finch et al. (2011) - fungal melanonychia

8/10/2019 Finch Et Al. (2011) - Fungal Melanonychia

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REVIEWS

Fungal melanonychia

Justin Finch, MD,a

Roberto Arenas, MD,b

and Robert Baran, MDc

Farmington, Connecticut; Mexico City, Mexico; and Cannes, France

Fungal melanonychia is a relatively rare nail disorder caused by nail infection that produces brown-to-blackpigmentation of the nail unit. The number of organisms implicated as etiologic agents of fungalmelanonychia is increasing, and the list currently tops 21 species of dematiaceous fungi and at least 8species of nondematiaceous fungi. These superficial infections may clinically mimic subungual melanomaand are often not responsive to traditional antifungal therapy. This article reviews the literature on fungalmelanonychia and the role of fungal melanin in infection. ( J Am Acad Dermatol 2012;66:830-41.)

Key words:Alternaria; dematiaceous fungi; dermatomycosis; fungal melanin; fungal melanonychia;fungus;Hendersonula toruloidea; melanonychia; nail;Nattrassia mangiferae; onychomycosis; phaeohy-phomycosis; pigmented nail infection;Scytalidium;Trichophyton rubrum; ungual phaeohyphomycosis.

Melanonychia refers to brown-to-black pig-mentation of the nail unit. Fungal melano-nychia, or dark pigmentation of nails as a

result of fungal infection, is a relatively rare naildisorder. However, each year an increasing numberof cases of fungal melanonychia are diagnosed, andthe list of causative organisms continues to expand.Most cases of fungal melanonychia are a result of nailinfection by dematiaceous fungi.

The terms dematiaceous and phaeoid de-scribe fungi that are darkly pigmented because of

melanin production. These fungi are largely ubiqui-tous environmental species, but include a growinglist of human pathogens. Although phaeohypho-mycosis has been used as a general term to describeany mycosis involving dematiaceous fungi, it specif-ically refers to infections caused by hyphomycetousfungi that grow as dark-walled dematiaceousseptate mycelia or yeasts in host tissues.Phaeohyphomycosis can be divided into superficial,subcutaneous, and deep (or disseminated) infection.Fungal melanonychia, or ungual phaeohyphomyco-sis, is a superficial infection. Whereas subcutaneousand deep tissue phaeohyphomycoses typically occur

in immunocompromised patients, nail infectionscaused by dematiaceous fungi generally occur inindividuals who have no underlying skin disease andare not otherwise immunocompromised.

Like subcutaneous and disseminated phaeohy-phomycosis, ungual phaeohyphomycosis is resistantto most antifungal therapies, making treatment ex-ceptionally challenging. Although the initial impactof fungal melanonychia is largely cosmetic, it is ofgreat clinical importance because it may mimicsubungual melanoma. Increased human travel and

migration have contributed to the worldwide distri-bution of these disorders.

ETIOLOGYAlthough the vast majority of onychomycosis is a

result of dermatophytes, the incidence of onycho-mycosis caused by nondermatophytic molds such asdematiaceous fungi is increasing. Nondermatophyticmolds account for 1.5% to 17.5% of onychomyco-sis.1,2 The number of organisms implicated as etio-logic agents of fungal melanonychia is increasing,and the list currently tops 21 species of dematiaceous

fungi (Table I) and at least 8 species of nondematia-ceous fungi (Table II). The dematiaceous fungi inTable Ihave in common the production of melanin,which is incorporated into their cell wall or secretedextracellularly, causing them to appear brown toblack when cultured. It should be noted that manyspecies of fungi produce melanin (detectable, eg, byimmunohistochemical examination) yet do not ap-pear pigmented in situ. These are not, strictly speak-ing, phaeoid. The dematiaceous fungusScytalidiumdimidiatum and the nondematiaceous dermato-phyteTrichophyton rubrumare the most frequently

isolated agents of fungal melanonychia, followed by

From the Department of Dermatology, University of Connecticuta;

Manuel Gea Gonzalez General Hospital, Mexico Cityb; and Nail

Disease Center, Cannes.c

Funding sources: None.

