emerging from beneath the nail.

can represent a reactive change equivalent to the development of a hammertoe. The immature muscles of the foot can direct the toe so that the digit pulp is plantar-exed, making the free edge of the nail tap against the ground. The nail reacts with hypertrophy and, sometimes, subungual hyperkeratosis. For this reason, it is important to examine young children as they move about the consulting room unhindered, so that the natural positions of the toes are apparent. Where there is thickening of the ngernails as well, this explanation does not hold, and the condition may have more long-term signicance.

biting is related to psychologic problems, but there is no conclusive answer. Each child is best assessed individually. Toes and ngers can show lamellar dystrophy. This condition often is most notable on the thumbs and big toes, where the feature resolves more gradually. The big toes may show a combination of koilonychia with lamellar changes. Koilonychia is dened as a concave dorsal surface to the nail, sucient to hold a drop or more of water; however, it is not feasible to make this test in a normal child. Both characteristics settle within the rst 10 years. Although there is an association between koilonychia and iron deciency in adults, the data are not conclusive in children [7]. Given its prevalence in otherwise healthy children, tests for iron deciency should be pursued only if koilonychia is widespread and the possibility of iron deciency is supported by other parts of the assessment. Thickening of the toenails should not be overinterpreted in children under the age of 10 years. In the early stages of walking, toenail thickening

Common diseases aecting the nail in childhood The common nail diseases of childhood are the same as those in adults: eczema, psoriasis, onychomycosis, and lichen planus. Some additional diseases, such as 20-nail dystrophy, have a special status in childhood. Eczema aects the periungual tissues and, in so doing, causes inammation of the nail matrix. An inamed matrix will generate an abnormal nail for which the most common features are transverse ridges and grooves. The eczema may be part of atopy or an irritant dermatitis for which thumb or nger sucking is the most common cause. In all variants, the proximal and lateral nail folds may be red and swollen, and there is loss of cuticle. Loss of cuticle means that there is no sealant preventing irritants from gaining access to the matrix. Once the cuticle is lost, there is a risk of paronychia becoming chronic. A similar pattern of nail fold changes occurs in psoriasis, although in psoriasis the nail plate may show more marked pitting and nail bed changes of onycholysis. Treatment is similar for eczema or psoriasis. Moderate- and high-potency steroids can be justied for several weeks, depending on the age of the child [8]. If the problem is partly related to habits such as sucking, it will not be cured with a topical steroid (Fig. 3). If prescribed without addressing the causative habits, steroid use may become long term because of diminished ecacy, with risk of atrophy. There is also the theoretical concern that children will ingest signicant amounts of steroid if they are sucking it o their ngers. Because most topical steroids come with the warning not to be taken internally, this ingestion can worry the parent. Small amounts of ingested steroid should do no harm. In a young adolescent, other practical issues are relevant;

Fig. 2. Distal and disto-lateral ingrowing in a 14-yearold boy who bites his nails.

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absence of infection, forms of juvenile arthritis [9] or sickle cell disease [10] must be considered.

20-nail dystrophy and lichen planus The risk of scarring nail dystrophy accompanies the diagnosis of lichen planus, which has a similar presentation to that of 20-nail dystrophy. When lichen planus presents with longitudinal splits, periungual purple changes, and pterygium formation, the clinical diagnosis is clear, and histopathology is not needed (Fig. 4). There are, however, many subtle variants of lichen planus, some of which are similar to the poorly termed 20-nail dystrophy. Twenty-nail dystrophy is an inaccurate descriptive term given to a collection of diseases that present with involvement of multiple nails, up to 20 in some instances. It is applied most commonly to such diseases occurring in childhood (Fig. 5): lichen planus and a category described according to its histology as spongiotic dystrophy [11]. Spongiotic dystrophy seems to be related to autoimmune diseases such as alopecia areata, with which it may co-present in all ages. A further term applied to variants of 20-nail dystrophy is trachyonychia, for which spongiosis or lichen planus may be the histologic diagnosis [12]. Trachyonychia is a clinical sign rather than a diagnosis [13], although the concepts are often confused. Trachyonychia is identied as a roughened nail surface with marked longitudinal striations, merging with grooves when it is more profound, ultimately resulting in longitudinal splitting and disintegration of the nail in extreme cases. These changes result in a rough distal free edge that may catch objects upon contact and lose surface luster. In adulthood, the term

Fig. 3. Chronic paronychia was complicated in this child by digit sucking. The inammation was sucient to prevent nail formation.

the patient may need to wear gloves when taking a shower or shampooing. Another potential concern involves co-existing Candida acting as a pathogen at the site, but Candida disappears once the eczema or psoriasis is settled and the skin environment is kept dry and supple with emollient. Acute paronychia may present as a symptom of eczema or of nail biting as an isolated event. If pus collection is limited to the lateral nail fold, oral antibiotics may be sucient. When there is involvement of the proximal nail fold or matrix, there is possible concern that the matrix will become damaged through a combination of inammation and pressure necrosis (see Fig. 1). This damage could lead to permanent nail dystrophy. Although it may be best to commence with oral antibiotics and observation for 48 hours, the possibility of surgical drainage should be assessed as early as possible. There are obvious problems in prevailing on a young person in pain to endure a ring block and then drainage of the pus while awake, but such circumstances rarely warrant a general anesthetic. Other patterns of periungual bacterial infection include impetigo and distal dactylitis, with common ground in their manifestations. Both can involve single or multiple digits. Crusting is typical of impetigo, but blistering may be seen in both conditions. A source of original infection within the child or family should be sought and treated. Treatment of the child includes antiseptic soaks, drainage where relevant, and oral antibiotics that sometimes may be combined with topical antibiotics. Staphylococcus aureus and beta-hemolytic Streptococcus are the most common pathogens for impetigo and dactylitis, respectively. Where there is dactylitis in the

Fig. 4. An isolated ridge, split, and pterygium in a 2-year-old may leave some uncertainty concerning diagnosis. This child turned out to have lichen planus.

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Fig. 5. An 11-year-old boy with surface changes on most of his nger and toenails classied as 20-nails dystrophy. The condition has not progressed to the loss of shine that would be described as trachyonychia.

20-nail dystrophy is sometimes used for nail psoriasis or even onychomycosis. A classic pediatric case would be a child of 8 years who presents with trachyonychia (the sign) in 14 nails (therefore called 20-nail dystrophy) with a yet-undened etiology (lichen planus or spongiosis). A search for the usual signs and historic details fails to distinguish between the etiologies or the possible early manifestations of psoriasis. The question then arises as to whether this condition is a benign or scarring process. If it is lichen planus, there is concern that it may be the latter, although lichen planus of the nails is not irrevocably scarring. Application of a potent topical steroid to the proximal nail fold for 2 to 3 months may allow a period of assessment and in turn allow the parents and child to consider their options. These options include watchful waiting, because the classic spongiotic pathology may resolve over a matter of a few years, and psoriasis will become manifest in other ways and is nonscarring. If it is lichen planus, it also may get better, but there remains a risk that it will deteriorate and cause scarring. Systemic steroids are the only treatment likely to be eective. To establish this diagnosis with certainty in the absence of clues elsewhere requires a matrix biopsy. This is not a good age in which to do a nail biopsy, however, because it will almost certainly require a general anesthetic. There also is the question whether it is justied to give systemic steroids to a child without a clear diagnosis. The answer to this question will vary in dierent circumstances and cultures. It common practice to oer a single course of oral steroid (0.25 0.5 mg/kg for 6 weeks, then tapering over 2 weeks) without biopsy in this age group when the nail

changes result in physical handicap. Tosti and colleagues [14] reported undertaking biopsy in all variants. Her experience is that children presenting with lichen planus manifesting as trachyonychia rather than violaceous change and pterygium improved without systemic steroids. When there were violaceous changes or pterygium, she opted for a treatment regimen with intramuscular triamcinolone acetonide, 0.5 to 1 mg/kg per month for 3 to 6 months, until the proximal half of the nail was normal. The time course of improvement was about 6 months for both regimens, although a margin of normal nail can appear sooner. There may be subsequent deterioration over the next 6 months in more aggressive disease, but for many the disease will improve greatly and will not require further treatment. If there is signicant relapse, greater emphasis should be placed on obtaining a tissue diagnosis, because it is worrisome to embark on serial courses of a systemic steroid without a clear diagnosis. Onychomycosis Onychomycosis in childhood resembles that in adults to a great extent. The cross- section of patterns is slightly dierent, in that supercial white onychomycosis is more common, and it rarely involves multiple digits. A family history of onychomycosis may be present and may be a factor in transmission as well as susceptibility. Severe onychomycosis in children raises concerns with respect to HIV, mucocutaneous candidiasis, or other forms of immunosuppression. The prevalence of childhood onychomycosis in community-based studies is in the order of zero to 0.2%, in comparison with the 2% to 5% reported in adults, and tends to be associated with concomitant tinea pedis or tinea of the scalp. In supercial white onychomycosis, treatment can be with topical therapy combined with de bridement of the involved surface layer of the nail. Nail lacquers are a good option because they are used once a week. One small study with children illustrated the benet of bifonazole with urea in an ointment base [15]. When used under occlusion, this combination promoted disintegration of the nail allowing subsequent use of the ointment on the exposed nail bed [15]. This method had some success in more dystrophic variants of infection, for which systemic agents are indicated in adults (Fig. 6). Licensing for systemic agents diers by country, but all the major systemic agents have

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Fig. 6. In a 12-year-old boy, this degree of onychomycosis is uncommon and would respond best to systemic treatment.

been used in children in small studies (Table 1), and their proles of side eects and adverse reactions are similar to those in adults [16]. There is less concern about drug interactions, because children seldom are taking concomitant medication. Leuconychia There are multiple patterns of leuconychia that occur in childhood [17]. Rare, congenital, dominantly inherited forms of total leuconychia exist, but the patchy pattern of partial, transverse white streaks is the most common (Fig. 7). This change can be brought about by mild or acute direct trauma and can also be an indirect manifestation
Table 1 Regimens of systemic antifungals recommended for children

of autoimmunity, because punctate leuconychia can be associated with alopecia areata or thyroid disease. Usually, no specic cause can be implicated, and leuconychia remains a common pattern in children that becomes less frequent with age. Most parents are not overly concerned by the condition, but they may fear that it represents a dietary deciency, in particular a lack of calcium. This concern is unfounded. Histologically, the change represents waves of nail production during which the nail plate contains a greater number of nucleated cells that, in turn, may be associated with lack of cohesion between the corneocytes. This production alters the reective properties of the nail so that light is reected o the imperfections within the nail plate rather than being transmitted to and from the nail bed. Genodermatoses and nails Some of the major structural genodermatoses have nail manifestations. Usually the diagnosis is apparent from the specic constellation of features, of which nail problems are only part. Occasionally, however, nail problems can be the clue for the diagnosis or be the only manifestation. One pattern of odd nails in infancy is a range of thickened toenails with a distortion of the shape, sometimes with subungual hyperkeratosis. When multiple nails are aected, the question arises as to whether this condition could be pachyonychia congenita (PC). Often, the answer

Duration Drug Griseofulvin Mode Continuous Continuous Itraconazole Pulse: 1 wk/mo Pulse: 1 wk/mo Pulse: 1 wk/mo Pulse: 1 wk/mo Terbinane Continuous Continuous Continuous Pulse: once per week Weight !50 kg !50 kg !20 kg 2040 kg 4050 kg O50 kg !20 kg 2040 kg O40 kg !50 kg Dose Microsize: 1520 mg/kg/d Ultramicrosize: 1013 mg/kg/d 5 mg/kg/d 100 mg/d 200 mg/d 200 mg twice daily 62.5 mg/d 125 mg/d 250 mg/d 36 mg/kg/d once per week Toes 2652 weeks 2652 weeks three pulses over 3 months three pulses over 3 months three pulses over 3 months three pulses over 3 months 12 weeks 12 weeks 12 weeks 1826 weeks Fingers 1840 weeks 1840 weeks two pulses over 2 months two pulses over 2 months two pulses over 2 months two pulses over 2 months 6 weeks 6 weeks 6 weeks 1216 weeks

Fluconazole

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the ecacy of duct tape in a randomized trial comparing it with cryosurgery in preadults [20]. The duct tape must be applied to the wart for up to 2 months with only one overnight break every 7 days. In those completing the study, 85% have resolution. The third option, cryosurgery, is limited because of the pain involved. Melanonychia A longitudinal dark streak in a childs nail is worrisome when the streak is isolated, particularly if the child is white, because it may represent a dysplastic melanocytic lesion in the nail matrix. There are many factors weighing against this interpretation and in favor of simply monitoring the appearance during childhood. The main factor is that subungual melanoma has been reported in children possibly as few as three times in the world literature. There are also reports of pigmented streaks resolving spontaneously [21]. In addition, there are two studies in which the nail matrix of the child participants was biopsied, and neither of these studies identied a dysplastic lesion [22,23]. There are also reasons for regarding the situation with more caution. First, some clinicians would want to make a distinction between one melanonychia and another. The mixes of dark pigmentation that might add weight to the diagnosis of subungual melanoma in an adult would also cause concern in a child. Second, destruction of the nail plate is also a cause for concern. The third and most dicult point is the childs age. Although dysplastic histology is almost never seen in patients younger than 12 years, this situation changes in early adulthood. A signicant number of people in this age group have been diagnosed with subungual melanoma, and many of them will have had a long-standing melanonychia. Common practice is to inform parents of young children that the lesion is almost certainly benign and that three choices exist. The rst is watchful waiting with complete excision if there are changes that cause concern. The second is to obtain an incisional biopsy and also watch long term because the growth probably will be benign, but to excise the growth completely if there is cause for concern in the future. The third is to excise the growth completely and discharge the patient from follow-up. Incisional biopsies are generally discouraged, because they are unlikely to clarify the situation in a young child, are uncomfortable, and can make denitive excision

Fig. 7. Patchy leuconychia in children often has some aspects of a punctuate or transverse pattern.

cannot be determined immediately, and there is little to do but wait and seedalthough PC is rarely the diagnosis. The diagnostic process requires eliciting a detailed family history and attention to the other possible manifestations of the disease, many of which can take many years to evolve. Certainty may require analysis of putative mutations on genes for keratin 6a and 16 for PC-1 and keratins 6b and 17 for PC-2 [18]. The variants of epidermolysis bullosa can present with anything from normal nails to complete loss and interdigital fusion. The greatest challenge is when the diagnosis is occult, and the only clue is a family history of acquired childhood nail dystrophy, mainly of the big toes. This sign can represent dystrophic epidermolysis bullosa, in which abnormalities of collagen VII make the nail attachment vulnerable to mild trauma. Recurrent nail loss then leads to scarring and nail dystrophy. A history of occasional blistering of the palms and soles in sweaty weather may help direct the diagnosis, but blistering is not always present, and diagnosis ultimately may rest on mutational analysis [19]. Periungual tumors The most common periungual tumor of childhood is a viral wart. These warts are usually easy to diagnose but can prove dicult to treat. They are made worse and are readily spread to other ngers when the child bites the nail, and the spread makes cure more dicult. There is great emphasis on nding a treatment that is both safe and pain free; therefore many adult options are not available. The standard approach of topical salicylic acid in collodion is a good choice. Alternatives include duct tape and, in some instances, cryosurgery. There is modest evidence for

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more dicult. In addition, melanonychias break the rule applied elsewhere on the body, that if a pigmented lesion gives rise to concern, it should be fully excised for assessment to avoid sampling error. As children become older children or young adults, complete excision is preferred. For dark-skinned children, a streak in the nail is more commonly part of normal nail coloring. If a single streak is the presenting feature, it is possible that further streaks will develop during the period of observation. This development can be coupled with the normal racial changes of macular pigmentation on mucosal surfaces. Ingrowing nails and malalignment Ingrowing of nails develops in dierent patterns at dierent ages. In the rst 2 years of life, there can be problems with distal ingrowing. The thin, sharp, leading edge of the big toenail embeds into the hypertrophic dorsal aspect of the distal pulp. This ingrowth can be a pattern in the very rst months of life, when the nail has never grown over the digit pulp. Usually, the nail is suciently soft to ex upwards as it grows over the soft tissues and so results in mild koilonychias, made worse in evolving stages of crawling and walking when there is downward force on the tip of the toe. Intervention is rarely needed. One study of more extreme patterns of infant nail ingrowing because of hypertrophic lateral nail folds illustrated that most resolved with use of a topical steroid. Although surgery has been used in this age group, it is uncommon [24]. The next period of problematic ingrowing is in adolescence when the classic patterns of lateral ingrowing are seen. This ingrowing arises from a combination of factors, any one of which may seem to be the primary problem and suggest its own solution. These factors include poorly tting footwear, sports in which kicking or running is important, sweaty feet, and the anatomy of the big toe. When the big toe is bulbous, with prominent soft tissue, and the nail has pronounced downward curvature at the lateral margin, a conict between the edge of the nail and lateral nail folds is more common. The risk of ingrowing can be increased by cutting the nail short and allowing the free edge to become lost in the nail fold. The rule is to cut the nails straight and ensure that the disto-lateral angle is clear of soft tissues. Apart from addressing these factors, medical treatments include application of a potent topical steroid combined with a topical or oral antibiotic.

