Longitudinal Melanonychia:How to Distinguish a Malignant Condition from a Benign One

Yi CAO,Dong HAN

Department of Plastic and Reconstructive Surgery,Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China

KEY WORDS Longitudinal melanonychia;Nail matrix nevi;Subungual melanoma

INTRODUCTION

Longitudinal melanonychia,also known as melanonychia striata,is not a rare clinical condition.It is mostly characterized by the presence of longitudinal,demarcated,and pigmented bands on the nail unit.Melanin pigment in the nail plate and/or nail bed manifests as tan,brown,or black streaks[1].In some cases,nail deformity/fragility can be observed along with the pigmented bands (Fig.1).Longitudinal melanonychia is quite common in darkskinned races,especially in people of African descent.It is reported that nearly 100% of African-Americans develop this condition before 50 years of age[1-3].Compared with dark-skinned races,the incidence in whites is very low at around 1%[3].Kopf and Waldo reported that longitudinal melanonychia occurs in 20% of Japanese individuals[1].However,comprehensive data regarding its incidence among Asians are lacking.

The thumbnails,index fingernails,and great toenails are the most affected nails with longitudinal melanonychia[4].Most clinical cases of melanonychia are benign lesions;however,some cases are finally diagnosed as subungual melanomas that require specific treatment and extensive care.Subungual melanoma is a malignant disease with a poor prognosis of only a 30% 5-year survival rate and a 13% 10-year survival rate[5-6].Among Chinese and Japanese individuals,subungual melanomas account for 17%[7]and 19%[8]of cutaneous primary melanomas in the whole body.Thirty percent or more of subungual melanoma cases begin with longitudinal melanonychia[8].

Fig.1 Nail deformity/fragility in some cases of longitudinal melanonychia.(A-B) Thumbnails.(C) The fifth toenail.

Haneke and Baran reported that approximately two-thirds of nail apparatus melanomas are characterized by longitudinal brown-to-black pigmentation in the nail unit[9].Therefore,since this malignant disease usually presents as longitudinal melanonychia in the initial stage and sometimes remains benign for many years,it has become highly important for doctors to accurately distinguish it from benign melanonychia without any delay.Misdiagnosis or delayed diagnosis of subungual melanoma usually results in poor outcomes and leads to mortalities in worstcase scenarios.

However,the manifestations of benign and malignant melanonychia present with similar clinical features.In particular,it is quite difficult to distinguish these two conditions in their early stages.Thus,in this review,we focus on the diagnosis and differential diagnosis of benign and malignant longitudinal melanonychia,and more importantly,the etiology of the disease,which is considered one of the most vital criteria to confirm the diagnosis.

ETIOLOGY

Melanin pigments present in the nail unit are secreted by melanocytes within the nail matrix,which is at the nail root and under the eponychium[10-11].Under normal circumstances,melanocytes in the nail matrix are in a nonactivated state and are unable to produce melanin.Once the melanocytes are activated and/or further progress into a hyperplastic state,secreted melanin pigments accumulate in the nail plate and eventually form pigmented bands.Based on the state in which the melanocytes are,the etiology of longitudinal melanonychia is generally classified into two major categories:melanocytic activation or melanocytic hyperplasia[9-10,12-14].

Melanocytic Activation

Melanocytic activation does not involve an increase in the number of melanocytes but mainly results in the production of more melanin pigment after melanocytes are activated[10,13].To our knowledge,there are various causes of melanocyte activation,which can be divided into physiological or pathological kinds.

Physiological causes are related to ethnicity and pregnancy.Longitudinal pigmented bands are commonly seen in the nail plates of those belonging to dark-skinned races,which show benign characteristics[6].The number of streaks and the widths of the bands usually increase with age[15].Aside from racial correlations,longitudinal melanonychia can sometimes be seen in pregnant women.In our experience,some female patients exhibit longitudinal melanonychia after pregnancy while others may have melanonychia before pregnancy,but the number of streaks or the widths of the bands generally increases with pregnancy (Fig.2).This indicates an effect of pregnancyrelated hormones on the progression of longitudinal melanonychia.After delivery wherein there is a decrease in hormone levels in the body,some of the melanonychia spontaneously regressed or gradually disappeared,seemingly confirming the aforementioned theory.

Fig.2 Melanocytic activation caused by pregnancy.(A)Pigmented streaks present during pregnancy and persists up to 6 months after delivery.(B) Pictures taken during the 38th week of pregnancy.Pigmentation was noted on both left and right 4th toenails before pregnancy;however,pigmented bands became darker during pregnancy,especially on the right toenail.