Conflicts of interest: None declared.

Reprint requests: Justin Finch, MD, Department of Dermatology,

University of Connecticut, 21 South Rd, Farmington, CT 06030.

E-mail:[email protected].

Published online January 18, 2011.

0190-9622/$36.00

2011 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2010.11.018

830
mailto:[email protected]://dx.doi.org/10.1016/j.jaad.2010.11.018http://dx.doi.org/10.1016/j.jaad.2010.11.018mailto:[email protected]


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dematiaceous fungi of the genera Alternaria andExophiala.

Dematiaceous pathogens are commonly found insoil, wood, decomposing plant matter, and pollutedwater,3 and are endemicto tropical and subtropicalregions such as Africa,4 India,5 Thailand,6 and theCaribbean.4 Many species, such as Chaetomiumperpulchrum, have been iso-lated from the air,7 and others,such as Alternaria species,are ubiquitous molds. Mostdematiaceous fungi are sap-rophytes or plant pathogens.Scytalidium dimidiatum, forexample, is a recognizedpathogen of fruit trees.8

Alternaria alternatais themost frequently isolatedAlternaria species inungualphaeohyphomycosis.9,10

Alternaria chlamydospora,11

Alternaria pluriseptata,12

and Alternaria humicola12

have also been recoveredfrom infected nails. A reviewof onychomycosis cases dur-ing a 15-year period in Italyrevealed thatAlternariaspe-cies account for 25.2% of moldonychomycosis and3.3% of onychomycosis overall.13 Alternaria infec-

tions, although locally invasive, show little propen-sity for dissemination, possibly because of theprogressive inhibition of growth at temperaturesabove 308C.9

Scytalidium dimidiatum and Scytalidium hyali-num are synanamorphs of the fungus Nattrassiamangiferae (formerly Hendersonula toruloidea).Scytalidium hyalinum is a mutant of Scytalidiumdimidiatum that has lost the ability to synthesizemelanin. Scytalidium infections have been welldescribed in Europe,14,15 Africa,16 and theCaribbean.4 In the African country Gabon, for ex-

ample, Scytalidium is implicated in more than onethird of cases of tinea pedis. On the Caribbean islandof Tobago, Scytalidium is a commoncause of footinfection in asymptomatic individuals.17 These epi-demiologic data highlight an important differencebetween Scytalidium and other agents of nonder-matophyte mold onychomycosis, such asScopulariopsis brevicaulis. That is, in contrast tomany other nondermatophyte agents of onychomy-cosis,Scytalidiumhas the ability to invade both skinand nails.

A retrospective review of 39,000 nail and skin

samples collected during a 6-year period in France

revealed that 3.6% of cases of onychomycosis were aresult ofScytalidium, making it the leading cause ofmold onychomycosis in France.14 Not surprisingly,nearly all of these patients were residents or visitorsof tropical or subtropical countries, and the infec-tions were likely imported. Mixed infections withdermatophytes andScytalidiumare not uncommon.

In a series of patients re-ported by Moore,15,18 mixedinfections occurred in aboutone third of patients withScytalidium dimidiatum

nail infection.There are a number of

dematiaceous fungi lessfrequently implicated in mel-anonychia. Exophiala (for-merly Wangiella) species,

includingE jeanselmeiand Edermatitidis, are relatively re-cent additions to the growinglist of etiologic agents. Mostreports of melanonychiacaused byExophialaspecieshave originated in Japan, al-though Exophiala specieshave been recovered fromnail samples in geographic

territory ranging from Mexico to the NorthernUnited States.19 Isolated cases of melanonychia

caused by Acrothecium nigrum, Botryodiplodia(Lasiodiplodia) theobromae,Homodendrum elatum,and Curvularia lunata have been recognized.Fusarium species, a hyaline (nonpigmented) fungus,may also cause dark nail pigmentation,9 but leuko-nychia is more common.20 Other reported cases ofmelanonychia caused byAureobasidium pullulans,21

Cladosporium sphaerospermum,22 andPhyllostictinasydowii23 do not completely fulfill diagnostic criteria.