Antiseptic soaks with potassium permanganate can be helpful. Podiatric help with pledgets between the nail and soft tissues can be employed, but the pledgets often fall out and are painful to insert. Taping is another relatively conservative measure that can help. It entails using strongly adhesive tape in a spiral with attachment at the painful nail fold and extending beneath the toe and up proximally toward the foot. This technique has been used in combination with plastic gutters made from longitudinally split medical tubing. The tubing is slipped in between the nail and nail fold and held in place with liquid acrylate that hardens in situ [25]. Such techniques can be successful when supervised by a person with the relevant expertise and in a patient of the right temperament. For many, the nal resort is lateral matrixectomy. Debate continues concerning the relative merits of cutting out the lateral portion of matrix and ablating it with phenol. Both methods are eective, having dierent attributes, although each can take 4 to 6 weeks to heal. A Cochrane review suggested that the outcome of chemical ablation was superior to that of surgery [26]. A surgical matrixectomy requires considerable skill because the lateral horn of the matrix can be deeply recessed in the periungual soft tissues, particularly in this group of patients. Consequently, unless the procedure is performed by a person with particular experience and expertise, there is a signicant chance of failure with a spur of lateral nail eventually growing back. Phenolic ablation requires much less skill and, unlike surgery, does not require nail fold incisions. The argument in favor of surgery is that it heals with less exudate. There also are concerns about the toxicity of phenol. It is true that the chemical phenolic burn can ooze for weeks and that daily cleansing and sometimes potassium permanganate soaks are needed. Although phenol is used as a neurotoxic chemical for nerve ablation, neurotoxic complications and other signicant toxic problems are not common after phenolic matrixectomy. When there was concern about this point, some clinicians have used concentrated sodium hydroxide in place of phenol with results still superior to that of surgical excision [27]. Malalignment can start early and, in its common mild forms, may resolve [28,29]. It can be as minor as a slight shift in the long axis of the big toenail in comparison with the underlying distal phalanx, with no obvious alterations of the nail plate. In more gross forms, the nail plate thickens and yellows, with marked transverse ridging,

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increased transverse curvature, and viable loss of attachment to the nail bed. The nail may become triangular with the apex lying medial to the midline distally. Once the nail has lost attachment, the prognosis is worse, because the nail is prone to catching, with upwards lifting and further loss of attachment. Once loss of attachment becomes chronic over a matter of years, it is dicult to reverse the character of the nail bed and return it to the state and shape that accommodates nail adhesion. Management depends on the degree of malalignment and whether there is loss of function. Loss of function usually is caused by the ingrowing of the distal and medial edge of the nail as it obliquely encounters the periunguium. For mild changes there is little treatment other than ensuring good footwear with plenty of space for the toes. Even moderate cases may warrant similar management. The management can change where the malalignment is extreme or where there is pain and loss of function. Corrective surgery is possible, and there is a dilemma as to whether it should be advocated early and in milder cases to ensure a good outcome or whether watchful waiting should be advocated to see if the problem self-corrects. The surgery entails undermining the entire nail bed and matrix and rotating it on the dorsal aspect of the phalanx to align long axis of the nail with the distal phalanx. The postoperative morbidity associated with such surgery is relatively high, and the child must not return to normal activities too soon for fear of disturbing the new geometry of the toe. If the problem evolves to the full pathology, however, there is little treatment other than partial or total ablation of the nail, coupled with help from a podiatrist for conservative measures to avoid ingrowing. References
[1] Turano AF. Transverse nail ridging in early infancy. Pediatrics 1968;41:9967. [2] Aplin CG, de Berker DAR. Chevron nails are a common nding in childhood: a nail survey. Br J Dermatol 2002;147(Suppl 62):6. [3] Shuster S. The signicance of chevron nails. Br J Dermatol 1996;135:1512. [4] Parry EJ. Chevron nail/herringbone nail. J Am Acad Dermatol 1999;40:4978. [5] Birch LB. The incidence of nail biting among school children. Br J Educ Psychol 1955;25:1238. [6] Odenrick L, Brattstro m V. Nail biting: frequency and association with root resorption during orthodontic treatment. Br J Orthod 1985;12:7881.

[7] Hogan GR, Jones B. The relationship of koilonychia and iron deciency in infants. J Pediatr 1970;77: 10547. [8] Tosti A, Piraccini BM, Ghetti E, et al. Topical steroids versus systemic antifungals in the treatment of chronic paronychia: an open, randomized double-blind and double dummy study. J Am Acad Dermatol 2002;47:736. [9] Petty RE. Juvenile psoriatic arthritis, or juvenile arthritis with psoriasis? Clin Exp Rheumatol 1994; 12(Suppl 10):S558. [10] Morris J, Serjeant BE, Serjeant G. Sickle cell anaemia in Nigeria: a comparison between Benin and Lagos. Afr J Med Med Sci 1994;23:1017. [11] Tosti A, Bardazzi F, Piraccini BM, et al. Idiopathic trachyonychia (twenty-nail dystrophy): a pathological study of 23 patients. Br J Dermatol 1994;131: 86672. [12] Joshi RK, Abanmi A, Ohman SG, et al. Lichen planus of the nails presenting as trachyonychia. Int J Dermatol 1993;32:545. [13] Samman PD. Trachyonychia (rough nails). Br J Dermatol 1979;101:7015. [14] Tosti A, Piraccini BM, Cambiaghi S, et al. Nail lichen planus in children: clinical features, response to treatment, and long-term follow-up. Arch Dermatol 2001;137:102732. [15] Bonifaz A, Ibarra G. Onychomycosis in children: treatment with bifonazole-urea. Pediatr Dermatol 2000;17:3104. [16] Gupta AK, Skinner AR. Onychomycosis in children: a brief overview with treatment strategies. Pediatr Dermatol 2004;21(1):749. [17] Grossman M, Scher RK. Leukonychia. Review and classication. Int J Dermatol 1990;29:53541. [18] Terrinoni A, Smith FJ, Didona B, et al. Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia congenita. J Invest Dermatol 2001;117:13916. [19] Dharma B, Moss C, McGrath JA, et al. Dominant dystrophic epidermolysis bullosa presenting as familial nail dystrophy. Clin Exp Dermatol 2001; 26:936. [20] Focht DR III, Spicer C, Fairchok MP. The ecacy of duct tape vs cryotherapy in the treatment of verruca vulgaris (the common wart). Arch Pediatr Adolesc Med 2002;156:9714. [21] Tosti A, Baran R, Morelli R, et al. Progressive fading of a longitudinal melanonychia due to a nail matrix melanocytic naevus in a child. Arch Dermatol 1994;130:10767. J, Belaich S. Longi[22] Goettmann-Bonvallot S, Andre tudinal melanonychia in children: a clinical and histopathologic study of 40 cases. J Am Acad Dermatol 1999;41:1722. [23] Tosti A, Baran R, Piraccini BM, et al. Nail matrix nevi: a clinical and histopathologic study of twenty-two patients. J Am Acad Dermatol 1996; 34:76571.

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[24] Piraccini BM, Parente GL, Varotti E, et al. Congenital hypertrophy of the lateral nail folds of the hallux: clinical features and follow-up of seven cases. Pediatr Dermatol 2000;17:34851. [25] Arai H, Arai T, Nakajima H, et al. Formable acrylic treatment for ingrowing nail with gutter splint and sculptured nail. Int J Dermatol 2004; 43:75965. [26] Rounding C, Bloomeld S. Surgical treatments for ingrowing toenails. Cochrane Database Syst Rev 2005;2:CD001541.

[27] Shaath N, Shea J, Whiteman I, et al. A prospective randomized comparison of the Zadik procedure and chemical ablation in the treatment of ingrown toenails. Foot Ankle Int 2005;26:4015. [28] Baran R, Bureau H. Congenital malalignment of the big toe-nail as a cause of ingrowing toe-nail in infancy. Pathology and treatment (a study of thirty cases). Clin Exp Dermatol 1983;8:61923. [29] Baran R. Signicance and management of congenital malalignment of the big toenail. Cutis 1996;58: 1814.

Dermatol Clin 24 (2006) 365369

Diagnosing Onychomycosis
Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Mary-Jo Ricci, MScb
a

Division of Dermatology, Department of Medicine, Sunnybrook and Womens College Health Sciences Centre (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada b Mediprobe Research, Inc., 645 Windermere Road, London, ON N5X 2P1, Canada

Prevalence of onychomycosis Onychomycosis, a fungal infection of the toenails or ngernails, is the most common nail disease, representing up to half of all onychopathies [1]. It has an estimated frequency of 10% to 20% in adults [2] and an overall incidence in the United States and Canada of 8.7% [3] and 6.5% [4], respectively, increasing in prevalence worldwide [25]. The cause of onychomycosis is multifactorial; most often it aects adults (the elderly in particular) [4,6], males [6], those with underlying medical conditions (such as diabetes, peripheral arterial disease, immunodeciency, psoriasis, history of tinea pedis, or nail trauma) [711], those exhibiting specic behaviors (such as smoking, physical activity, or religious practices) [79,11], and those with predisposing genetic factors [11]. Dermatophytes, including Trichophyton rubrum and T. mentagrophytes, are the causative agents in more than 90% of all cases of onychomycosis [1,4], whereas other pathogens, including yeasts (Candida spp) and nondermatophyte molds [4], have been recovered as primary pathogens much less frequently. Clinical presentation In 1998, Baran and colleagues [12] reported a new classication system for the onychomycotic condition. Onychomycosis was classied into ve clinical subtypes, including distal and lateral
* Corresponding author. Mediprobe Research, Inc., 645 Windermere Road, London, Ontario N5X 2P1, Canada. E-mail address: agupta@execulink.com (A.K. Gupta).

subungual onychomycosis (DLSO), supercial onychomycosis, proximal subungual onychomycosis (PSO), endonyx onychomycosis (EO), and total dystrophic onychomycosis (TDO). Of these, DLSO is the most common. Invasion of fungal hyphae begins at the hyponychium and spreads along the nail bed proximally, with concurrent digestion of the stratum corneum and the inferior aspect of the nail plate resulting in discoloration, thickening of the nail, subungual hyperkeratosis, and onycholysis [13,14]. Supercial onychomycosis develops as an invasion of the dorsal surface of the nail plate, appearing as a white or black powdery and patchy discoloration [13,15]. White supercial onychomycosis typically is caused by T. mentagrophytes var. interdigitale, whereas black supercial onychomycosis is caused primarily by dematiaceous or black fungi, such as Scytalidium dimidiatum, and T. rubrum [15]. PSO is characterized by fungal invasion of the proximal nail fold followed by a deeper infection of the nail plate [15]. Infection presents as a distally progressing white spot under the lunula and may be associated with paronychia [14]. In most cases, PSO is caused by T. rubrum [16]. Immunocompromised individuals are particularly susceptible to proximal white subungual onychomycosis, a subset of PSO, because of the loss of barrier function of the cuticle, usually of the toenail [13]. EO occurs most infrequently and usually is caused by infection with T. soudanense [17]. The fungus invades the surface of the nail and penetrates deep into the nail plate [12]. Clinical presentation of the condition is similar to that of DLSO; however, nail thickness may appear normal, with hyperkeratosis and onycholysis being absent [18]. Finally, the most advanced form of onychomycosis is TDO [16]. In this condition the nail crumbles away
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0733-8635/06/$ - see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2006.03.008

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exposing a thickened, abnormal nail bed that retains some fragments of the nail plate [16]. TDO may be primary or secondary in nature, with the former aecting patients in immunodecient disease states, especially chronic mucocutaneous candidiasis, and the latter occurring as the advanced end stage of any of the other forms of onychomycosis [14,15].

black E, or Calcouor white also may enhance visualization [23,24]. Chlorazol black E is chitin specic and stains the cell walls of the hyphae a blue-black color, whereas Calcouor white, a uorescent dye, binds to cellulose and chitin, selectively highlighting fungal cell walls [23,24]. Fungal culture Identication of causative fungal pathogens by culture involves the inoculation of pulverized nail samples onto two types of media, usually one with and one without cycloheximide. Specically, cycloheximide-free Sabourauds glucose agar or other media (eg, Littman-oxgall agar, Borelli medium) allow for the growth of most fungi, whereas Sabourauds glucose agar with cycloheximide selects for dermatophytes and Candida albicans [22,24]. Bacterial growth is inhibited by the addition of chloramphenicol and gentamicin to the media. Fungi are identied based on their growth rates following incubation at 26 to 30 C for up to one month. Yeasts and nondermatophyte molds tend to grow more rapidly than dermatophytes, in a matter of days versus weeks, respectively. Histopathology The histologic analysis of nails involves an invasive nail biopsy, a procedure in which the distal free edge of the nail is clipped at its attachment to the nail bed. The nail sample is thinly sectioned and analyzed using the periodic acid-Schi (PAS) stain that demonstrates the presence of glycogen and mucoproteins in the cell walls of fungal hyphae [23]. Cell walls of the fungal hyphae appear red, indicating a positive stain [13]. Immunohistochemistry With this procedure, nail sample sections are exposed to labeled antibodies specic to suspected fungal pathogens. Monoclonal anti-Trichophyton spp (dermatophytes), anti-Candida spp (yeasts), and anti-Aspergillaceae spp (molds) antibodies are used for the identication of the fungi [23]. Visualization is achieved by direct immunouorescence, immunoperoxidase, or avidinbiotin complex methods [23]. Flow cytometry Flow cytometry is based on the ability to identify molecular variances among fungal species. Dissociated nail samples are ltered to collect