Pathologic causes of melanocytic activation are quite extensive,such as regional,dermatologic,systemic,iatrogenic,and certain syndromic causes[13].Table 1 provides the detailed causes pertinent to the different pathological factors.Among these,some are relatively common in clinical practice.For instance,regional repeated traumaassociated longitudinal melanonychia is often accompanied by deformity/fragility of the nails or periungual tissues[10,16].If some of the melanonychia on the toenails exhibit symmetry,which is not unusual in clinical cases(Fig.2B),repeated trauma caused by unsuitable shoes may be a consideration[13,17].Moreover,among iatrogenic causes,drug intake might be related to the process of melanocytic activation in the human body.As a result,drugs such as bleomycin sulfate,busulfan,cyclophosphamide,dacarbazine,daunorubicin hydrochloride,doxorubicin,etoposide,5-fluorouracile,hydroxyurea,imatinib,adrenocorticotropic hormone,amodiaquine,amorolfine,chloroquine,clofazimine,cyclones,fluconazole,fluorides,gold salts,ibuprofen,ketoconazole,mepacrine,mercury,melanocyte-stimulating hormone,minocycline,procarbazine,phenytoin,phenothiazine,psoralen,roxithromycin,steroids,sulfonamide,thallium,timolol,and zidovudine could cause subsequent longitudinal melanonychia[10,13,18-22].Drug intake-induced melanonychia is more likely to affect multiple fingernails or toenails.However,most cases of drug-associated melanonychia gradually regress once patients stop taking these medications.Malignancy in this type of melanonychia is rare.Fig.3 shows a 17-year-old female patient with ulcerative colitis who developed longitudinal melanonychia on the thumbnail as well as two other pigmented nevi separately on the skin of the hand and forearm after receiving regular corticosteroid treatment.

Table 1 Pathological causes of melanocytic activation in longitudinal melanonychia (contents adapted from Jefferson &Rich,2012 [13])

Melanocytic Hyperplasia

Fig.3 A 17-year-old female patient with ulcerative colitis who developed longitudinal melanonychia and other nevi after receiving corticosteroid treatment

Unlike melanocytic activation,the main pathologic feature of melanocytic hyperplasia involves an increase in the number of melanocytes within the nail matrix[10,13].There are three types of longitudinal melanonychia in this category:lentigo,nail matrix nevus,and subungual melanoma.The former two conditions are benign lesions,while the latter is malignant.

Lentigo and nail matrix nevi are benign conditions that share similar clinical characteristics.The differences between these two conditions lie in the patient’s age and histopathologic findings.Lentigo is usually observed in adult patients,whereas nail matrix nevi are mostly found in children.As for the histopathologic analysis,there is no melanocytic nest within lentigo specimens,while at least one melanocytic nest can be found in nail matrix nevi[10,13].Nail matrix nevi can be further classified according to whether it is congenital or acquired.In pediatric patients,especially those under 3 years,it is difficult to determine whether the melanonychia is congenital or acquired because nail matrix nevi may present as colorless bands in the early stages[23-26].

More than one-third of clinical cases of subungual melanoma (Fig.4) begin with benign longitudinal melanonychia commonly in the form of nail matrix nevi[8,27].Like melanomas in other parts of the human body,age is an important causative factor in the development of subungual melanoma.This disease mostly occurs around the age of 50 to 70 years[28-30,43].There is no statistical difference in the incidence between male and female patients[31].Although nail matrix nevi are not a rare condition in children,subungual melanoma is not commonly found in children[32].Some retrospective studies have suggested that local repeated trauma on the hands or feet is an important cause of malignant melanoma formation[33].Milton et al.[34]concluded that trauma may cause 41% of cases of subungual melanomas.However,some studies report that trauma is not a crucial factor[29-30].

Fig.4 Subungual melanoma on the right little fingernail

In addition to the two major categories of melanocytic activation and melanocytic hyperplasia described above,some pathogens,such as bacteria and dermatophytes,can cause linear brown or black streaks to appear on the nail plate due to their ability to secrete melanin pigments[9,35].It should be noted,however,that this is not the same as the longitudinal melanonychia caused by the above-mentioned onychomycosis-or paronychia-induced inflammation as described under the etiology of melanocytic activation.