Although this article primarily discusses dematia-ceous fungi, fungal melanonychia is not limited tonail invasion by dematiaceous fungi. Among the

nondematiaceous fungi, the dermatophytes T ru-brum (strains of which can produces a diffusibleblack pigment24,25) and T soudanense may causebrown or black nail pigmentation. The conidia ofAspergillus niger, darkly colored by the pigmentaspergillin,26 may also impart a dark-brown color tothe nail and proximal nailfold. Lastly, Candidaspecies, common agents of fingernail onychomyco-sis,27 may rarely cause melanonychia. Candidaalbicans,28 Candida humicola,29 Candida tropica-lis,30 and Candida parapsilosis31 have all beenreported to cause nail pigmentation, with the major-

ity of these cases originating in Europe or Korea.

CAPSULE SUMMARY

d Fungal melanonychia is a relatively

uncommon nail infection caused by

species of fungus that produce melanin

pigment.

d This article reviews the causative agents

of fungal melanonychia, therapeutic

approach on a species-by-species basis,

and differential diagnosis of nailpigmentations that include melanoma of

the nail matrix.

d With increasing international travel and

immigration, many cases of fungal

melanonychia are imported and may

easily be overlooked or misdiagnosed

without appropriate scrutiny.

J AMACADDERMATOLVOLUME66, NUMBER5

Finch, Arenas, and Baran 831


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Although melanonychia caused by Candida albi-canshas been recognized for some time, it was not

revealed until recently that Candida albicans isactually capable of producing melanin.32

EPIDEMIOLOGYThe geographic distribution of the etiologic

agents of phaeohyphomycosis is widespread, in-creasing with proximity to the equator. As withdermatophyte onychomycosis, the prevalence offungal melanonychia increases with age, has a higherincidence in men than in women, and more fre-quently involves toenails than fingernails. However,although infections as a result of dermatophytes are

contagious, infections caused by dematiaceous fungihave not been shown to be contagious.3

Given our knowledge of the geographic distribu-tion and native habitats of these fungi, the risk factorsfor fungal melanonychia are largely intuitive. Theseinclude travel to or residence in endemic areas,contact with wood or soil, and nail trauma.Because of the high incidence in populations work-ing with organic matter such as wood or soil, fungalmelanonychia is often considered an occupationaldisease. Indeed, among 9 cases of ungual Alternariainfection reported in a retrospective study of alter-

nariosis by Romano et al,

11

5 patients had a history of

contact with soil (4 of the patients were farmers andanother was a gardener), and 4 of 9 had nail traumabefore contracting mycosis.

Interestingly, immunocompromise is conspicu-

ously absent from the list of risk factors. Only twoof the 9 patients in the aforementioned study byRomano et al11 were immunosuppressed, one withdiabetes mellitus and another taking systemic ste-roids. Hay and Moore4 reviewed 128 cases of super-ficial infection caused byScytalidium, revealing justtwo patients with serious underlying systemic dis-ease. As these studies demonstrate, the majority ofpatients with fungal melanonychia have no under-lying disease that would predispose them to infec-tion. Most cases of subcutaneous and deep-tissuephaeohyphomycosis, on the other hand, occur in

patients with immunocompromise. Notably, a recentreview by Lyke et al33 revealed that 52 of 89 (58%)cases of cutaneous alternariosis occurred in patientsreceiving systemic corticosteroids.

THE ROLE OF FUNGAL MELANIN ININFECTION

There is growing evidence that melanin may playan important role in the pathogenesis of fungalmelanonychia. Melanins are high moleculareweightbrown-to-black pigments that are found in humanbeings, plants, and fungi alike, although their mo-

lecular structure and synthesis vary. Fungal melaninsare synthesized in the cytoplasm and subsequentlyexcreted as extracellular polymers or deposited inthe cell wall. In most dematiaceous fungi, melanin isincorporated into the cell wall.