Diagnostic techniques Although onychomycosis is the most common cause of nail abnormalities, other disorders also produce nail changes. Indeed, 50% of cases believed to be onychomycosis actually are other types of disorders [19]. Psoriasis, chronic onycholysis, lichen planus, alopecia areata, chronic paronychia, hemorrhage or trauma, onychogryphosis, aging, median canalicular dystrophy, subungual malignant melanoma, and subungual squamous cell carcinoma all may cause nail changes that can be mistaken for onychomycosis [20,21]. Further complicating the accurate diagnosis of onychomycosis is the correct identication of the causative organism. Because onychomycosis can be caused by several pathogens whose appearance may be indistinguishable clinically, it is essential that the causative organism is positively identied so that the appropriate course of treatment may be initiated. At present, a diagnosis of onychomycosis commonly is conrmed by clinical examination and specimen analysis by direct microscopy and fungal culture. Other analytic techniques include histologic analysis, immunohistochemistry, ow cytometry, in vivo confocal microscopy, scanning electron microscopy, and polymerase chain reaction (PCR) methods. In the following sections we discuss the ecacy and sensitivity of these various techniques as diagnostic strategies for the verication of onychomycosis in a clinical setting. Microscopy Direct examination by light microscopy allows for visualization of fungal hyphae in nail specimens, usually within 20 to 30 minutes [22]. Nail samples are treated with a 20% to 30% potassium hydroxide (KOH) solution that softens and clears the cells of the stratum corneum allowing for visualization of refractile septate hyphae [19,23]. Sensitivity is enhanced by the addition of 40% dimethyl sulfoxide to the preparation [19]. Counterstaining with Parkers blue-black ink, Chlorazol

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Table 1 A comparison of diagnostic techniques for onychomycosis Diagnostic procedure Microscopy (KOH preparation) Advantages  Establishes the presence or absence of fungal laments in a nail sample  Sometimes can distinguish between dermatophyte/nondermatophyte hyphae and pseudohyphae of yeasts  Immediate results  Permits species identication of invading pathogen  Conrms viability of fungal infection in nail specimen  Prompt results  Highly sensitive in combination with fungal culture  In situ identication of fungal pathogens (decreased likelihood of false-positive results because of contamination)  May be useful in the identication of mixed infections  Provides information about fungal load  Allows for identication of fungal species  The nail can be examined in vivo (there is no need for stains or dyes)  Fungal hyphae can be detected in the nail plate and the nail bed  More discriminatory than standard microscopic techniques  Generates 3D images of high resolution, high magnication, and large focal depth  Detailed imaging of the spatial orientation, penetration, and integration of fungal elements in the nail plate  Based on genotypic characteristics (not phenotypic)  When used with restriction fragment length polymorphism technique it allows for the identication of fungal species, strain, and subtype Disadvantages  Cannot identify specic genus or species of the invading pathogen  False-negative results may occur because of poor visualization of fungal laments (counterstaining yields fewer false-negative results)  Lengthy process  Possibility of erroneous results because of sample contamination  Causative pathogen cannot be determined  Does not provide information about viability of the pathogen  Limited selection of antibodies does not permit for identication of all potential pathogens  Complicated and costly procedure

Mycologic examination (fungal culture)

Histopathology with periodic acid-Schi stain

Immunohistochemistry

Flow cytometry

 Complicated, costly procedure requiring experienced sta and specialized data analysis software  Limited ability to distinguish between dermatophyte/ nondermatophyte hyphae and pseudohyphae of yeasts

In vivo confocal microscopy

Scanning electron microscopy

 Expensive

PCR

 Sucient nail material containing adequate amounts of fungal DNA must be taken in the sample to perform PCR analysis

single fungal cells that are analyzed with a ow cell sorter on the basis of DNA and protein detection, cell size, and cell granulosity. Data acquisition and analysis software is used to generate distinct proles for fungal species [23].

In vivo confocal microscopy In vivo confocal microscopy is a highly discriminatory technique that facilitates the examination of living tissue. Reected light is used to

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penetrate the nail at various depths, thus imaging layers of the nail optically. Detection of fungal hyphae in the nail plate and nail bed depends on light penetration into the tissue and the reectivity of the structures being observed [25,26]. Scanning electron microscopy Scanning electron microscopy generates threedimensional images of high resolution, high magnication, and large focal depth. Cross-sectioned nail specimens are xed, dehydrated, and dried for viewing with a scanning electron microscope, allowing for detailed imaging of the spatial orientation, penetration, and integration of fungal hyphal elements in the nail plate [27]. Polymerase chain reaction methods PCR provides sensitive and specic detection of DNA sequences. DNA extracted from nail specimens is amplied by PCR methods. Detection and dierentiation of dermatophytes, nondermatophyte molds, and yeasts is achieved by amplication with specic fungal DNA primer sets. Subsequent digestion by restriction enzymes in restriction fragment length polymorphism analysis allows for identication of fungal species, strain, and subtype [2832].

specimens. This technique is of limited usefulness in the detection of mixed infections [15]. Recent studies by Borkowski and coworkers [35] and Lawry and coworkers [36] have compared the ecacy of various methods in the diagnosis of onychomycosis. Both of these studies concluded that histopathologic examination with PAS was more eective than KOH and fungal culture for the diagnosis of onychomycosis [35,36]. With PAS examination, however, it is not possible to establish the identity of the causative organism. Lawry and colleagues further concluded that PAS examination in combination with fungal culture is the most sensitive method of detection [36]. Advanced diagnostic techniques, including immunohistochemistry, ow cytometry, confocal and scanning electron microscopy, and PCR methods, have been used successfully in the diagnosis of onychomycosis [23,2532]; however, the wide implementation of these techniques is unlikely, because they are complicated and prohibitive in cost.

Summary A myriad of techniques exists for the diagnosis of onychomycosis, some more ecacious than others. The successful long-term treatment of this condition is incumbent upon the proper identication of the causative pathogen. Common clinical practice is to use KOH-based microscopy with fungal culture for conrmation of the diagnosis of onychomycosis. More sensitive methods of diagnosis are available, specically histopathology with PAS. In clinical practice, therefore, it would be prudent to consider the available methods of evaluation of nail specimens in suspected cases of onychomycosis to ensure accurate diagnosis.

Assessment and comparison of techniques The management of onychomycosis is not merely a cosmetic issue. If left untreated, onychomycosis may result in secondary bacterial infection. It can cause pain and discomfort, thus aecting mobility in the case of toenail onychomycosis. Of further concern are the psychosocial implications of abnormal-appearing nails: patients may experience an impaired quality of life and a reduced self-esteem; they also may limit interaction with other individuals [33]. A denitive diagnosis of onychomycosis is an essential step in the proper management of the disease because eective treatment by various antifungal agents depends on the pathogenic organism. Although several methods exist for the diagnosis of onychomycosis, each with specic advantages and limitations (Table 1), the clinical standard for diagnosis is KOH-based direct microscopy combined with fungal culture, despite the fact that false-negative culture rates may be as high as 30% [34]. Summerbell and colleagues [15] suggest that the sensitivity of this method is improved with longitudinal sampling of nail

References
[1] Summerbell RC, Kane J, Krajden S. Onychomycosis, tinea pedis and tinea manuum caused by nondermatophytic lamentous fungi. Mycoses 1989;32: 60919. [2] Haneke E. Achilles foot-screening project: background, objectives and design. J Eur Acad Dermatol Venerol 1999;12:S25. [3] Elewski BE, Charif MA. Prevalence of onychomychosis in patients attending a dermatology clinic in northeastern Ohio for other conditions. Arch Dermatol 1997;133:11723. [4] Gupta AK, Jain HC, Lynde CW, et al. Prevalence and epidemiology of onychomychosis in patients

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[5]

[6] [7]

[8]

[9]

[10]

[11]

[12] [13]

[14] [15]

[16]

[17]

[18]

[19] [20] [21]

visiting physicians oces: a multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol 2000;43(2 pt 1):2448. Burzykowski T, Molenberghs G, Abeck D, et al. High prevalence of foot disease in Europe: results of the Achilles project. Mycoses 2003;46:496505. Gupta AK. Onychomycosis in the elderly. Drug Aging 2000;16:397407. Sigurgeirsson B, Steingrimsson O. Risk factors associated with onychomycosis. J Eur Acad Dermatol Venereol 2004;18:4851. Gupta AK, Gupta MA, Summerbell RC, et al. Epidemiology and prevalence of onychomycosis: possible role of smoking and peripheral arterial disease. J Eur Acad Dermatol Venereol 2000;14: 4669. Gupta AK, Taborda P, Taborda V, et al. Epidemiology and prevalence of onychomycosis in HIV-positive individuals. Int J Dermatol 2000;39:74653. Gupta AK, Lynde CW, Jain HC, et al. A higher prevalence of onychomycosis in psoriatics compared with non-psoriatics: a multicentre study. Br J Dermatol 1997;136:7869. Tosti A, Hay R, Arenas-Guzman R. Patients at risk of onychomycosis-risk factor identication and active prevention. J Eur Acad Dermatol Venereol 2005;(Suppl 1):136. Baran R, Hay RJ, Tosti A, et al. A new classication of onychomycosis. Br J Dermatol 1998;139(4):56771. Lemont H. Pathologic and diagnostic considerations in onychomycosis. J Am Podiatr Med Assoc 1997;87(11):498506. Mahoney JM, Bennet J, Olsen B. The diagnosis of onychomycosis. Dermatol Clin 2003;21:4637. Gupta AK, Ryder JE, Summerbell RC. Onychomycosis: classication and diagnosis. J Drugs Dermatol 2004;3(1):516. Hay RJ, Baran R, Haneke E. Fungal (onychomycosis) and other infections involving the nail apparatus. In: Baran R, Dawber RPR, editors. Baran and Dawbers diseases of the nails and their management. 2nd edition. Oxford: Blackwell Science; 2001. p. 12971. Fletcher CL, Moore MK, Hay RJ. Endonyx onychomycosis due to Trichophyton soudanense in two Somalian siblings. Br J Dermatol 2001;145:6878. Tosti A, Baran R, Piraccini BM, et al. Endonyx onychomycosis: a new modality of nail invasion by dermatophytes. Acta Derm Venereol 1999;79:523. Zaias N, Glick B, Rebell G. Diagnosing and treating onychomycosis. J Fam Pract 1996;42:5138. Lynde C. Nail disorders that mimic onychomycosis: what to consider. Cutis 2001;68(Suppl 2):812. Jae R. Onychomycosis: recognition, diagnosis and management. Arch Fam Med 1998;7:58792.

[22] Feuilhade de Chauvin M. New diagnostic techniques. J Eur Acad Dermatol Venereol 2005; 19(Suppl 1):204. [23] Pierard GE, Arrese JE, DeDoncker P, et al. Present and potential diagnostic techniques in onychomycosis. J Am Acad Dermatol 1996;34(2 Pt 1):2737. [24] Elewski BE. Diagnostic techniques for conrming onychomycosis. J Am Acad Dermatol 1996;35:S69. [25] Kaufman SC, Beuerman RW, Greer DL. Confocal microscopy: a new tool for the study of the nail unit. J Am Acad Dermatol 1995;32(4):66870. [26] Hongcharu W, Dwyer P, Gonzalez S, et al. Conrmation of onychomycosis by in vivo confocal microscopy. J Am Acad Dermatol 2000;42(2 Pt 1):2146. [27] Scherer WP, Scherer MD. Scanning electron microscope imaging of onychomycosis. J Am Podiatr Med Assoc 2004;94(4):35662. [28] Arca E, Saracli MA, Akar A, et al. Polymerase chain reaction in the diagnosis of onychomycosis. Eur J Dermatol 2004;14:525. [29] Machouart-Dubach M, Lacroix C, Feuilhade de Chauvin M, et al. Rapid discrimination among dermatophytes, Scytalidium spp., and other fungi with a PCR-restriction fragment length polymorphism ribotyping method. J Clin Microbiol 2001;39(2): 68590. [30] Mochizuki T, Ishizaki H, Barton RC, et al. Restriction fragment length polymorphism analysis of ribosomal DNA intergenic regions is useful for differentiating strains of Tricophyton mentagrophytes. J Clin Microbiol 2003;41(10):45838. [31] Yazdanparast A, Jackson CJ, Barton RC, et al. Molecular strain typing of Trichophyton rubrum indicates multiple strain involvement in onychomycosis. Br J Dermatol 2003;148(1):514. [32] Shin JH, Sung JH, Park SJ, et al. Species identication and strain dierentiation of dermatophyte fungi using polymerase chain reaction amplication and restriction enzyme analysis. J Am Acad Dermatol 2003;48(6):85765. [33] Scher RK. Onychomycosis is more than a cosmetic problem. Br J Dermatol 1994;130(43):15. [34] Fletcher CL, Hay RJ, Smeeton NC. Onychomycosis: the development of a clinical diagnostic aid for toenail disease. Part I. Establishing discriminating historical and clinical features. Br J Dermatol 2004;150:7015. [35] Borkowski P, Williams M, Holewinski J, et al. Onychomycosis: an analysis of 50 cases and a comparison of diagnostic techniques. J Am Pod Med Assoc 2001; 91(7):3515. [36] Lawry MA, Haneke E, Strobeck K, et al. Methods for diagnosing onychomycosis. A comparative study and review of the literature. Arch Dermatol 2000; 136:11126.