DIAGNOSIS

History

For most patients,the main purpose of consulting a doctor about longitudinal melanonychia is to determine whether they have malignant subungual melanomas.Thus,it is extremely important for doctors to acquire a detailed history and thorough physical examination before reaching a precise diagnosis.Full history taking should include sex,age,time after onset,location of lesions,change in color and width of the pigmented bands,nail pain and/ or bleeding,nail deformity/fragility,patients’ occupation,trauma history,family history,medical history,and drug history[13,36].Female patients should be asked about their history of pregnancy as well as the relationship between pregnancy and the occurrence or progression of longitudinal melanonychia.

Physical Examination

The initial physical examination mainly relies on gross observation of longitudinal melanonychia.According to Jefferson et al.[13],there should be a careful assessment of all the fingernails and toenails of the patient.The number of involved fingernails or toenails,the color and width of the pigmented bands,and skin involvement of the eponychium,hyponychium,or lateral grooves should all be meticulously evaluated.In particular,the following details should be noted:Ⅰ) the location of the pigmented steaks,if they are on top of,within,or beneath the nail plate;Ⅱ)if the pigmented streaks are linear in orientation;Ⅲ) if the pigmented streaks are wider or darker proximally;Ⅳ)if nail plate dystrophy coexists[13].In our experience,if the pigmented streak looks wider or darker proximally,or forms a trapezoid-like shape with a wide proximal bottom and a narrow distal top,these normally indicate that the formation of melanonychia is either in the initial or progressive stage of melanocytic hyperplasia.This is a specific situation in which doctors must remind the patients to observe the changes in pigmented streaks on their own nail plates in a close and careful manner.

If the melanin pigment extends into the skin and soft tissue surrounding the nail plate,such as the eponychium,hyponychium,or lateral grooves,it is identified as a positive Hutchinson’s sign (Fig.5).Hutchinson’s sign is considered to be almost pathognomonic of subungual melanoma and usually requires attention and further examination[37].However,noting some periungual pigmentation does not definitively merit noting a positive Hutchinson’s sign.The following are some mimickers of Hutchinson’s sign[4,38,44]:Ⅰ) Laugier-Hunziker syndrome;Ⅱ) congenital nevi of the nail unit;Ⅲ) radiation therapy;Ⅳ) malnutrition;Ⅴ) ethnic nail pigment changes,especially in dark-skinned individuals;Ⅵ) acquired immunodeficiency syndrome;Ⅶ) drug intake;Ⅷ) regressive nevoid nail melanosis in Japanese children.Furthermore,in some children whose periungual skin is thinner than adults,the pseudo-Hutchinson’s sign may present more often and make confirmation of the diagnosis more complicated.Under these circumstances,dermoscopy and/or biopsy may be required.

Fig.5 Hutchinson’s sign

In 2000,Levit et al.[39]established an“ABCDEF”rule for the clinical detection of subungual melanoma.Of this rule,“A”stands for theageof the patient.Subungual melanoma mostly occurs at the age of 50-70 years.“B”stands for thebrown-to-blackpigmented streaks present on the nail unit with abreadthof over 3 mm and irregular orblurred borders.“C”stands for a recent sudden or rapidchangein the width of the pigmented bands as well as in nail plate morphology.“D”stands for the singledigitinvolvement of mostly the thumb,index finger,and great toe.“E”stands forextensionof pigmentation into the perionychium,which shows a positive Hutchinson’s sign.“F”stands forfamilyhistory or personal medical history of melanoma[13,39].

Dermoscopy

For patients with longitudinal melanonychia,dermoscopy offers more visual information to help confirm the diagnosis and decide whether a biopsy is necessary[12,40].With the use of dermoscopy,it is not difficult to differentiate melanonychia from blood spots and exogenous substances such as dirt,tar,and tobacco[13].To examine melanin pigmentation,dermoscopy is usually performed to differentiate pigment in the skin of the proximal nail fold from the transmission of the underlying pigmented nail streak through the thin cuticle and distal part of the proximal nail fold.The latter description regarding underlying pigmentation is referred to as pseudo-Hutchinson’s sign,which is not significant when diagnosing malignant melanoma[4,15].Ohn et al.conducted a comparative analysis regarding dermoscopic features of nail matrix nevus in adults and children.An irregular pattern and pseudo-Hutchinson’s sign were found more frequently in pediatric patients,suggesting that melanonychia has more melanoma-associated features in children[41].Nevertheless,the dermoscopic findings pertinent to benign or malignant melanonychia still lack convincing evidence and remain controversial among doctors[13].