Unlike tyrosine-derived human melanin, the de-matiaceous fungi synthesizemelanin via the penta-ketide pathway (Fig 1).34 The final enzymaticproduct of this pathway is dihydroxynaphthalene,which spontaneously polymerizes to form melanin.The absence of enzyme catalyzation of this final step,along with the complex and highly diverse nature of

the high moleculare

weight molecules that result,

Table I. Phaeoid agents of fungal melanonychia

Acrothecium nigrum77

AlternariaspeciesAlternaria alternata9,10,11,51,71,78,79

Alternaria chlamydospora11

Alternaria tenuis80

Alternaria humicola12

Alternaria pluriseptata12

Aureobasidium pullulans(possible case)21

Botryodiplodia (Lasiodiplodia) theobromae81

Chaetomium perpulchrum7

Cladosporium (Cladophialophora) carrionii82

Cladosporium sphaerospermum22,83

Curvularia lunata84

Exophiala (Wangiella) jeanselmei85

Exophiala (Wangiella) dermatitidis19,86

Fusarium oxysporum87,88

Homodendrum elatum89

Microascus desmosporus50

Phyllostictina sydow (possiblecase)23

Pyrenochaeta unguis-hominis90

Nattrassia mangiferae (Hendersonula

toruloidea)*4,15,52,74,91,92

Scytalidium dimidiatum8,73,93,94

Scytalidium hyalinumy15,95,96

*Synanamorph of Scytalidium dimidiatum.yHyaline mutant of Scytalidium dimidiatum.

Table II. Nonphaeoid agents of fungalmelanonychia

Aspergillus niger1,12,55

Blastomyces89

Candidaspecies

Candida albican28

Candida humicola29

Candida parapsilosis30,31

Candida tropicalis31

Trichophyton rubrum48

Trichophyton soudanense97

J AMACADDERMATOLMAY2012

832 Finch, Arenas, and Baran


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may partially explain why no known enzyme can

hydrolyze melanin. For some time it was thought thatthese properties of melanin also prevented it frombeing immunogenic. However, Nosanchuk et al35

have since demonstrated that fungal melanin canincite a T celleindependent humoral immune re-sponse in mice.

In fungi, melanins aid in protection from envi-ronmental stresses and confer acompetitive advan-tage in some environments.36 For example,melanized fungi are more resistant to extreme tem-perature variations and to ultraviolet, x-ray, andgamma radiation than are nonmelanized fungi.37-39

Melanin can also protect the fungal cell wall againstenzymatic hydrolysis.40 Much of this knowledge ofthe function of fungal melanin is derived fromstudies in the plant kingdom, where melanin evenenables some plant pathogenic fungi to penetratethrough the cell wall of the host plant.41

In human infection, melanins appear to protectagainst hostdefense systems byacting as free radicalscavengers.42 Scnitzler et al43 demonstrated thatmelanin is capable of protecting E dermatitidisfrom being killed by the phagosomal oxidative burstof human neutrophils. Similarly, albino strains of

Alternaria alternata have been shown to be moresusceptible to oxidative killing than melanizedstrains.44 The additional finding that the antioxidantcapacity of some fungal melanin is in the same rangeas the quantityof oxidants produced by stimulatedmacrophages45 hints at coevolution and further sug-gests a specific role for melanin as a free radicalscavenger.

The role of melanin in fungal virulence andpathogenicity has been highlighted by murinemodels of disease. For example, wild-typestrains of E (Wangiella) dermatitidis capable of

synthesizing melanin produce an infection in mice

that is 100% lethal in 5 to 6 days. In contrast, albino Edermatitidismutants lacking melanin exhibit a sig-nificant reduction in lethality, with most mice sur-viving the acute infection. Interestingly, however,mice surviving acute infection later develop symp-toms of central nervous system infection. In thismodel, fungal virulence and the acute phase ofinfection appear to be related to melanin production,whereas the pathogenicity of the fungi as judged bycentral nervous system symptoms appears to bemelanin independent.46

CLINICAL PRESENTATIONThe nail in fungal melanonychia is typically

brown to black in color, sometimes dystrophic, andmay be raised as a result of subungual hyperkeratosis(Fig 2). Periungual inflammation is common. Theclinical pattern of nail involvement can raise clues asto the origin of infection. For example, longitudinalmelanonychia is more common with strains of der-matophyte such asT rubrum varietas nigricansthatproduce a soluble, nongranular pigment that im-

pregnates the nail bed, staining it brown to black.