Dermatol Clin 24 (2006) 371374

Spotlight on Nail Histomycology

rald E. Pie rard, MD, PhD*, Pascale Quatresooz, MD, PhD, Ge Jorge E. Arrese, MD, PhD
Department of Dermatopathology, University Hospital of Lie`ge, CHU Sart Tilman, B-4000 Lie`ge, Belgium

Some practitioners remain under the misconception that onychomycoses are diagnosed easily. Accurate diagnosis may be problematic [1,2], but proper diagnosis is imperative to prevent ineective and expensive therapy [3,4], disease relapse, and drug-related risk exposure. Precision in the clinical diagnosis and the expertise with which the nail material is sampled for laboratory purposes have a major inuence on the nal diagnosis. Diculties in diagnosing onychomycoses primarily result from the etiologic diversity regarding the nature of the invading fungus. A large proportion of onychomycoses are caused by dermatophytes, predominantly from the genus Trichophyton. Nondermatophyte molds and yeasts also can be responsible for the disease, however. In temperate countries, dermatophytes may account for approximately 75% of all fungal infections, whereas yeasts and nondermatophyte molds account for 5% to 15%, respectively [5,6]. Diagnostic problems may be caused by the presentation of mixed fungal infections involving a combination of distinct pathogens [1,2,7,8]. Following a presumptive clinical diagnosis of onychomycosis, mycologic assessments designed to identify the causative pathogens should be performed before treatment. The identication of the exact pathogens involved is crucial because some fungi, particularly yeasts and nondermatophyte molds, are less sensitive or even unresponsive to some antifungal drugs. Both microscopy of potassium hydroxide (KOH) preparations and culture performed on adequate specimens are essential for improving diagnostic

* Corresponding author. E-mail address: Gerald.pierard@ulg.ac.be rard). (G.E. Pie

accuracy [1,912]. The sensitivity of microscopy may be enhanced by the use of stains, including blue Parker ink and several specic uorochromes [1,13]. Nevertheless, the combination of culture and direct microscopy may yield 30% to 50% false-negative data, depending on the methods used to collect and prepare the samples [1,1416]. The limited dependability of these detection methods is because of the numerous sources of error that might be involved [1,14,16]. Aside from correct nail sampling, the successful culture of an infectious agent requires adequate selection of the culture medium, optimal temperature conditions, suciently large samples of the material, and the presence of viable fungi [14]. Possible contamination with some bacteria or nondermatophytic molds can prevent the growth of the actual infectious agent, or mask its presence in the case of contaminant overgrowth [14]. Various structures, such as bers, air bubbles, and fat droplets, may resemble fungal cells in the KOH preparations and thereby may lead to falsepositive results. Fungi are modular organisms that can have visible but dead sections in direct microscopy. This phenomenon leads to a KOH-positive but culture-negative sample. Conversely, subungual scraping samples may yield few viable arthroconidia that may be all but overlooked in direct microscopy yet grow with culture. In these instances, the issue is a KOH-negative but culturepositive sample. The use of vital stains, such as neutral red, can help in distinguishing living from dead fungal cells under the microscope [8]. This examination can be performed only on fresh smears from subungual hyperkeratosis and from scrapings of supercial white onychomycosis. Reliable dierentiation between pathogenic fungi that have invaded the nail and nonpathogenic
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et al

secondary colonizers or contaminants cannot be made with condence at culture. There is a diagnostic gap that should be closed through an additional method, such as histomycology. Histomycology Histomycology is a time-honored method [17 21] that has been rened and revisited during the past decade or so. The method refers to the microscopic examination of histologic sections of nail material after staining with periodic acid-Schi to reveal the presence of fungi, if any. The microorganisms are recognized as positively stained thread-like structures (hyphae and pseudohyphae) or dots (yeasts and arthroconidia) [1,7,8,14,15,2231]. These fungal cells are present among onychocytes in the bulk of the nail plate or in the subungual transitional zone below the body of the nail (Fig. 1). The fungal cells are readily visible even when scantily scattered fungal material is present in the nail sample. This method has a high degree of sensitivity and specicity [1,7,14,15,26,28,31]. Histologic sections of nail clippings notably increase the diagnostic accuracy because the invasiveness of the fungus can be observed clearly [7,8,2831]. The location of the fungus also can be determined with precision. In some instances, this cannot be guessed by clinical inspection alone. Invading fungi thus can be distinguished from colonizing or contaminating agents [32]. The morphologic aspect of the fungus can, in some instances, distinguish dermatophytes from yeasts and nondermatophytic molds (Fig. 2). These morphologic dierences can help identify mixed infection involving more than one fungus [7,8,28,31].

Two types of mixed infections can be observed according to the presence of the fungi at the same site or at dierent sites of the nail plate. In the rst instance, one of the fungi may represent a passive bystander or an opportunistic agent. In the second case, both fungi must be primary invaders and pathogens. Although additional diagnostic procedures, such as immunohistochemistry, ow cytometry, and PCR analysis, are perhaps more sensitive [1,23] these methods are not generally available to the practicing clinician. The probability of a positive identication of a pathogen by histomycology is substantially greater than those observed for the other methods of mycologic detection [1,7,14,15]. Based on the few interfering factors (eg, artifacts from starch particles, serum, and parakeratotic cells) that might conceivably result in false-positive results, it is assumed that nearly all cases in which the results are evaluated as being positive by histomycology are actually true positive results. Prognostic factors Some aspects revealed by histomycology can be interpreted as prognostic factors for the

Fig. 1. Fungal hyphae invading the transition zone between the nail plate and its subungual keratinized portion.

Fig. 2. Septate hyphae and conidia (A, B).

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evolution of the onychomycosis under consideration. No other laboratory method provides similar information. The various fungi responsible for onychomycoses do not respond equally to antifungal therapies. Furthermore, the presence of some easily recognizable species, such as Scopulariopsis brevicaulis, may complicate treatment. The situation is similar when some lamentous, irregularlyshaped, nondermatophyte molds are seen and identied at culture. The extent of the fungal load may be related to a lower therapeutic response. Dermatophytoma is the archetype of such a situation [33]. The application of image analysis to histomycology is an objective means to quantify the amount of fungal cells present inside a given nail [1]. The biology of fungi is inuenced notably by the environment. Filamentous fungi may form chlamydospores and arthroconidia, commonly referred to as spores. These dormant cells survive adverse conditions and they are largely refractory to the current antifungals. When they are entrapped inside the nail, spores may survive therapy and give rise to recurrent onychomycosis. Scrutinizing nail samples by histomycology led to the identication of sporodochia (Figs. 3 and 4) that have been described in association with onychomycosis [34]. These fungal structures correspond to collections of parallel-oriented, cushion-like hyphal aggregates on the surface of the tissue, upon which a lawn of conidia, chlamydospores, or budding conidia develop. Sporodochia have been found at the surface of cutaneous wounds [35]. Histomycology of onychomycoses revealed that sporodochium formation occurred only at the distal part of the

Fig. 4. Sporodochium depicted in Fig. 3 showing a mixture of hyphae and spores.

subungual structure protected by the nail plate, forming a roof above it [34]. With the presence of numerous budding cells, chlamydospores, and conidia at the surface of sporodochia, there exists the potential for these to be aerosolized and spread from one site to another by autoinoculation, person-to-person spread, and fomites. Conclusion Because there is no clinical sign specic to onychomycosis, nail sampling is mandatory to conrm the diagnosis. Before starting treatment, which is lengthy, costly, and has a potential for causing side eects, the clinician needs to ascertain that the prescription choice is justied and appropriate. Despite possible laboratory errors and cost to the health care system, appropriate mycologic diagnosis is a worthwhile procedure. Histomycology is quick and easy to perform. It increases the sensitivity in diagnosing onychomycosis above that achieved by culture and KOH preparation alone. Because information concerning the vitality of the fungi and accurate identication of the specic pathogen is not available through this investigation alone, however, mycologic culture continues to be necessary in combination with histomycology. References
rard GE, Arrese JE, De Doncker P, et al. Present [1] Pie and potential diagnostic techniques in onychomycosis. J Am Acad Dermatol 1996;34:2737. rard-Franchimont C, Pie rard GE. [2] Arrese JE, Pie Facing up to the diagnostic uncertainty and management of onychomycoses. Int J Dermatol 1999; 38(suppl 2):16.

Fig. 3. Sporodochium of the distal part of the nail contiguous with invasive hyphae inside the nail.

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et al tude histochimi[19] Achten G, Simonart JM. Longle: e que et mycologique. Ann Dermatol Syphil 1963;90: 56986. [20] Gentles JC. Laboratory investigations of dermatophytic infections of nails. Sabouraudia 1971;9: 14952. [21] Achten G, Wanet-Rouard J. Onychomycoses in the laboratory. Mykosen 1978;23:1257. [22] Suarez SM, Silvers DN, Scher RK, et al. Histologic evaluation of nail clippings for diagnosing onychomycosis. Arch Dermatol 1991;127:15179. rard-Franchimont C, Greimers R, [23] Arrese JE, Pie et al. Fungi in onychomycosis: a study by immunohistochemistry and dual ow cytometry. J Eur Acad Dermatol Venereol 1995;4:12330. rard-Franchimont C, Pie rard GE. Fa[24] Arrese JE, Pie tal hyalohyphomycosis following Fusarium onychomycosis in an immunocompromised patient. Am J Dermatopathol 1996;18:12968. rard-Franchimont C, Pie rard GE. [25] Arrese JE, Pie Onychomycosis and keratomycosis caused by Alternaria sp. A bipolar opportunistic infection in a woodpulp worker on chronic steroid therapy. Am J Dermatopathol 1996;18:6113. [26] Machler BC, Kirsner RS, Elgart GW. Routine histologic examination for the diagnosis of onychomycosis: an evaluation of sensitivity and specicity. Cutis 1998;61:2179. [27] Gianni C, Morelli V, Cerri A, et al. Usefulness of histological examination for the diagnosis of onychomycosis. Dermatology 2001;202:2838. rard GE. Treatment failures and re[28] Arrese JE, Pie lapses in onychomycosis: a stubborn clinical problem. Dermatology 2003;207:25560. rard-Franchimont C, [29] Arrese JE, Quatrezooz P, Pie ale. Ann Dermatol et al. Histomycologie ungue Venereol 2003;130:12549. [30] Baran R, Hay R, Perrin C. Supercial white onychomycosis revisited. J Eur Acad Dermatol Venereol 2004;18:56971. rard GE, Arrese JE, Quatresooz P. Histomycologie [31] Pie des onychomycoses. In: Baran R, de la biodiversite rard GE, editors. Onychomycoses. Paris: Abre ge s Pie Masson; 2004. p. 91104. rard GE, Pie rard-Franchimont C, Arrese JE, [32] Pie et al. Onychomycoses caused by primary pathogens and opportunistic fungi. Chinese J Dermatol 1998; 31:3089. [33] Roberts DT, Evans EG. Subungual dermatophytoma complicating dermatophyte onychomycosis. Br J Dermatol 1998;138:18990. rard GE. Spores, sporodochia and the fomites in [34] Pie onychomycosis. Dermatology In press. [35] Smith M, McGinnis MR. Fusarium sprodochia on cutaneous wounds. Med Mycol 2005;43:836.

[3] Mehregan DC, Gee SL. The cost eectiveness of testing for onychomycosis versus empiric treatment of onychodystrophies with oral antifungal agents. Cutis 1999;64:40710. rard-Franchimont C, Pie rard GE. A [4] Arrese JE, Pie plea to bridge the gap between antifungals and the management of onychomycosis. Am J Clin Dermatol 2001;2:2814. [5] Summerbell RC. Epidemiology and ecology of onychomycosis. Dermatology 1997;194(suppl 1):326. [6] Haneke E, Roseeuw D. The scope of onychomycosis: epidemiology and clinical features. Int J Dermatol 1999;38:712. rard GE, Arrese JE, Pierre S, et al. Diagnostic [7] Pie microscopique des onychomycoses. Ann Dermatol Venerol 1994;121:259. rard GE, Arrese JE, Pie rard-Franchimont C, et al. [8] Pie Onychomycosis under the microscope. Monograph. Beerse, Belgium: Janssen Pharmaceutica; 2003. [9] Lawry MA, Haneke E, Strobeck K, et al. Methods for diagnosing onychomycosis: a comparative study and review of the literature. Arch Dermatol 2000; 136:11126. [10] Borkowski P, Williams M, Holewinski J, et al. Onychomycosis: an analysis of 50 cases and a comparison of diagnostic techniques. J Am Podiatr Med Assoc 2001;91:3515. [11] Gupta AK, Cooper EA, Macdonald P, et al. Utility of inoculum counting (Walshe and English criteria) in clinical diagnosis of onychomycosis caused by nondermatophytic lamentous fungi. J Clin Microbiol 2001;39:211521. [12] Summerbell RC, Cooper E, Bunn U, et al. Onychomycosis: a critical study of techniques and criteria for conrming the etiologic signicance of nondermatophytes. Med Mycol 2005;43:3959. [13] Sparkes AH, Werrett G, Stokes CR, et al. Improved sensitivity in the diagnosis of dermatophytosis by uorescence microscopy with calcouor white. Vet Rec 1994;134:3078. [14] Reisberger EM, Abels C, Landthaler M, et al. Histopathological diagnosis of onychomycosis by periodic acid-Schi-stained nail clippings. Br J Dermatol 2003;148:74954. [15] Weinberg JM, Koestenblatt EK, Tutrone WD, et al. Comparison of diagnostic methods in the evaluation of onychomycosis. J Am Acad Dermatol 2003;49:1937. rard-Franchimont C, Khar M, Pie rard GE. [16] Pie le ` vement et examen mycologiques des onychoPre rard GE, editors. Onychomycoses. In: Baran R, Pie ge s Masson; 2004. p. 7990. mycoses. Paris: Abre [17] Sagher F. Histologic examinations of fungous infections of the nails. J Invest Dermatol 1948;11:33757. [18] Jillson OF, Piper EL. The localization of fungi within human nails. J Invest Dermatol 1957;28:13746.

