Classification of and the latest photoelectric therapy for epidermal nevi

Liyun Liu ,Huijing Wang ,Jiying Dong

a Anhui Medical College,Anhui No.2 Provincial People’s Hospital,Hefei 230601,Anhui,China

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

c Department of Laser and Aesthetic Medicine,Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China

Keywords:Epidermal nevus Epidermal nevus syndrome Verrucous epidermal nevus Nevus sebaceous Inflammatory linear verrucous epidermal nevus Becker nevus Smooth muscle hamartoma Nevus comedonicus

ABSTRACT An epidermal nevus (EN) is a common disease of various types,including verrucous EN,nevus sebaceous,inflammatory linear verrucous EN,Becker nevus,smooth muscle hamartoma,and nevus comedonicus.EN syndrome is a serious and difficult-to-treat syndrome that is complicated by two or more abnormal organs or systems.To date,the mechanism of an EN is still unclear,and the therapies remain unsatisfactory.The most frequently used treatments are surgery and laser therapy.Several drugs have also been tested.An EN requires more attention,and further research is needed to provide appropriate and effective treatments for each patient.

1.Introduction

An epidermal nevus (EN) is a hyperproliferative hamartoma of skin keratinocytes and/orepidermal appendages that can involveall components of the epidermis,such as keratinocytes,glands,hair follicles,and muscles.Often,it manifests as an isolated birthmark.Multiple cells can be involved in a singlelesion;however,the classification is based on the main affected cells.The most common types of an EN are verrucous epidermal nevus(VEN)and nevus sebaceous(NS).The other types include inflammatory linear verrucous epidermal nevus(ILVEN),Becker nevus(BN),smooth muscle hamartoma (SMH),nevus comedonicus (NC),porokeratotic eccrine nevus,1rounded and velvety epidermal nevus,2and nevus lipomatosus superficialis.3An EN complicated by malformations or abnormalities of any organ of any system other than the skin is collectively called epidermal nevus syndrome(ENS),including malformations or abnormalities of the skin,eyes,nerves,bones,and cardiovascular and genitourinary systems.4

The incidence of an EN is 1/1 000 to 3/1 000 newborns.5The majority of patients have a strong cosmetic appeal and require the removal of abnormal skin pigments or vegetation.All types of an EN commonly easily relapse,making them difficult to cleanly remove at once.Since the success of surgery constantly depends on the size and location of the lesions,many non-surgical techniques have been considered,including cryotherapy,electrocautery,skin abrasion,chemical peeling,and laser therapy.Unfortunately,the results of previous studies have been inconsistent.Moreover,the problem of scar formation is inevitable.In recent years,with the development of photoelectric therapy,minimally invasive methods have gradually attracted attention.Different types of ablative lasers have become the main methods of EN cosmetic treatment,and their outcomes are promising and encouraging.

2.Verrucous epidermal nevus

A VEN is caused by epidermal localized developmental abnormalities due to the overgrowth of epidermal cells,which may be related to mutations in keratinocytes.Chromosomal breakpoints indicating genetic mosaicism have been found in some cell lines of patients.6Occasionally,a VEN can be a familial disease.7According to the distribution pattern,it is classified as localized VEN,systematized VEN,ILVEN,nevus unius lateralis,and ichthyosis hystrix.8A small number of head and facial lesions may be accompanied by an NS or a papillary sweat duct cystadenoma.An ILVEN also causes focal hypokeratosis,mild acanthal edema,and mild chronic inflammatory infiltration in the dermis.Part of the generalized type and a few of the limited patients can show epidermolysis hyperkeratosis,which often spreads to the entire epidermis.9

Traditionally,topical drugs are used,such as 5-fluorouracil,calcipotriol,tretinoin,corticosteroids,crisaborole,and podophyllin resin;however,the outcomes are uncertain,and recurrence always occurs.10-13Surgical excision can also be performed to remove the lesion;however,permanent scarring may be obvious and ugly.Cryotherapy may yield benefits and suit small lesions;however,it requires many repeat sessions on a large VEN.14,15It has been proven that pulsed carbon dioxide(CO2)laser and erbium:YAG laser have similar efficacy and complications,but erbium:YAG laser has better accuracy and recovery.8Recently,23 patients were treated with ablative lasers,and 11 of them relapsed;nevertheless,82.6% expressed their satisfaction with the treatment results.16Especially when a VEN occurs at a specific site,such as the genital part and nipple,CO2laser is an ideal option since it removes the nevus completely and shows excellent outcomes.17-19Except for ablative laser,532-nm picosecond laser has been found to be useful in treating a VEN.20Besides,the combination of micro-plasma radio-frequency treatment and photodynamic therapy (PDT) has been proven to remove a VEN effectively and safely and is able to prevent scarring and pigmentation.21,22Although an ILVEN is difficult to cure and has a strong resistance to CO2laser,23UV 308-nm excimer laser is a promising method but still requires an extended period for multiple treatments.24,25Meanwhile,2 940-nm erbium laser with a fractional mode yields better tolerance and fewer side effects during therapy.26An ILVEN may cause intense pruritus,which is usually tricky to relieve;in such cases,thalidomide is thought to be helpful.27Further,pulsed dye laser(PDL)could ease the erythematous parts of ILVEN lesions.16