47

Fig 1. Pentaketide pathway of fungal melanin synthesis.

Fig 2. Fungal melanonychia.




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On the other hand, black molds such as Scytalidiumdimidiatum,Aspergillus niger, andAlternaria alter-natausually cause diffuse brown nail pigmentation.Care has to be taken in the case of Scytalidiuminfection to distinguish between fungal pigmenta-tion and longitudinal melanonychia as a result ofendogenous hyperpigmentation (see section onCandida below); patients with a Caucasian ethnicbackground often show evident fungal-associated

pigmentation of the nails as a result ofScytalidium.When fungal nail infection produces longitudinal

melanonychia, the band of pigmentation is typicallywider distally and tapers proximally, consistent withdistal-to-proximal extension of infection (Fig 3). Theblack streak may have several pointed extensionsproximally, and staining mayshow this melanin tobe either argentaffin positive48 or negative.49

Proximal subungual onychomycosis, with infec-tion beginning at the proximal nailfold and extend-ing distally, is a common presentation ofonychomycosis as a result of nondermatophytic

molds. It is often accompanied by paronychia.20

Ina recent prospective study of 431 cases of onycho-mycosis, 38 of 50 (76%) patients with onychomycosisas a result of nondermatophytic molds presentedwith proximal subungual onychomycosis accompa-nied by inflammation of the proximal nailfold.1 Bycomparison, a 2005 retrospective study of more than4000 cases of onychomycosis in Italy revealed thatjust 3% overall were proximal subungual onycho-mycosis.13 Paronychia is common in nail infectionscaused byCandida, andalthough Candidais capa-ble of melanin synthesis,32 nail pigmentation more

commonly results from activation of host

melanocytes caused by paronychial inflammation(Fig 4). Thus, melanonychia caused byCandida ismore common in darker skin phototypes.50

Distal and lateral subungual onychomycosis isthe most common clinical pattern of nail infectionas a result ofAlternaria alternata and Scytalidiumspecies. Distal and lateral subungual onychomyco-sis is the presenting pattern ofScytalidiuminfectionin up to 88% of cases.16 Infection usually beginswith involvement of the distal corner of the nail andprogresses proximally along the undersurface of thenail plate, most commonly affecting the great toe.Affected nails can become markedly thickened, andkeratinous debris that collects under the nail mayraise the nail plate.27 The clinical manifestations of

Alternaria infection most often reported are distal

Fig 3. A,Clinically dystrophic nail.B,Dermatoscopy shows linear bands, rounded proximallyand tapered distally.

Fig 4. Melanonychia caused byCandidainfection of nail.




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subungual onychomycosis11 and occasionally distalonycholysis.11,51 In cases of Scytalidium infection,painful paronychia is often the presenting symp-

tom.52

In fingernails, Scytalidium hyalinum infec-tion commonly exhibits lateral onycholysis andparonychia, mimicking Candida onychomycosis,4

but there is also often extensive undermining of thenail plate with severe onycholysis leading to trans-verse fracture of the nail plate. Mycotic foot infec-tion caused by Scytalidium often involves multiplesites, including simultaneous colonization of toewebs, soles, and toenails in up to one third ofcases.16

Infection involving the surface of the nail istraditionally known as superficial white onychomy-

cosis. In the case of fungal melanonychia, thispattern is probably more appropriately referred toas superficial black onychomycosis. Superficial blackonychomycosis is more commonly caused by non-phaeoid molds with pigmented conidia, such asAspergillus niger. It is the most common clinicalpatternof onychomycosis as a result of Aspergillusniger,53 frequently accompanied by periungual in-flammationand black pigmentation of the proximalnailfold.54,55 The black affected areas of the nail aremicroscopically rich with the black conidia ofAspergillus niger. These areas are soft and can bescraped off with a curette. Scopulariopsis brevicaulismay also infect the surface of the nail plate, exhibit-ing pigmented conidia on microscopic examination.But overt clinical melanonychia as a result ofScopulariopsisis less common.