Dermatol Clin 24 (2006) 375379

Therapies for Onychomycosis: A Review

Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Linh Q. Tu, HBHScb
a

Division of Dermatology, Department of Medicine, Sunnybrook and Womens College Health Sciences Centre, (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue Toronto, ON M4N 3M5, Canada b Mediprobe Research, Inc., London, ON N5X 2P1, Canada

Onychomycosis, a chronic fungal infection of the nail, can be treated using various modalities: nail removal and management via surgical or mechanical procedures, chemical treatment, topical lacquer, oral antimycotic agent, or a combination of one or more of these therapeutic options. In the past, onychomycosis was regarded primarily as a cosmetic problem and treatment was not always sought because ecacy rates of available treatments at the time were not that encouraging. Currently, onychomycosis is recognized as a health issue that requires attention, especially because untreated onychomycosis has the potential to cause serious complications in certain special populations. In persons who have diabetes, the onychomycotic nail that becomes thick and jagged may predispose the surrounding skin to trauma, which may result in bacterial or fungal infection that can compound the morbidity of the diabetic foot [1]. Foot and leg ulcerations, a common and serious aspect of the diabetic foot, frequently lead to lower extremity amputations. More than 80% of lower extremity amputations among individuals who have diabetes are the result of complications of a foot ulcer [2]. When treating onychomycosis, it is imperative to consider several factors before selecting a therapy: ngernail or toenail disease, severity of the onychomycosis, number of nails aected, causative organism, concomitant drugs, and patient/ physician preference [3]. Identication of the

specic causative organism is important because some organisms are less likely to respond to certain antifungal agents. For example, if the onychomycosis is caused by Scytalidium dimidiatum, it is possible that none of the approved antifungal agents for onychomycosis will be particularly eective, and mechanical avulsion of the nail becomes a management option [4]. Treatment options for onychomycosis include oral, topical, mechanical, and chemical therapies or a combination of these modalities. Fig. 1 summarizes the therapies for onychomycosis that are approved in North America. Mechanical Mechanical procedures include debridement and surgical avulsion. The objective of debridement is to reduce the thickness of the nail plate so that any associated pain is reduced and the probability of success of oral/topical therapies is enhanced. The thickened, ragged, misshaped toenail or ngernail can be bued and smoothed down using a rotary burr to prevent further trauma caused by clothing or footwear [5]. Attempts to remove the infected nail by the patient may be of limited benet and may result in complications, such as traumatic partial avulsion or onychocryptosis (ingrown toenail). Debridement of the infected nail by a trained health care professional can help manage the onychomycosis but is unlikely to cure the onychomycosis when used as monotherapy. Total or partial surgical nail avulsion is another technique for removing the onychomycotic nail. Completely removing the nail plate relieves the counterpressure on the nail bed, which in turn allows the distal soft tissue to expand and
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Fig. 1. Summary of approved onychomycosis therapies in North America.

promotes ingrown nails [6]. The use of a prosthetic nail could maintain the normal width of the nail bed and avoid subsequent ingrowth [7]. Partial nail avulsion is preferred over total nail avulsion because it can avoid the problems mentioned previously. Surgical nail avulsion and manual debridement should be followed up with either a topical or oral antifungal agent. Chemical Chemical nail avulsion, equivalent to surgical partial nail avulsion, is a painless method of removing the infected portion of the nail plate. Once the surrounding skin has been protected to prevent irritation, 40% urea ointment (or another formulation) is applied to the nail, and the entire distal end of the digit is kept bandaged for 1 week. The urea ointment enables the diseased nail to be removed, leaving the healthy tissue intact. Topical Conventional topical antifungal agents, which are formulated in creams, ointments, powders, and solutions, are most appropriately used when the nail plate has been removed, because topical formulations are typically unable to penetrate the nail plate through to the nail bed. Even with the nail plate removed, however, topical applications still have shortcomings that result in low cure

rates. Conventional topical treatments are easily removed by rubbing, wiping, and washing. Topical nail lacquers The newest advance in topical treatments has been the introduction of amorolne and ciclopirox nail lacquers. Upon application, the solvent in the solution evaporates, which increases the concentration of the active drug in the remaining lm reservoir and provides the necessary high concentration gradient for maximal penetration through the nail plate. The high concentration of active ingredient is maintained in the nail plate by the components of the lacquer formulation (eg, solvent, polymer, plasticizer), which can optimize and modulate the release of the antifungal agent. This formulation also allows the active ingredient to remain in contact with the nail plate for a longer duration, again increasing the potential for successful treatment. Ciclopirox nail lacquer solution Ciclopirox nail lacquer solution is the only topical treatment indicated for onychomycosis that is approved by the US Food and Drug Administration. Researchers hypothesize that ciclopirox acts as a chelating agent and primarily aects iron-dependent mitochondrial enzymes of the fungi [8,9]. The ecacy of ciclopirox nail lacquer 8% has been evaluated in the United States, where two

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pivotal multicenter, randomized, double-blind, vehicle-controlled, parallel-group studies were conducted and showed a combined mycologic cure (negative KOH, negative culture) rate of 32%, a treatment cure (negative KOH, negative culture, global evaluation score cleared) rate of 7%, and a treatment success (negative KOH, negative culture, %10% involvement of target nail) rate of 9% in the active group, compared with 10%, 0.4%, and 0.9%, respectively, in the vehicle group [10]. Amorolne nail lacquer Amorolne is a phenyl-propyl morpholine derivative. Like most other antifungal agents, it interferes with ergosterol biosynthesis. Its broadspectrum fungicidal activity depends on concentration of the drug and duration of contact. The formulation, tolerability, and ecacy of amorolne nail lacquer have been reported by various researchers [1114]. These studies have shown amorolne to be a tolerable and eective treatment; however, this agent is not approved in North America for the treatment of onychomycosis.

including Trichophyton spp, Microsporum spp, and Epidermophyton occosum. It is not eective against Candida spp and the nondermatophyte molds. Griseofulvin inhibits fungal reproduction by preventing the formation of the fungal intracellular microtubules, disrupting the mitotic spindle, and preventing the division of fungal cells [15]. Azoles (imidazoles and triazoles) The azole class of antifungal agents used to treat onychomycosis includes itraconazole, ketoconazole, and uconazole. They are fungistatic against a broad spectrum of pathogens, including dermatophytes, yeasts (eg, Candida spp), and other fungi (eg, Aspergillus spp). The azoles function primarily by selectively inhibiting fungal cytochrome P-450 (14a-sterol demethylase), which is an enzyme responsible for converting lanosterol to 14a-demethyllanosterol in the ergosterol biosynthesis pathway. Ergosterol is essential to fungus because it is a major membrane sterol; impairing the synthesis of ergosterol ultimately interferes with the function and permeability of the cell membrane of the fungal organism. Terbinane

Oral antifungal agents Oral antifungal agents are the most eective agents available to treat onychomycosis. Griseofulvin, itraconazole, and terbinane are approved by the US Food and Drug Administration for this treatment, although uconazole and ketoconazole are also occasionally prescribed for onychomycosis. Before initiating systemic treatment, it is imperative to consider several factors, such as concomitant medications and patient preference. Accounting for concomitant medications is especially important when treating persons who have diabetes and patients who are HIV positive. Patient preference is also important because it can aect compliance. Patients who know that they have diculty complying with a long course of therapy may fare better with regimens that involve short-term therapy.

Terbinane is the rst oral allylamine approved to treat onychomycosis. Unlike other oral antifungal agents, its action against dermatophytes is fungicidal as opposed to fungistatic. It is, however, fungistatic against some nondermatophyte molds and yeasts [15]. Terbinane acts at an earlier stage in the fungal reproductive cycle and inhibits squalene epoxidase, which is another key enzyme in the production of ergosterol. This inhibition prevents squalene metabolism and results in toxic accumulation of squalene with depletion of ergosterol [16].

Ecacy Terbinane, itraconazole, and uconazole are eective and safe treatments for onychomycosis [1725]. Meta-analyses and systematic reviews that compare the ecacy rates of terbinane, itraconazole, uconazole, ketoconazole, and griseofulvin in the treatment of dermatophyte toenail onychomycosis indicate that the continuous regimen of terbinane (250 mg/d for 12 weeks for dermatophyte toenail onychomycosis) remains superior to the other four oral antifungal agents [2628]. A cumulative meta-analysis of randomized, controlled trials conducted by Gupta

Mechanism of action Griseofulvin Griseofulvin was the rst oral antifungal drug approved by the US Food and Drug Administration for the treatment of onychomycosis. It is fungistatic in nature and active against dermatophytes,

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and colleagues [27] reported the following mycologic cure (negative KOH, negative culture) rates: terbinane 76% G 3%, itraconazole pulse 63% G 7%, itraconazole continuous 59% G 5%, uconazole 48% G 5%, and griseofulvin 60% G 6%. The corresponding clinical response (visually clear of infection or marked improvement) rates are as follows: terbinane 66% G 5%, itraconazole pulse 70% G 11%, itraconazole continuous 70% G 5%, uconazole 45% G 21%, and griseofulvin 2% G 2%. They found that the mycologic cure rates of most antifungal agents, especially terbinane, have remained relatively constant since their introduction for the management of dermatophyte toenail onychomycosis. The meta-analysis conducted by Haugh and colleagues [28] also endorses terbinane as the most eective treatment for dermatophyte toenail onychomycosis. Included in the analysis were studies that compared continuous terbinane to placebo, itraconazole, or griseofulvin. The results indicated that there was a statistically signicant advantage in favor of terbinane over the aforementioned treatments. Various pulse regimens using terbinane have been evaluated for the treatment of dermatophyte toenail onychomycosis [2931]. None of these regimens has been approved by the US Food and Drug Administration, however. A commonly used pulse regimen is terbinane, 250 mg once or twice daily for 1 week each month for 3 months. The causative organism implicated with toenail onychomycosis in North American studies is a dermatophyte in 90% or more of the cases [32]. In the case of onychomycosis caused by a nondermatophyte mold or Candida sp, no randomized, controlled studies have evaluated the ecacy of the oral or topical lacquers for the management of onychomycosis. It is more dicult to provide guidance about the agent to use in such an instance. Strategies to improve ecacy of therapy for onychomycosis For many patients, the standard approved regimen may not be sucient and supplemental therapy may be required. This aspect of management is discussed elsewhere in this issue. Prevention of recurrence of onychomycosis once treatment cure has been achieved In a substantial number of patients who seem to achieve clinical cure, onychomycosis appears to

recur (either relapse or reinfection). Strategies to reduce recurrence of disease are discussed elsewhere in this issue. Summary Onychomycosis has a prevalence rate of approximately 6% to 13% in North American studies, with dermatophytes (particularly Trichophyton rubrum) being the most prevalent organism. The treatment options for the management of onychomycosis are oral therapies, topical nail lacquer, mechanical or chemical treatments, or a combination of one or more of these modalities. The topical and oral therapies approved in North America for the management of onychomycosis are ciclopirox nail lacquer, griseofulvin, terbinane, and itraconazole. Currently, griseofulvin and ketoconazole are not generally used to treat toenail onychomycosis. Terbinane is the most eective oral agent for the treatment of dermatophyte onychomycosis. The management of onychomycosis must be individualized for each patient, taking into consideration several factors, including the causative organism, the potential for drug interactions and adverse eects, the severity of onychomycosis including the number of nails involved, the cost of therapy, and patient/physician preferences. References
[1] Rich P. Special patient populations: onychomycosis in the diabetic patient. J Am Acad Dermatol 1996; 35:S102. [2] Goodridge D, Trepman E, Embil JM. Healthrelated quality of life in diabetic patients with foot ulcers: literature review. J Wound Ostomy Continence Nurs 2005;32:36877. [3] Denning DW, Evans EG, Kibbler CC, et al. Fungal nail disease: a guide to good practice (report of a Working Group of the British Society for Medical Mycology). BMJ 1995;311:127781. [4] Elewski BE. Onychomycosis caused by Scytalidium dimidiatum. J Am Acad Dermatol 1996;35:3368. [5] Markinson BC, Monter SI, Cabrera G. Traditional approaches to treatment of onychomycosis. J Am Podiatr Med Assoc 1997;87:5516. [6] Daniel CR III. Traditional management of onychomycosis. J Am Acad Dermatol 1996;35:S215. [7] Hay RJ, Baran R, Haneke E. Fungal (onychomycosis) and other infections involving the nail apparatus. In: Baran R, Dawber RPR, de Berker DAR, et al, editors. Baran and Dawbers diseases of the nails and their management. Oxford: Blackwell Science Ltd.; 2001. p. 12971.

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[8] Bohn M, Kraemer K. The dermatopharmacologic prole of ciclopirox 8% nail lacquer. J Am Podiatr Med Assoc 2000;90:4914. [9] Sigle HC, Thewes S, Niewerth M, et al. Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans. J Antimicrob Chemother 2005;55:66373. [10] Dermik Laboratories. Penlac (ciclopirox) topical solution 8%: product monograph. Berwyn (PA): Dermik Laboratories; 2005. [11] Reinel D, Clarke C. Comparative ecacy and safety of amorolne nail lacquer 5% in onychomycosis, once-weekly versus twice-weekly. Clin Exp Dermatol 1992;17(Suppl 1):449. [12] Lauharanta J. Comparative ecacy and safety of amorolne nail lacquer 2% versus 5% once weekly. Clin Exp Dermatol 1992;17(Suppl 1):413. [13] Mensing H, Polak-Wyss A, Splanemann V. Determination of the subungual antifungal activity of amorolne after 1 months treatment in patients with onychomycosis: comparison of two nail lacquer formulations. Clin Exp Dermatol 1992;17(Suppl 1): 2932. [14] Reinel D. Topical treatment of onychomycosis with amorolne 5% nail lacquer: comparative ecacy and tolerability of once and twice weekly use. Dermatology 1992;184(Suppl 1):214. [15] Debruyne D, Coquerel A. Pharmacokinetics of antifungal agents in onychomycoses. Clin Pharmacokinet 2001;40:44172. [16] Ryder NS. Terbinane: mode of action and properties of the squalene epoxidase inhibition. Br J Dermatol 1992;126(Suppl 39):27. [17] Drake L, Babel D, Stewart DM, et al. Once-weekly uconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the ngernail. J Am Acad Dermatol 1998;38:S8794. [18] Evans EG, Sigurgeirsson B. Double blind, randomised study of continuous terbinane compared with intermittent itraconazole in treatment of toenail onychomycosis: the LION Study Group. BMJ 1999; 318:10315. [19] Gupta AK, Maddin S, Arlette J, et al. Itraconazole pulse therapy is eective in dermatophyte onychomycosis of the toenail: a double-blind placebocontrolled study. J Dermatolog Treat 2000;11:337. [20] Havu V, Brandt H, Heikkila H, et al. A doubleblind, randomized study comparing itraconazole pulse therapy with continuous dosing for the

[21]

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treatment of toe-nail onychomycosis. Br J Dermatol 1997;136:2304. Heikkila H, Stubb S. Long-term results in patients with onychomycosis treated with terbinane or itraconazole. Br J Dermatol 2002;146:2503. Ling MR, Swinyer LJ, Jarratt MT, et al. Onceweekly uconazole (450 mg) for 4, 6, or 9 months of treatment for distal subungual onychomycosis of the toenail. J Am Acad Dermatol 1998;38:S95102. Scher RK, Breneman D, Rich P, et al. Once-weekly uconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail. J Am Acad Dermatol 1998;38:S7786. Sigurgeirsson B, Olafsson JH, Steinsson JB, et al. Long-term eectiveness of treatment with terbinane vs itraconazole in onychomycosis: a 5-year blinded prospective follow-up study. Arch Dermatol 2002;138:3537. Warshaw EM, Fett DD, Bloomeld HE, et al. Pulse versus continuous terbinane for onychomycosis: a randomized, double-blind, controlled trial. J Am Acad Dermatol 2005;53:57884. Crawford F, Young P, Godfrey C, et al. Oral treatments for toenail onychomycosis: a systematic review. Arch Dermatol 2002;138:8116. Gupta AK, Ryder JE, Johnson AM. Cumulative meta-analysis of systemic antifungal agents for the treatment of onychomycosis. Br J Dermatol 2004; 150:53744. Haugh M, Helou S, Boissel JP, et al. Terbinane in fungal infections of the nails: a meta-analysis of randomized clinical trials. Br J Dermatol 2002;147:11821. Zaias N, Rebell G. The successful treatment of Trichophyton rubrum nail bed (distal subungual) onychomycosis with intermittent pulse-dosed terbinane. Arch Dermatol 2004;140:6915. Pavlotsky F, Armoni G, Shemer A, et al. Pulsed versus continuous terbinane dosing in the treatment of dermatophyte onychomycosis. J Dermatolog Treat 2004;15:31520. Sanmano B, Hiruma M, Mizoguchi M, et al. Combination therapy consisting of week pulses of oral terbinane plus topical application of terbinane cream in the treatment of onychomycosis. J Dermatolog Treat 2004;15:24551. Foster KW, Ghannoum MA, Elewski BE. Epidemiologic surveillance of cutaneous fungal infection in the United States from 1999 to 2002. J Am Acad Dermatol 2004;50:74852.