Biopsy

Owing to the difficulties in the clinical diagnosis of melanonychia,performing a biopsy is sometimes necessary to exclude subungual melanoma[12-13].A 2-to 3-mm punch biopsy is usually done to harvest the specimen[4,36].It is unnecessary to remove the nail plate before a biopsy.A punch biopsy is performed at the proximal part of the pigmented streaks and at the distal part of the nail matrix.Normally,the biopsy is taken directly through the nail plate to the underlying bone,and a round specimen is subsequently removed from the nail unit[4].Since biopsy is possibly associated with later development of nail deformity or dystrophy,careful management after the procedure is required.Krull[4]highlighted six possible indications for biopsy,some of which were in accordance with the“ABCDEF”rule proposed by Levit et al.[39].These indications are as follows[4]:Ⅰ) suddenly becomes wider and/or darker;Ⅱ) blurred borders rather than sharply welldemarcated;Ⅲ) irregular color of the pigmented band;Ⅳ)solitary black streaks,especially in white individuals;Ⅴ)nail plate deformity or dystrophy;Ⅵ) a wide band.

Lee et al.[36]reported the largest case series of biopsyconfirmed nail matrix nevi in 2018.They found melanonychia to be wider among children than among adults,which presented as a sharply demarcated pigment band of even width.More importantly,the presence of Hutchinson’s sign with longitudinal brush pigmentation may favor a diagnosis of benign nail matrix nevus over subungual melanoma[36].

TREATMENT

The treatment of longitudinal melanonychia discussed in this review will focus on our experience with surgical excision of the nail matrix nevus.The treatment of subungual melanoma is comprehensive and will not be reviewed here.For pediatric patients,we usually ask the parents to closely observe the change in melanonychia.Since malignancy is rarely found in children,surgical removal is not necessary in most cases.For adult patients,especially those above the age of 50 years,if the increase in width of the pigmented band is rapid or sudden,the width is over 5 mm,or the border becomes blurred,we will strongly recommend surgical treatment.

The surgical procedure is not complex and is done quite similarly among experts.It usually involves longitudinal excision of longitudinal melanonychia.However,Richert et al.[42]reported the use of a tangential excision technique for pigmented lesions.They developed a new surgical procedure,the shave biopsy technique,for the removal of longitudinal melanonychia.A shallow incision through the matrix epithelium and the papillary dermis was made around the identified pigmented lesion with 1-to 2-mm margins.Despite the lower incidence of nail deformity after surgery (74% without nail plate dystrophy),the recurrence of pigmentation was quite high (70% with recurrence)[42].

In our clinic,we prefer to completely excise the suspicious pigmented bands from the nail matrix to the distal hyponychium.To do so,a skin incision is made through the entire width of the proximal fold of the eponychium.After careful removal of the nail plate,the nevus and pigmented streaks are visualized and located under a microscope.The pigmented streaks mostly originate from the distal part of the nail matrix (Fig.6);therefore,a tapered pointed excision that avoids the proximal part of the nail matrix is made to remove the pigmentation.The width of the specimen includes 1-or 2-mm lateral margins.If the lesions on the nail unit are broad,periungual soft tissue will be extracted toward the center of the nail and then sutured together.All excised specimens are further sectioned and subjected to histological examination.If the pathological findings indicate malignancy,we will normally refer the patients to a cancer center for further comprehensive treatment of melanoma.Recurrence after surgical excision is not rare especially in cases of large or total melanonychia,but in our clinic,over two-thirds of patients who underwent surgery had no recurrence(Fig.7).In conclusion,although it is not easy for doctors to distinguish malignant melanoma from benign longitudinal melanonychia,a careful history,thorough physical examination,as well as dermoscopy and biopsy whenever necessary can be obtained or performed to aid in diagnosis.For elderly patients,if the pigmented band is solitary and/or obvious changes in the band can be observed,complete excision is highly recommended.

Fig.6 (A) Preoperative view.(B) A skin incision is made through the entire width of the proximal fold.The nail plate is removed.The pigmentation originates from the distal part of the nail matrix.(C) Complete removal of the nail matrix nevus.

Fig.7 (A) Preoperative view.(B) Pigmentation could clearly be found on the nail matrix.(C) One-year follow-up shows a nail deformity.No recurrence of the pigmentation.

ETHICS DECLARATIONS

Ethics Approval and Consent to Participate Not applicable.

Consent for Publication All the authors have consented to the publication of this article.

Competing Interests

The authors declare no conflicts of interest.The authors state that the views expressed in the article are their own and not the official position of the institution or funder.