Any of the above clinical patterns of onychomy-cosis may lead to complete destruction of the nail,known as total nail dystrophy.11

DIFFERENTIAL DIAGNOSISSeveral noninfectious conditions can cause

brown-to-black pigmentation of the nail that may

resemble fungal melanonychia and are worthy of

mention. A detailed patient history is an importantpart of the clinical examination of a pigmented nail.

Occupational exposures, athletic activities, medica-tions, and changes in the nail over time can contrib-ute to the differential diagnosis of the pigmentation.For a detailed summary of the differential diagnosisof nail pigmentations, refer to the recent excellentarticle by Braun et al.56

Racial longitudinal melanonychia, a physiologicactivation of melanocytes in the nail matrix, is themost common cause in patients with darker skinphototypes. Although unusual in Caucasians (occur-ring in \1%), physiologic longitudinal melanony-chia occurs in 77% of African Americans older than

20 years and nearly 100% of those older than 50 years(Fig 5).50 From 10% to 20% of Japanese people alsohave racial longitudinal melanonychia. Patients withdarker phototypes also more commonly have longi-tudinal melanonychia resulting from nail trauma orinflammation. Nail biting,57 friction,58 inflammatorydiseases such as psoriasis and systemic lupus eryth-ematosus,59 hydroxyurea treatment,60 psoralen plusultraviolet A,61 pregnancy,62 and drugs (amongwhich chemotherapeutics are most common)63

have all been associated with melanotic pigmenta-tion of the nail resulting from stimulation of mela-

nocytes (Fig 6). In drug-induced melanonychia,pigmentation will usually fade over months toyears after withdrawal of the offending agent.Dermatoscopically, focal melanocyte activation usu-ally has a grayish color. Brownish color is moreindicative of melanocyte hyperplasia.56

Exogenous pigments including tobacco, dirt,potassium permanganate, tar, iodine, and silvernitrate may cause a brown-to-black pigmentationof the nail, mimicking fungal melanonychia. Becausethe discoloration in these instances is not a result ofmelanin, pigmentation caused by exogenous sub-

stances is probably more appropriately referred to as

Fig 5. Racial melanonychia.Fig 6. Medication-induced nail pigmentation in patientreceiving pegylated interferon and ribavirin for hepatitis C.




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chromonychia. Most exogenous pigmentation canbe easily scratched off, and with the exception

of silver nitrate, it does not show up onhistopathology.64

Subungual hematoma can arise in a longitudinalband that mimics fungal melanonychia. The thick-ened, dystrophic nails present in dermatophyte on-ychomycosis may lead to chronic minor trauma tothe nail (eg, via pressure exerted by surface of shoe),resulting in subungual hemorrhage forming a thinlongitudinal band. This combination of nail dystro-phy and longitudinal dark band represent a diag-nostic challenge. The pigment of subungualhemorrhage is usually reddish and does not reach

the free edge of the nail (Fig 7).

Melanocytic hyperplasia encompasses a finallarge category of nail pigmentation disorders.

Melanocytic hyperplasia refers to an increased num-ber of nail matrix melanocytes and includes lentigo,nevus, and subungual melanoma. Lentigo (in whichnests of melanocytes are absent) and nevus (withnesting of melanocytes) are benign melanocytichyperplasias. Lentigo is observed in 9% of biopsyspecimens of adult longitudinal melanonychia. Nailmatrix nevi are a more common cause of longitudi-nal melanonychia in children, accounting for almosthalf of biopsied pediatric cases. Nevi represent 12%of longitudinal melanonychia in adults and morecommonly occur onthe fingers than the toes in all

age groups (Fig 8).

50,65

Dermatoscopically, small

Fig 7. Reddish-brown pigmentation of subungual hematoma.

Fig 8. Melanocytic nevus of distal nail matrix.




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dark granules less than 0.1 mm in diameter, repre-senting intracellular melanin inclusions, can be vi-sualized.56 The dark pigment of fungal nail infectionis typically more homogenous (Fig 9).