Dermatol Clin 24 (2006) 381386

Onychomycosis Therapies: Strategies to Improve Ecacy

Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Linh Q. Tu, HBHScb
a

Division of Dermatology, Department of Medicine, Sunnybrook and Womens College Health Sciences Centre, (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada b Mediprobe Research, Inc., 645 Windermere Road, London, ON N5X 2P1, Canada

The prevalence of onychomycosis in North America is estimated to be between 6% and 13% [13]. In North America, terbinane and itraconazole are the most frequently prescribed oral antifungal agents, whereas ciclopirox nail lacquer is the only approved topical therapy for onychomycosis. Mechanical and chemical debridement are potential adjunctive therapies. Although oral terbinane and itraconazole have a much higher ecacy than griseofulvin and ketoconazole, they still have a failure rate between 20% and 50% [46]. A means to increase the response rate is warranted. Reducing recurrence rates also should be an objective, because relapse and reinfection are common [7]. There are strategies that may improve treatment ecacy and these must be considered on a patientby-patient basis. The main components to improving ecacy are: (1) accurately distinguishing onychomycosis from other nail disorders and identifying the pathogenic species, (2) recognizing nail characteristics that may impact treatment success, and (3) recognizing patient characteristics that may impact treatment success. Furthermore, it is important to educate the patient on the need for treatment compliance, issues with treatment, the lengthy process of nail regrowth, and foot and nail hygiene to reduce relapse or reinfection.

Correct diagnosis of onychomycosis Many conditions can mimic onychomycosis infection [8]; therefore, conrmation of fungal elements in the nail is essential before initiating antifungal therapy. It also is important to determine the identity of the fungal infection because species do not respond equally to antimycotic agents. Microscopic examination using potassium hydroxide techniques or periodic acid-Schi staining is sucient to detect the presence of dermatophyte hyphae, yeasts, and other molds. Laboratory cultures enable the causative organism to be identied [3,4,9,10]. Though dermatophyte species most frequently cause onychomycosis, a small proportion of infections result from nondermatophyte organisms, which may respond poorly to the traditional therapies. When nondermatophyte mold onychomycosis is suspected, the methodology for conrming diagnosis is more rigorous compared with dermatophyte onychomycosis [11]. Although onychomycosis is the most common nail disorder, there are several disease states associated with abnormal-appearing nails that may have some features of an onychomycotic nail, for example, psoriasis, eczema, lichen planus, and trauma [8]. These conditions may predispose the nail to increased risk for developing concomitant onychomycosis and it is important that these mixed infections are recognized, conrmed, and treated. It must also be recognized that when conditions such as previous trauma or coexisting disease are present the nail may not return to a normal appearance despite successful fungal eradication.
derm.theclinics.com

* Corresponding author. Mediprobe Research, Inc., 645 Windermere Road, London, Ontario N5X 2P1, Canada. E-mail address: agupta@execulink.com (A.K. Gupta).

0733-8635/06/$ - see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2006.03.009

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Nail characteristics Some nail presentations may not respond well to standard regimens, and may require supplemental therapy. Severe onycholysis may prevent optimal penetration of an orally administered drug throughout the nail plate. Extreme thickness can reduce antifungal agent penetration through the nail plate. In such instances, mechanical or chemical debridement may enhance penetration of the antifungal agent to the entire nail plate and unit. Where antifungal drug penetration may be limited through the fungal lament clumps of a dermatophytoma, debridement of the dermatophytoma can lessen the burden of infection and enable better access to the antimycotic agent [12]. Reduced perfusion to the toes resulting in slow nail outgrowth may prevent clearance of infection and leave the subject vulnerable to reinfection.

interactions. There are several medications contraindicated with the azole antifungals itraconazole and uconazole [16,18]. In contrast, there are no drugs contraindicated with terbinane, and fewer drug interactions compared with the triazoles [19]. Patient characteristics Patient compliance can have a large impact on the success of antimycotic therapy. Patients who do not adhere to the prescribed treatment regimen are less likely to achieve complete cure because of reduced concentrations of the antifungal agent in the nail unit. Treatment should be appropriate to the patients abilities and lifestyle if possible, to aid with compliance. For example, some patients may be unable to bend over and apply lacquer to infected toenails; other patients may prefer a regimen involving an oral agent that is taken once daily for a short duration. On the other hand, oral treatment may not be a practical option for patients with certain comorbid medical conditions or those who are receiving contraindicated drugs. Knowledge of the individual characteristics of the patient seeking treatment for onychomycosis, along with the medical history, is essential in selecting the most appropriate agent and regimen. Certain lifestyle choices predispose the individual to a greater likelihood of developing onychomycosis. Frequenting public swimming pools and walking barefoot, especially in exercise clubs, are

Pharmacology issues Knowledge of the pharmacologic properties of antifungal medications, particularly the oral drugs, is essential. Patients must be educated about the drug regimen, such as whether the drug is to be taken with or without food. Proper administration is essential to maximize absorption and bioavailability (Table 1) [1317]. It also is important to consider all concomitant medications, herbal preparations, or supplements that the patient may be taking, to avoid drug
Table 1 Antifungal administration strategies to optimize absorption Antifungal Griseofulvin Strategy

Absorption of griseofulvin tablets aected by fat content [14]  Administer with high fatcontent meal or whole milk  Treatment failure may occur when griseofulvin is administered in fasting state

Itraconazole Capsules

Absorption of itraconazole capsules aected by gastric acidity [15]  Administer with full meal to take advantage of increased gastric acid secretion  In fasting conditions, or for patients with naturally low gastric acidity levels, administer with soft drink or cola beverage

Oral Solution Terbinane Fluconazole Ketoconazole

 Administer oral solution under fasting conditions [16,17] Not aected by food intake Not aected by food intake Adequate bioavailability requires low pH  May need to administer with a soft drink or cola beverage  Eect of bioavailability has not been determined

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known risk factors for developing fungal foot infection. Athletic activities may increase the likelihood of injury and microtrauma to toes. Repeated microtrauma to the nail, such as overriding of the toes, can create an environment favorable to infection [20]. Keeping feet cool and dry and wearing clean socks and shoes are important to preventing spread of infection or reinfection. Walking barefoot should be avoided, especially on surfaces that may have a high density of fungal spores. Clippers used to cut infected nails should not be used for normal nails [21]. Similarly, infected individuals should not share clippers with uninfected individuals within the same household.

Therapeutic strategies Monotherapy with a topical nail lacquer may be considered in mild to moderate cases of onychomycosis [4,22]. Lacquer is applied to the dorsal nail surface and penetrates through the nail plate [9]. Oral therapies may be considered for mild to severe cases of onychomycosis. The active ingredient is delivered to the site of infection by way of the nail bed and nail matrix and subsequently diuses into the nail plate [9]. Debridement followed by either topical or oral therapy, or a combination of topical and oral therapy, may increase treatment success rate. This technique is used most often for nails that exhibit lateral onychomycosis, thick nails, dermatophytomas, and severe onycholysis [12,21]. Booster or supplemental therapy Booster (or supplemental) therapy involves administration of additional oral therapy, typically

at months six to nine after the start of treatment for onychomycosis (Fig. 1) [3]. The objective of this supplemental dosage is to maintain a drug concentration greater than the minimal inhibitory concentration for a longer period of time than with standard therapy duration, thus increasing the chances of eliminating infection. Booster therapy may be considered at 3 to 6 months after completing the initial 3-month course of oral terbinane or itraconazole if any of the following conditions are met: there is poor nail outgrowth (!50% reduction in the initial nail plate area that was diseased at baseline) [3]; the nail plate is thickened (O2 mm thickness); there is a positive culture at month six post-initiation of oral antifungal therapy; severe onychomycosis was present at baseline (proximal involvement or O75% of nail plate or bed is diseased); there is dermatophytoma, lateral onychomycosis, severe onycholysis, or immunosuppression; or there is a history of relapse [21].

Boosted therapies It has been hypothesized that complete cure is not achieved because of dormant chlamydospores and arthroconidia present inside the infected nail plate [23]. These spores are less susceptible to antifungal drugs compared with fungal laments. Boosting their germination using agar may increase response to treatment and reduce recurrence. Boosted antifungal topical treatment and its counterpart, boosted oral antifungal treatment, have been evaluated in pilot studies [23,24]. There is some concern that the use of agar to help grow the hyphae within the nail actually could aggravate the onychomycosis, particularly in patients whose infections showed

Fig. 1. Suggested booster therapy regimens.

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previous resistance to oral or topical antifungals, or who are immunocompromised. Combination therapy A combination of two or more therapies may improve treatment ecacy and shorten the duration of treatment with a given antimycotic agent. Combinations of regimens typically provide complementary mechanisms of attack. Topical and oral combinations provide dual penetration routes such that fungal organisms are attacked from both the dorsal and ventral aspects of the nail plate, with high antifungal concentrations being maintained across the entire nail unit. This may be particularly useful for thick nails,

onycholytic nails, lateral presentations, or dermatophytomas, in which drug penetration using a single treatment modality may be insucient to achieve a high concentration of drug within the nail plate and unit. Combination of oral regimens may provide dual points of attack in the fungal metabolic pathway. In vitro testing has suggested that some combinations of antimycotic agents may be synergistic, whereby the eect of the combined agents exceeds the ecacy of each individual agent resulting in a broader spectrum of antifungal activity and the possible eradication of less common pathogens that may also be present [9,25]. Use of a combination regimen has been hypothesized to reduce the amount of medication

Box 1. Strategies to improve efcacy of treatment Accurately distinguish fungal infection and pathogenic organism  Differential diagnosis with psoriasis or other diseases, or concomitant with these conditions  Identify pathogenic organism to ensure proper selection of antifungal agent Recognize nail characteristics that may impact treatment success  Thick nails  Lateral infection  Dermatophytoma  Severe onycholysis Recognize patient characteristics that may impact treatment success  Poor perfusion  Diabetic  Immunocompromised  Elderly Recognize and implement techniques to increase success  Debride thick nails, lateral infection, onycholytic nails, dermatophytomas  Choose medications that are safe and convenient for the patient and appropriate for the infecting organism  Assess the possibility or need for prophylactic therapy (eg, topicals for long-term follow-up of cured nails, treatment for tinea pedis)  Be open to the possibility of combination therapies as treatment (ie, in the event a standard therapy fails) Educate the patient about onychomycosis  Ensure the patient understands that toenail regrowth is a time-consuming process and may require several treatments and follow-up sessions to successfully eradicate fungus  Educate the patient on the need for compliance with therapy and follow-up for the best possible results  Educate the patient about foot and nail hygiene and strategies to prevent recurrence (reinfection or relapse)

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used by patients, which may improve the safety prole of onychomycosis treatment, particularly if oral drugs are used. This may be relevant for patients who would benet from minimal drug exposure, such as those using drugs with potential interaction with antifungal agents or with comorbid medical conditions. Reduction of the amount of drug also may prove nancially benecial in the long term. Though many combination regimens have been studied [2628], currently no combination regimen has been approved for the treatment of onychomycosis. Prevention of recurrence of disease (reinfection or relapse) Relapse rates following onychomycosis cure are high, and prevention of recurrence therefore is important [29]. Prevention of onychomycosis reinfection with the use of 2% miconazole powder has been examined in a double-blind, placebocontrolled pilot study, with negative results [29]. Further and larger studies are required to investigate eective strategies to prevent the recurrence of onychomycosis. Proper foot care is crucial and is one aspect in which the patient can play an important role in the prevention of onychomycosis; trimming toenails straight across rather than rounding the edges can help prevent fungal invasion. Following up with the patient for an adequate period of time also is important. If recurrence of onychomycosis occurs it should be treated early. Tinea pedis frequently occurs concomitantly with onychomycosis and, if present, should be treated immediately to prevent the potential spread of fungus to the cured toenails [7]. Summary Adequate treatment begins with having an accurate diagnosis of onychomycosis and correct identication of the likely pathogen to ensure proper selection of antifungal therapy (Box 1). Characteristics of the nail and the patient that can have a negative eect on treatment ecacy need to be recognized and addressed. The use of booster or combination therapy may be of benet in certain situations. Steps should be taken to prevent the recurrence of onychomycosis (relapse or reinfection). Patient education and foot and nail care are important considerations during therapy and following successful treatment.

References
[1] Gupta AK, Jain HC, Lynde CW, et al. Prevalence and epidemiology of onychomycosis in patients visiting physicians oces: a multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol 2000; 43:2448. [2] Gupta AK, Kohli Y, Summerbell RC. Variation in restriction fragment length polymorphisms among serial isolates from patients with Trichophyton rubrum infection. J Clin Microbiol 2001;39:32606. [3] Gupta AK, Ryder JE. How to improve cure rates for the management of onychomycosis. Dermatol Clin 2003;21:499505. [4] Arrese JE, Pierard GE. Treatment failures and relapses in onychomycosis: a stubborn clinical problem. Dermatology 2003;207:25560. [5] Epstein E. How often does oral treatment of toenail onychomycosis produce a disease-free nail? An analysis of published data. Arch Dermatol 1998;134:15514. [6] Sigurgeirsson B, Paul C, Curran D, et al. Prognostic factors of mycological cure following treatment of onychomycosis with oral antifungal agents. Br J Dermatol 2002;147:12413. [7] Tosti A, Hay R, Arenas-Guzman R. Patients at risk of onychomycosis: risk factor identication and active prevention. J Eur Acad Dermatol Venereol 2005;19(Suppl 1):136. [8] Gupta AK, Lynde CW, Jain HC, et al. A higher prevalence of onychomycosis in psoriatics compared with non-psoriatics: a multicentre study. Br J Dermatol 1997;136:7869. [9] Evans EG. The rationale for combination therapy. Br J Dermatol 2001;145(Suppl 60):913. [10] Shuster S. Onychomycosis: making sense of the assessment of anti-fungal drugs. Acta Derm Venereol 1998;78:14. [11] Gupta AK, Cooper EA, Macdonald P, et al. Utility of inoculum counting (Walshe and English criteria) in clinical diagnosis of onychomycosis caused by nondermatophytic lamentous fungi. J Clin Microbiol 2001;39:211521. [12] Roberts DT, Evans EG. Subungual dermatophytoma complicating dermatophyte onychomycosis. Br J Dermatol 1998;138:18990. [13] Schmidt LE, Dalho K. Food-drug interactions. Drugs 2002;62:1481502. [14] Grifulvin V (griseofulvin tablets) [package insert]. Raritan, NJ: Ortho Pharmaceutical Corporation; 1997. [15] Gupta AK, De Doncker P, Scher RK, et al. Itraconazole for the treatment of onychomycosis. Int J Dermatol 1998;37:3038. [16] Sporanox (itraconazole capsules) [package insert]. Titusville, NJ: Janssen Pharmaceutica; 2004. [17] Gupta AK, Konnikov N, Lynde CW, et al. Onychomycosis: predisposed populations and some predictors of suboptimal response to oral antifungal agents. Eur J Dermatol 1999;9:6338.