Finallyeand most importantlyepigmentation ofthe nail should raise the suspicion of melanoma. Asmany as two thirds of ungual melanomas begin withbrown-to-black pigmentation of the nail. Because of

the high mortality associated with subungual mela-noma, it is imperative to exclude this diagnosis. Thenail is a more common site for melanoma in AfricanAmericans, in whom 15% to 20% of melanomasoccur in the nail apparatus. By contrast 1% to 3% ofmelanomas in Caucasians involve the nail appara-tus.66 Hutchinson sign, or periungual spread ofpigmentation to the proximal or lateral nailfolds, isan important clinical sign of subungual melanoma(Fig 10). This should be differentiated from pseudo-Hutchinson sign, a benign pigmented streak visiblethrough a thin proximal nailfold (Fig 11).

Dermatoscopy can be a useful diagnostic tool,

56,67

but even with the aid of a dermatoscope, the diag-nosis may be overlooked in 50% of cases.68

Sudden onset of nail pigmentation, sudden dark-ening or widening of an existing pigmented band,nail dystrophy, personal history of melanoma, orpresence of Hutchinson sign should all prompt aworkup to rule out melanoma of the nail apparatus.The shared clinical features of ungual melanoma andungual phaeohyphomycosis make precise clinicaldiagnosis very difficult. If there is any suspicion ofmelanoma or any diagnostic uncertainty regardingfungal infection, a biopsy should be performed.

DIAGNOSIS

With the ever-lengthening list of causative agentsof fungal melanonychia and their resistance to mostantifungal therapy, it is important to accuratelyidentify the causative organism to aid in appropriatetreatment. Direct microscopic examination (eg, withpotassium hydroxide or chlorazol black E) is essen-tial to confirm infection by ascertaining the presenceof fungal hyphae/filaments or yeast pseudohyphae.With dematiaceous organisms, the pigmentation isoften clearly seen in direct microscopy (Fig 12).

Fungal cultures are the most important method foridentification of the causative organism and should

be performed by an experienced laboratory. Many

Fig 9. Dermatoscopy of Aspergillus infection, showinghomogenous black pigment.

Fig 10. Hutchinson sign in patient with melanoma ofthumb.

Fig 11. Pseudo-Hutchinson sign in patient with subun-gual hematoma.

Fig 12. Direct microscopic examination of Scytalidiumspecies culture.




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laboratories routinely use culture media containingcycloheximide to inhibit the growth of environmen-tal molds and may overlook an important diagnosisof dematiaceous mold infection. Cycloheximide in-hibits the growth of dematiaceous fungi, and culturescarried out on cycloheximide-containing media willyield false-negative results. Cultures of suspectedphaeohyphomycosis should be carried out oncycloheximide-free media.

Demonstrating that a dematiaceous mold is thecausative agent of melanonychia can be challengingbecause these species are common environmentalcontaminants or secondarilycolonizing agents. Thecriteria set forth by English69 can be helpful inestablishing the pathogenicity of nondermatophytesin onychomycosis. By these criteria, at least 5 of 20inocula should yield growth of the suspected agent inthe absence of dermatophyte growth. If a dermato-

phyte is isolated, it is considered to be the most likelypathogen. The aforementioned cases of melanony-chia as a result of Aureobasidium pullulans,21

Cladosporium sphaerospermum,22 andPhyllostictinasydow23 do not fulfill these diagnostic criteria.

When direct microscopic examination and cul-tures are insufficient or inconclusive, histologicanalysis of nail biopsy specimens can be helpful bydemonstrating the invasive nature of the fungus inquestion. Fontana-Masson stain highlights melaninand can aid in species identification. When exactidentification of the organism is mandatory, fungal

invasion of nail tissue can be precisely visualized byimmunohistochemistry and flow cytometry.70

TREATMENTUngual phaeohyphomycosis is notoriously diffi-

cult to treat. Given the low incidence of fungalmelanonychia, most of the knowledge of treatmentefficacy has been derived from case reports or smallopen clinical trials. It is unlikely that large prospec-tive randomized trials will be conducted. There havebeen many in vitro studies of antifungal therapydirected at a wide range of dematiaceous molds, but

because of variability in nail penetration and drugmetabolism, results of in vitro studies do not alwaystranslate to in vivo success. Indeed, there are noestablished correlations between in vitro suscepti-bility and in vivo effectiveness of antifungals.Because of the variability in response to antifungals,a discussion of treatment of fungal melanonychia isbest undertaken with a species-by-species approach.

Data derived from a number of case series suggestthat oral itraconazole is a good first-line treatment forAlternaria melanonychia. A look at these studiesattests to the difficulty of conducting large prospec-

tive trials of fungal melanonychia treatment. In a

1997 multicenter study71 evaluating the efficacy ofitraconazole in the treatment of nondermatophyticmold onychomycosis, only one of 36 patients hadonychomycosis as a result of Alternaria species(itraconazole therapy was successful in this patient).In a retrospective series reported by Romano et al,11

complete (mycological and clinical) cure wasachieved in 6 of 7 (87%) patients treated withitraconazole. Arrese et al9 used partial chemical nailavulsion, followed by 3 weeks of local infraredtherapy and 200 mg of itraconazole daily for 3months, in the successful treatment of two affectedfingernails associated with distant spread of infectionto the cornea. Voriconazole has also seen somesuccess in the treatment of subcutaneousalternariosis.72

Treatment ofScytalidium dimidiatuminfection isexceptionally difficult. Scytalidium dimidiatum

does not respond to griseofulvin, ketoconazole,fluconazole, itraconazole, or terbinafine,73 and de-spite in vitro effectiveness, topical imidazole deriv-atives are not curative. A literature review conductedat the time of this writing revealed just one report ofsuccessful treatment ofScytalidiumdimidiatumnailinfection. Rollman and Johansson74 reported a singlecase of successful treatment ofHendersonula toru-loidea (Scytalidium dimidiatum) fingernail infectionwith nail avulsion followed by a lengthy course oftopical 1% ciclopirox amine cream. Although am-photericin B has been effective in a few isolated

cases of deep infection,75 there remains no specifictreatment for ungualScytalidiuminfection.

Aspergillusonychomycosis (a nondematiaceousfungus), on the other hand, responds quite well totreatment. In the aforementioned study of nonder-matophyte onychomycosis,1 all 7 patients withAspergillusinfection (including 3 with onychomyco-sis caused by Aspergillus niger) were cured withtopical ciclopirox, oral terbinafine, or oral itracona-zole. In another series reported by Gianni andRomano,76 30 of 34 (88%) patients with onychomy-cosis caused byAspergillusspecies achieved clinical

and mycological cure recovery at 1 year, after treat-ment with a 3-month course of pulsed terbinafine.

Reports on treatment ofExophialaonychomyco-sis are scarce.E dermatitidisnail infection has beensuccessfully treated with 1% topical bifonazole solu-tion in a case involving both great toenails of aJapanese woman.19

Tosti et al1 reported treatment results of 59 casesof nondermatophyte onychomycosis. Among 20patients with onychomycosis caused by Fusariumspecies, cure was achieved in only 8 of 20 (40%)patients. Pulse itraconazole (400 mg daily for 1 week

each month for 3 months) affected cure in 3 of 13




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(23%) patients. Terbinafine was effective in two of 4(50%) patients, one of whom had previously faileditraconazole pulse therapy. Topical ciclopirox naillacquer achieved cure in all 3 patients treated,whereas nail avulsion followed by topical terbinafinefailed in each of two patients treated.

Isolated case reports have contributed importantbut limited data to our knowledge of fungal mela-nonychia therapy. In the future, fungal melanin mayserve as a novel target for antifungal pharmacother-apy. Melanin biosynthesis inhibitors have beenfound to reduce the pathogenic potential of manyplant fungi and may be an effective adjunct toantifungal therapy. But currently, treatment of theseinfections continues to be guided by these anecdotalreports.

The authors would like to thank Dr Rod Hay for his

assistance in the preparation of this manuscript and DrSiobhan Collins for her contribution of clinical photogra-phy (Fig 11).

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