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[18] Diucan (uconazole tablets) [package insert]. New York: Pzer; 2004. [19] Gupta AK, Ryder JE, Lynch LE, et al. The use of terbinane in the treatment of onychomycosis in adults and special populations: a review of the evidence. J Drugs Dermatol 2005;4:3028. [20] Scher RK, Baran R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J Dermatol 2003;149(Suppl 65):59. [21] Gupta AK, Daniel CR. Onychomycosis: strategies to reduce failure and recurrence. Cutis 1998;62:18991. [22] Baran R, Hay RJ. New evidence for the ecacy of combination therapy in onychomycosis. Br J Dermatol 2001;145(Suppl 60):1. [23] Pierard GE, Pierard-Franchimont C, Arrese JE. The boosted antifungal topical treatment (BATT) for onychomycosis. Med Mycol 2000;38:3912. [24] Pierard GE, Pierard-Franchimont C, Arrese JE. The boosted oral antifungal treatment for onychomycosis beyond the regular itraconazole pulse dosing regimen. Dermatology 2000;200:1857.

[25] Hay RJ. The future of onychomycosis therapy may involve a combination of approaches. Br J Dermatol 2001;145(Suppl 60):38. [26] Baran R, Kaoukhov A. Topical antifungal drugs for the treatment of onychomycosis: an overview of current strategies for monotherapy and combination therapy. J Eur Acad Dermatol Venereol 2005;19: 219. [27] Gupta AK, Lynch LE. Management of onychomycosis: examining the role of monotherapy and dual, triple, or quadruple therapies. Cutis 2004;74: 59. [28] Olafsson JH, Sigurgeirsson B, Baran R. Combination therapy for onychomycosis. Br J Dermatol 2003;149(Suppl 65):158. [29] Warshaw EM, St Clair KR. Prevention of onychomycosis reinfection for patients with complete cure of all 10 toenails: results of a double-blind, placebo-controlled, pilot study of prophylactic miconazole powder 2%. J Am Acad Dermatol 2005;53: 71720.

Dermatol Clin 24 (2006) 387391

Drug-induced Nail Diseases

Bianca Maria Piraccini, MD, PhD*, Matilde Iorizzo, MD, Michela Starace, MD, Antonella Tosti, MD
Department of Dermatology, University of Bologna, Via Massarenti, 1-40138 Bologna, Italy

Although many nail disorders have been associated with drug intake, most reports are anecdotal. Most nail changes caused by drugs are the outcome of acute toxicity to the nail epithelia, but other mechanisms can be involved. Nail symptoms vary depending on which nail structure is aected. Drug-induced nail changes usually involve several or all 20 nails and appear in temporal correlation with drug intake. Some nail changes are asymptomatic and cause only cosmetic problems, whereas others cause pain and discomfort and impair manual activities or ambulation. Drug-induced nail abnormalities are usually transitory and disappear with drug withdrawal, but they may persist over time. Three factors may complicate the diagnosis: 1. The nail changes may appear several weeks after drug intake because of nail kinetics and the slow growth rate of the nail plate. 2. Nail symptoms often improve or resolve without drug withdrawal. 3. Rechallenge often is negative. This article reviews drugs that consistently have been associated with nail abnormalities. For a more exhaustive review please see Tosti and colleagues [1]. Anticoagulants Anticoagulants, especially warfarin, if taken during pregnancy may interfere with nail development of the fetus [2]. Nail abnormalities will be

evident in newborns, ranging from mild hypoplasia to complete absence of the nail; distal digit malformation may also be associated with the condition. Nail hypoplasia may partially improve during the rst months of life. Anticoagulants also can cause subungual hemorrhages. These hemorrhages are especially evident in the toenails where several digits with splinter hemorrhages and subungual hematomas may be involved. The diagnosis of subungual hemorrhages caused by anticoagulant treatment is suggested by multiple nail involvement in the absence of clinical history of mechanical trauma. Anticonvulsants Carbamazepine, hydantoin, trimethadione, and valproic acid, if taken during pregnancy, may be responsible for ngernail and toenail hypoplasia in the newborn [3]. Nail hyperpigmentation, onycholysis, and onychomadesis also may be seen in adults receiving these drugs. Antimalarials Antimalarials are responsible for a blue-brown pigmentation of the nail bed because of their deposition in the dermis [4]. Diuse pigmentation as well as transverse hyperpigmented bands can occur. Nail pigmentation takes several months to decrease in intensity after discontinuation of therapy and may not disappear completely. Antiretrovirals

* Corresponding author. E-mail address: bmpiracc@med.unibo.it (B.M. Piraccini).

Paronychia and pseudopyogenic granulomas of the ngernails and toenails have been observed in patients treated with lamivudine, azidothymidine
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(AZT), and indinavir [5,6]. One or several nails exhibit tissue granulation with the formation of painful bleeding nodules located in the proximal or lateral nail folds or in the nail bed (Fig. 1). It is important to recognize this condition as a potential nail side eect that usually appears soon after starting therapy and often is dose-related, because bleeding and exudation of the nail soft tissues may be a source of viral contagion. The pathogenesis is still unknown, but it has been suggested that indinavir may activate angiogenic factors. The same side eects occur with dierent drugs (ie, retinoids and indinavir), probably because the HIV-1 protease catalytic site and the retinoid cellular receptor CRABP have structural analogies. A decreased rate of nail growth has been observed in patients treated with AZT and can be explained by a decreased mitotic activity of the nail matrix keratinocytes. AZT also can be responsible for dierent patterns of nail pigmentation; blue-brown nail discoloration and transverse or longitudinal bands have been described. Fingernails are more aected than toenails. AZTinduced melanonychia most commonly appears 3 to 8 weeks after drug intake. Pigmentation is usually reversible within 6 to 8 weeks but may persist for months after drug interruption. Rechallenge is usually negative. Recently the authors have described a case of splinter hemorrhages caused by the nucleotide analogue ganciclovir [7]. Beta-blockers Drugs that impair the distal digital perfusion may damage the nail unit with ischemic changes or necrosis. Raynauds phenomenon is the rst typical sign of digital ischemia; the digit becomes cold and gradually develops gangrene if the blood ow is not restored (Fig. 2). These side eects may

Fig. 2. Gangrene of the third and fourth toenail in a patient treated with propanolol.

occur during systemic administration of b-blockers, especially propanolol. Non-cardioselective b-blockers, especially propanolol, provoke ischemia because there is no peripheral vasodilation in response to the reduced cardiac output induced by cardiac b1 blockade. Instead, vasoconstriction is induced by peripheral b2 blockade [8]. Symptoms do not always regress with drug withdrawal.

Cancer chemotherapeutic agents Beaus lines and onychomadesis are frequently observed during chemotherapy [9] and are typical signs of acute and severe toxicity to the nail matrix keratinization with transient decrease or arrest in the nail plate production. In Beaus lines, the depth of the depression indicates the degree of the damage, and the width indicates the duration of the insult. Onychomadesis can be considered as the extreme degree of Beaus lines. A drug always should be suspected when these symptoms aect all nails at the same level. A drug taken 2 to 3 weeks before the appearance of these nail symptoms should be considered, because a ngernail takes about 40 days to emerge from the proximal nail fold, and a toenail about takes 80 days. Nail fragility Chemotherapeutic agents are responsible for nail fragility that is a consequence of alteration of the nail plate production. Supercial nail fragilityd elkonyxixdresults from a toxic eect on the proximal nail matrix, whereas diuse damage to the nail matrix gives rise to a thin, brittle nail plate.

Fig. 1. Paronychia and pseudopyogenic granulomas of the toenails in a patient treated with indinavir.

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Onycholysis Onycholysis results from acute toxicity to the nail bed epithelium with loss of the nail plate and loss of nail bed adhesion. The nail plate is detached from the nail bed and appears white. Detachment may be preceded or accompanied by pain. The cause of the pain is unknown, but changes in the peripheral blood ow play an important role. Onycholysis is frequent in patients treated with the taxane chemotherapeutic agents, such as docetaxel and paclitaxel; in these patients onycholysis may be complicated by subungual abscesses (Fig. 3).

Fig. 4. True transverse leukonychia.

Paronychia associated with pyogenic granulomas True transverse leukonychia True transverse leuconychia is a sign of transient impairment of the distal nail matrix keratinocytes, resulting in the persistence of cell nuclei in the nail plate. It appears as one or several parallel transverse white and opaque bands affecting all nails at the same level and moving distally with nail growth. The bands are usually 1 or 2 mm wide. This sign has been reported during treatment with doxorubicin, cyclophosphamide, and vincristine (Fig. 4). Paronychia associated with pyogenic granulomas recently has been reported with cetuximab/ C225 (anti-epidermal growth factor receptor antibody) [10,11] and getinib (epidermal growth factor receptor tyrosine kinase inhibitor) [12] used as chemotherapeutic agents. Nail changes appear 1 to 3 months after starting treatment. The nail abnormalities typically regress with interruption of treatment. Melanonychia Chemotherapeutic agents may activate clusters of nail matrix melanocytes to produce melanin, giving rise to melanonychia appearing as multiple light brown-black longitudinal or transverse bands. Generally, several nails are aected with multiple bands, but in some cases only one digit may be involved. A diuse activation of nail

Apparent leukonychia Apparent leukonychia appears as transverse, parallel, pale white bands (Muehrckes lines) resulting from nail bed damage (Fig. 5). The pathogenesis is still unknown, and it resolves after drug withdrawal. It can be easily distinguished from true leukonychia because it fades with digital compression and does not migrate with nail growth.

Fig. 3. Hemorrhagic onycholysis subungual abscesses caused by taxanes.

Fig. 5. Melanic pigmentation of the rst ngernail and apparent leukonychia of the second, third, fourth, and fth ngernail (Muehrckes lines) in a patient treated with combined chemotherapy for breast cancer.

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matrix melanocytes produces a pigmentation of the entire nail plate (Fig. 5). Subungual hemorrhages

onychomadesis, and diuse hyperpigmentation of the nail have been reported with lead intoxication. Lithium

Splinter hemorrhages appear as multiple, longitudinal, tiny, purple-to-brown streaks most often evident in the distal nail bed. These hemorrhages usually are seen in the ngernails. Hematomas appear as a red-to-black discoloration of the nail that slowly migrates distally with nail growth. Cancer chemotherapeutic agents, especially the taxanes, can cause subungual hemorrhages and hematoma by thrombocytopenia or extravasation of blood. Hemorrhages are dose-related and cease formation after drug withdrawal. Clofazimine Clofazimine may produce a dark-brown pigmentation of the nail plate where the drug is stored [13], subungual hyperkeratosis, onycholysis, and melanonychia. The nail changes usually regress when the dosage of the drug is reduced. Cyclosporin-A Decreased nail growth rate and true transverse leukonychia have been described with cyclosporin-A intake. Heavy metals Some heavy metals, such as arsenic and thallium, can cause nail abnormalities that aect most or all ngernails and can be recognized easily (ie, the transverse white lines of true leukonychia known as Mees lines). Mees lines typically appear 2 to 6 weeks after an acute episode of arsenic/thallium poisoning. The lines are multiple and parallel, reecting repetitive exposure to the poison. Blue discoloration of the nail plate has been described in argyria, in which a slate-blue permanent pigmentation of the proximal nail bed is typical and most evident in the lunula. The reduction of silver salts to black metallic silver under the inuence of ultra-violet rays may explain the pathogenesis of pigmentation involving both skin and nails. A grayish-brown discoloration of the nail plate and nail fragility have been reported with chronic exposure to mercury. Additionally, leukonychia,

Therapy with lithium carbonate may induce a yellow color of the distal portion of the nail plate as well as transverse, brown-black pigmented bands of the ngernails with onychomadesis. A decreased rate of nail growth has also been reported during lithium therapy. Psoralens Patients undergoing therapy with psoralens plus UVA radiation may develop drug-induced photoonycholysis in which the detachment of the nail plate or nail bed is caused by a photo-mediated toxic or allergic eect of the drug. Typically the thumbs are spared. Four types of photo-onycholysis can be distinguished, depending on the site of the detachment [14]. The detachment may be preceded or accompanied by pain. The cause of pain is unknown, but changes in the peripheral blood ow probably play an important role. Longitudinal melanonychia can also be seen in ngernails of patients treated with psoralens. Retinoids Retinoids are responsible for various nail changes [15], most of which result from the eects of retinoids on keratinization; they may appear 2 weeks to 18 months after retinoid use. Sometimes the nail changes are transient, even if the therapy is continued. Beaus lines, onychomadesis, and true transverse leukonychia are consequences of nail matrix damage caused by the drug. They usually are dose-related and are reproducible with repetitive cycles of drug intake. Nail fragility, especially lamellar onychoschizia, has been observed during etretinate therapy. Retinoids have also been associated with both decreased and increased nail growth. In retinoid-induced acute paronychia, the proximal nail fold becomes erythematous, inamed, and painful; several nails usually are involved soon after drug intake. Loss of the nail plate also can be associated with drug exposure. The pathogenesis is still unclear, but a toxic eect of the drug on nail epithelia or a pyogenic infection may be responsible for the clinical presentation. Paronychia caused by retinoids is more

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frequent with isotretinoin and usually improves with a reduction in the dosage of the drug. Multiple pyogenic granulomas may arise from proximal and lateral nail folds as a typical side eect of treatment with retinoids. One or several nails show granulation of tissue with the formation of painful bleeding nodules. Nail plate fragility resulting in spicule formation is one of the multiple factors responsible for this side eect. Tetracyclines Tetracyclines may produce a yellow uorescence of the lunulae under Woods lamp [16] or a yellow discoloration of the entire nail plate. Photo-onycholysis also has been reported during tetracycline therapy, especially with doxycycline. Minocycline may be responsible for a blue-gray pigmentation of the proximal nail bed [17]. References
[1] Tosti A, Baran R, Dawber RPR. The nail in systemic diseases and drug-induced changes. In: Baran R, Dawber RPR, de Berker DAR, et al, editors. Baran and Dawbers diseases of the nails and their management. 2nd edition. Oxford (UK): Blackwell Science; 2001. p. 2239. [2] Pettifor JM, Benson R. Congenital malformation with the administration of oral anticoagulant during pregnancy. J Pediatr 1975;86(3):45962. [3] Holmes LB, Harvey EA, Brown KS, et al. Anticonvulsant teratogenesis: I. A study design for newborn infants. Teratology 1994;49(3):2027. [4] Tuanelli D, Abraham RK, Dubois EI. Pigmentation from antimalarial therapy. Arch Dermatol 1963;88:11320.

[5] Tosti A, Piraccini BM, DAntuono A, et al. Paronychia associated with antiretroviral therapy. Br J Dermatol 1999;140(5):11658. [6] Calista D, Boschini A. Cutaneous side eects induced by indinavir. Eur J Dermatol 2000;10(4): 2926. [7] Lorenzi S, DAntuono A, Iorizzo M, et al. Skin rash and splinter haemorrhages from ganciclovir. J Dermatol Treat 2003;14(3):1778. [8] Stringer MD, Bentley PG. Peripheral gangrene associated with b-blockade. Br J Surg 1986;73(12):1008. [9] Minisini AM, Tosti A, Sobrero AF, et al. Taxaneinduced nail changes: incidence, clinical presentation and outcome. Ann Oncol 2003;14(2):3337. [10] Boucher KW, Davidson K, Mirakhur B, et al. Paronychia induced by cetuximab, an antiepidermal growth factor receptor antibody. J Am Acad Dermatol 2002;47(4):6323. [11] Busam KJ, Capodieci P, Motzer R, et al. Cutaneous side eects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol 2001;144(6):116976. [12] Nakano J, Nakamura M. Paronychia induced by getinib, an epidermal growth factor receptor tyrosine kinase inhibitor. J Dermatol 2003;30(3):2612. [13] Tosti A, Piraccini BM, Guerra L. Reversible melanonychia due to clofazimine [abstract no. 183]. Proceedings of the 18th World Congress of Dermatology. New York, June 1218, 1992. [14] Baran R, Juhlin L. Photoonycholysis. Photodermatol Photoimmunol Photomed 2002;18:2027. [15] Baran R. Retinoids and the nail. J Dermatol Treat 1990;1:1514. [16] Hendricks AA. Yellow lunulae with uorescence after tetracycline therapy. Arch Dermatol 1980; 116(4):43840. [17] Kimyai-Asadi A, Jih MH. Minocycline induced nailbed pigmentation. J Drugs Dermatol 2002;1(2): 1978.

Dermatol Clin 24 (2006) 393399

Nail Cosmetics
Phoebe Rich, MD
Oregon Health and Sciences University, 2565 NW Lovejoy Street, Portland, OR 97210, USA

Nail cosmetics are used worldwide by millions of women who desire attractive, adorned nails. Smooth, shiny ngernails and toenails are highly desirable and an entire industry is devoted to achieving that end for the consumer. The grooming and decoration of nails is a well-ingrained cultural ritual in many countries of the world. In the United States alone, $6.4 billion was spent on nail salon services in the year 2004. Benets of nail cosmetics Nail cosmetics hide a multitude of unsightly nail problems. Pitting, discoloration, ridging, onycholysis, and other unattractive nail features can be disguised by a simple coat of nail lacquer. Weak, brittle, and dystrophic nails are fortied by several nail enhancement coatings. Decorative nishes are painted or airbrushed onto the nail to provide color and decoration and hide ugly or diseased nails. A coating of nail product can fortify thin, weak nails and make brittle nails appear stronger. These temporary cosmetic xes for diseased nails do not provide a cure for the problem, but they do cover and conceal the undesirable features of diseased or aging nails. Nail cosmetics can give the illusion of healthy nails in the face of nail disease and provide a youthful appearance for aging nails. Harmful features of nail cosmetics Nail cosmetics are not inherently dangerous, but there are some signicant medical problems that can occur with the use or application of nail cosmetics. These problems are divided into two

categories: those associated with the nail cosmetic materials used to adorn nails, and those associated with the procedures and processes used to groom and beautify natural nails (Box 1). A description of the chemistry of nail cosmetic materials is useful in evaluating and understanding the problems associated with nail cosmetics. Principles and chemistry of nail cosmetic materials An understanding of the properties and chemistry of nail cosmetic materials is based on three chemical and physical principles of adhesion, polymerization, and evaporation as described by Schoon [1] in his book titled Nail Structure and Product Chemistry. Adhesion The concept on which nail extension is based emphasizes the importance of adhesion of a product to the natural nail plate. The natural nail plate should be free of oil and dirt that would weaken the attachment of the product to the plate. The base coat or primer is material that sticks to the nail plate and the overlay material. Primers for nail extensions are corrosive acids and can burn the nail bed and nail folds if too much is used, or if it is splashed onto skin. The practice of roughing up the surface of the nail plate by ling is highly discouraged because it thins and damages the nail plate. Polymerization Nail enhancement requires the application of a liquid monomer consisting of single molecules. In the presence of an initiator and an energy source (heat or UV light) these molecules join together to form strong bonds through a chain
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Box 1. Adverse problems associated with nail cosmetic materials and procedures Nail cosmetic materials Contact irritant and allergic reactions to materials Allergic Contact irritants: Nail polish remover, Nail polish Nail plate staining Nail cosmetic procedures and salon services Trauma caused by instruments and tools Cutting the skin and cuticle Probing under the free edge Filing the surface of the nail plate Mechanical damage from rigid and excessively long nail extensions Mechanical damage to the nail plate by ling and bufng Infections caused by improper sanitation of implements used on multiple clients Bacterial: Mycobacterium Fungal: Yeast (Candida), Dermatophyte Viral: Herpetic, Verruca, Other systemic viral diseases
Fig. 1. Periungual erythema and scaling from acrylic nail monomer.

reaction that results in the cross-linking of the molecules into chains and webs. These bonds are tight and require a strong solvent to break them. This chemical reaction requires heat or light, plus an initiator and a catalyst to make the reaction happen quickly. The energy source can be UV or visible light, depending on the material being polymerized, or heat from the body. Polymerization causes shrinkage of the material of up to 20% and sometimes causes heat release (exothermic reaction). There are three categories of enhancement materials: cyanoacrylate in wraps and nolight gels, methacrylates in two parts (powder polymer and liquid monomer) in sculpted nails, and acrylates in UV light gels. Evaporation Evaporation of solvent is the method of hardening of various coatings, such as nail base coat, topcoat, and nail polish. Various polymers

are dissolved in a volatile solvent (often toluene) and as the solvent evaporates, the material hardens. These coatings do not contain monomers (hence no polymerization); however, they do contain dissolved mature polymers. The materials used in nail cosmetics can cause allergic reactions and irritant reactions around the nail unit or at distant sites, such as the face and neck, and changes in the nail plate itself. Some of the more commonly found allergens are toluene sulfonamide formaldehyde resins (TSFR), the thermoplastic resin in nail polish, nickel in metal mixing beads in nail polish, and formaldehyde in nail hardeners (Fig. 1). TSFR-free polishes are now available that contain other resins, including epoxy or phthalic-polyester based products. Although less sensitizing, these alternative products provide a less durable nish. Nail cosmetology Most of the potential complications of the procedures involved in manicure, pedicure, and

Fig. 2. Subungual dermatitis with ssures from allergy to acrylic compounds.

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Fig. 3. Fingernails are soaked and cuticles groomed.

Fig. 5. Fingernails are nished with nail polish (enamel).

application of nail enhancements are related to trauma and infection when the tissue around the nail is manipulated and injured allowing access of pathogenic organisms (Fig. 2). A manicure or pedicure begins with soaking the nails in soapy water to soften the cuticles, which are then pushed back, usually with a metal implement. Cuticle remover is sometimes used, and often the cuticles are clipped or trimmed with nippers or small scissors. The nails are shaped by ling and then are painted or bued to obtain a highly desirable shiny and smooth nish (Figs. 39). Problems associated with nail cosmetics can aect the nail plate, the periungual tissue, and distant ectopic sites, such as the face and neck (Fig. 10). The nail plate is adversely aected by nail enamel that stains the nail plate yellow because of the yellow dye in the product. The yellow color is more intense distally than proximally and can be scraped away with a blade (Fig. 11); it dissipates slowly over time if polish is avoided.

The nail plate can become crumbled and friable on the surface because of nail products, described by Baran [2] as keratin granulations (Fig. 12). This white crumbling of the nail plate surface looks similar to white supercial onychomycosis, which is dierentiated by a positive potassium hydroxide preparation for fungal elements. It is not clear if the granulations predispose the nail to the occurrence of subsequent fungal infection. Keratin granulation is more common in pedicures in which a base coat is used and the polish remains undisturbed on the nail for several months. It also is seen when the polish is reapplied without removing the rst layers. The mechanism of this supercial granulation of keratin is not known, but it tends to be more common following salon pedicures during which a primer base coat is used to enhance adherence of the subsequent nail enamel. Articial nail wear causes thinning of the nail plate when the nail is led before application, a practice that is used widely but highly

Fig. 4. Nails are led and shaped.

Fig. 6. Toenails soaked in pedicure spa.

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Fig. 7. Cuticle remover applied and scraped o.

Fig. 9. Toenails shaped and nished.

discouraged because of the deleterious eect on the nail plate. If acrylic nail enhancements are not properly maintained small areas of loosening occur causing moisture to collect and providing a hospitable niche for microorganisms; Pseudomonas species are common (Fig. 13). Articial nail enhancements that are too long initiate a lever eect and result in onycholysis, which may become secondarily infected with yeast and bacteria. Some of the materials used in nail enhancements, especially primers, can irritate proximal and lateral nail folds and result in chronic paronychia. The periungual tissue is aected by materials that cause allergic reactions and irritant reactions, exacerbating preexisting conditions, such as onycholysis and paronychia [3]. Nail cuticle remover contains keratolytic materials that are irritating to the nail fold and can initiate paronychia. The primer used to enhance adhesion of the acrylic material to the nail plate usually is methacrylate acid, a strong irritant that results in irritation and even

chemical burns of the paronychial tissue if accidentally spilled or splashed onto skin. Allergic reactions cause itching and burning sensations after the product is applied. This phenomenon is common particularly in photobonded gel nails whereby the liquid gel material is hardened (polymerized) by several minutes of UV light exposure. Several articles suggest screening for acrylate allergy by patch testing to ethyl methacrylate [4].

Nail cosmetic controversies Infections in nail salons There is no data on the prevalence of infections transmitted through nail salons. Theoretically, bacterial, viral, and fungal infections are spread by poor sanitation and inadequate precautions with nail salon procedures. This problem is intensied if there are breaks in the integrity of the paronychial skin. Cutting the cuticle or probing

Fig. 8. Cuticles cut.

Fig. 10. Eyelid and facial dermatitis from TSFR in nail enamel.

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Fig. 11. Yellow staining of nail plate from dye in nail polish (enamel).

under the nails opens portals for infection from improperly cleaned implements. Although many salons safely follow the guidelines for sanitation, many other salons do not properly sanitize the implements used on multiple clients. It is recommended, therefore, that women bring their own les and implements to the salon for their own use. The most risky implements are les that cannot be sterilized that carry fungal spores, viral particles, and even bacteria from client to client. The insucient number of state inspectors for the 250,000 salons in the United States makes enforcing rules nearly impossible. There are several measures that the consumer can use to avoid nail salon infections (Box 2). A recent concern is that of pedicure spas spreading Mycobacterium infections. Many women in a salon in California were infected by Mycobacterium fortuitum when the pedicure tubs were not properly cleaned and the Mycobacterium organisms were sequestered in the debris in the lter of the circulating whirlpool footbaths. Women who had shaved their legs recently before the pedicure developed furuncles on their legs (Fig. 14) [5,6]. Similar cases have been seen in Texas, Oregon, and Florida.

Fig. 13. Pseudomonas bacteria in an onycholytic nail.

Box 2. Patient information on safe use of nail products and salons  Use a licensed nail technician and licensed salon.  Wash hands before any nail salon services.  Look for cleanliness in the salon.  Ask about sanitization and sterilization in the salon.  Bring your own instruments, particularly les that cannot be sterilized.  If you experience any itching or burning after a service, it could signal a reaction.  Allergy to nail polish can show up on the face, eyelids, and neck.  Keep nail extensions short.  Do not allow the technician to le the surface of the nail plate in preparation for extensions.  Do not overbuff the nails, which weakens them.  Wear gloves for all wet work chores to protect the manicure and help prevent infections associated with articial enhancements.  If you experience a nick or cut during a salon procedure, seek medical attention to avoid infections.

Fig. 12. Keratin granulations of nail plate from prolonged polish exposure.

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in one small study of six salons [8]. Contact sensitization occurred in nail technicians who were exposed to the chemicals and lings of nail acrylic enhancement materials. A total of 20 nail technicians and 20 controls in the salons were questioned about their individual symptoms, and the only statistically signicant health eect noted was throat irritation. Also noted, but not statistically signicant, were symptoms of dizziness, drowsiness, skin irritation, and trembling of hands [9]. A recent report about dibutyl phthalate in nail polish has shown it to be teratogenic at high doses in rats [10].
Fig. 14. Furuncle on leg from Mycobacterium in pedicure spa.

Furuncle lesions are rm, nontender nodules that on tissue culture grow the Mycobacterium organism (Fig. 15). The safety of the nail salon as workplace Many nail technicians spend long hours applying materials to clients nails and in the process breathe in fumes and dust particles that are released by ling the articial nails. Salons follow the Occupational Safety and Health Administration rules and have material data safety sheets; however, not all salons are well ventilated [7]. Particles in the air range up to 15.6 ppm, as reported

Should nail cosmetics be allowed in operating rooms? Numerous case reports support the potential hazards of articial nails in the health care setting [11]. Articial nails have been implicated in some cases of medical complications of infections, which has led the Association of Operating Room Nurses to advise against wearing articial nails in the operating room setting [12,13,14].

References
[1] Schoon D. Nail sturcture and product chemistry. New York: Milady Publishing; 1996. [2] Brauer E, Baran R. Cosmetics: the care and adornment of the nail. In: Baran R, Dawber RPR, de Berker D, et al, editors. Diseases of the nail and their management. 3rd edition. Oxford (UK): Blackwell; 2001. p. 35869. [3] Daniel III CR, Daniel MP, Daniel J, et al. Managing simple chronic paronychia and onycholysis with ciclopirox 0.77% lotion and an irritant avoidance regimen. Cutis 2004;73:8514. [4] Koppula SV, Fellman JH, Storrs FJ, et al. Screening allergens for acrylate dermatitis associated with articial nails. Am J Contact Derm 1995;6: 7885. [5] Winthrop KL, Albridge K, South D, et al. The clinical management and outcome of nail salon acquired Mycobacterium fortuitum skin infections. Clin Infect Dis 2004;38(1):3844. [6] Winthrop KL, Abrams M, Yakrus M, et al. An outbreak of furunculosis associated with footbaths at a nail salon. N Engl J Med 2002;346(18): 136671. [7] Sniezek PJ, Graham BS, Busch HB, et al. Rapidly growing mycobacterial infections after pedicures. Arch Dermatol 2003;139(5):62934. [8] National Institute of Occupational Safety and Health (NIOSH). Controlling chemical hazards

Fig. 15. Pedicure spa. Note the lters or screens that collect debris and microorganisms.

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during the application of articial ngernails. Appl Occup Environ Hyg 2001;16(5):50911. [9] Hiipakka D, Samimi B. Exposure of acrylic ngernail sculptors to organic vapors and methacrylate dusts. Am Ind Hyg Assoc J 1987;48(33):2307. [10] LoSasso GL, Rapport JL, Axelrod BN. Neuropsychological symptoms associated with low-level exposure to solvents and meth-acrylates among nail technicians. Neuropsychiatry Neuropsychol Behav Neurol 2001;14(3):1839. [11] Ema M, Kurosaka R, Amano H, et al. Comparative developmental toxicity of n-butylbenzyl phthalate

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