3.Nevus sebaceous

An NS is also known as organoid nevus,congenital sebaceous hyperplasia,or sebaceous gland hamartoma.It is an organoid nevus composed of the epidermis,dermis,and epidermal appendages,and its main component is the sebaceous glands.An NS usually presents at birth and equally occurs in boys and girls;its incidence in newborns reaches up to 0.3%.28In 1965,Mehregan and Pinkus described the developmental process of a typical NS and divided it into the following three stages:(1)Infancy and childhood:The rash is manifested as static yellow hairless plaques with a smooth surface,and histopathological findings show immature sebaceous glands;(2) Puberty:The skin lesions gradually increase;the surface is warty or nodular;and the histopathology of the skin lesions are sebaceous gland hyperplasia,epidermal hyperkeratosis,and papillomatous hyperplasia;(3) Old age or tumor stage:If there are manifestations,such as rapid plaque enlargement and nodule or ulcer formation in a short period,there is a possibility of a secondary tumor.29A tumor is the most common complication of an NS.Patients usually develop only one type of tumor;however,some patients,unfortunately,develop two or more types of tumors simultaneously.Generally,these tumors are benign.It has been reported that the probability of complicated benign or malignant tumors ranges from 10%to 40%.30,31Among benign types,papillary syringadenoma and piloblastoma are the most frequent.An NS is a rare malignant tumor,with the majority being basal cell carcinoma,which accounts for approximately 0.8%of all cases.32

Most surgeons suggest complete surgical excision of an NS to avoid malignancy.33However,the timing of surgery should be discussed cautiously because of the low incidence of malignancy.Ablative lasers are widely used but have a high recurrence rate.16CO2laser can be combined with topical medicines as joint therapy.When it is used with isotretinoin,the formation of scar is reduced.34More than 10 years ago,a dermatology doctor began to test the combination of CO2laser and PDT using 5-aminolevulinic acid or methyl aminolevulinate for treating a facial NS.The result was quite promising;however,partial recurrences persisted.35-37When fractional CO2laser treatment was followed by 595-nm PDL treatment,the result was cosmetically acceptable,and interestingly,there was no recurrence.38As a type of ablative laser,erbium:YAG laser is less commonly used in treating an NS because of its severe destructive effects on deep tissue and bleeding issues.Chung et al.used the continuous-wave mode of erbium:YAG laser to create pinholes to treat an NS.Although some patients had pigmentation or scarring,the outcomes were satisfying,without any recurrence.39Nevertheless,a fractional CO2laser is a more effective and safer technique for ablating large lesions on the skin and may be a better method than erbium:YAG laser in most cases.

4.Becker nevus

A BN is also known as a pigmented hairy EN,with an incidence of approximately 0.25%-0.52%.40,41It was first reported by Becker in 1948.42A BN is mainly seen in young individuals,especially during the period of puberty and sexual maturity,43and is more prevalent in men than in women,with a male-to-female sex ratio of approximately 5:1.40Most skin lesions are accompanied by acne,with more sebum secretion,and easily complicating tinea versicolor.They are most likely to occur in the shoulders,chest,and scapula,followed by the forearm,wrist,face,and neck.A BN tends to grow at a single site on one side of the body.However,it is not impossible that multiple areas in the entire body could be involved.The skin lesions typically have a patchy brown characteristic owing to different degrees of pigmentation,irregular borders,and a map-like appearance.Newly occurring pigment spots merge with each other and reach the size of the palm or even larger.Some patients may have thickened body hair after 1-2 years,while other patients may appear hairless or mildly hairy.44,45Therefore,according to the amount of hair,a BN can be classified into hairless and hirsute types.46The central skin texture of a BN is slightly thicker,and the edges remain unchanged.Other intradermal nevus or EN can be detected in the skin lesions.

The primary purpose of all types of treatments for a BN is cosmetics.Hence,doctors should provideadvice on the treatment method that causes the least apparent scarring,considering the different appearances and features of a BN.Surgical excision will definitely result in permanent scarring,while the use of medicines(e.g.,topical application of glycolic acid) and lasers may prevent it.47Nevertheless,there once was an exception that dermabrasion involving the epidermis and upper dermis did not cause scarring.48Zhong et al.49summarized the outcomes and characteristics of various laser treatments for a BN.PDL (504 nm) and erbium-doped fiber laser (1 550 nm) were only effective for pigment cleaning.50,51Further,577-nm pro-yellow laser treatment is a potential method for removing a BN without hair.52Q-switched lasers at 532 nm and 1 064 nm performed poorly on a BN,16,53-55whereas a laser at 694 nm showed satisfactory results.56-59Long-pulsed 755-nm alexandrite laser alone and long-pulsed 1 064-nm Nd:YAG laser alone as well as the combination of long-pulsed Nd:YAG laser and alexandrite laser are both efficacious and safe in treating a BN on both hyperpigmentation and hypertrichosis.60-64Application of intense pulsed light(IPL)with a filter of 550 nm and 590 nm has yielded effective results.The 590-nm filter was well tolerated in both hypertrichotic and atrichotic BN,65,66while the 615-nm filter was less useful.67Nevertheless,a Chinese retrospective study demonstrated that IPL did not benefit a BN in the long term.68Diode laser alone exhibited moderate effects and yielded a high recurrence rate.69,70Unlike in other EN,the evaluation of ablative lasers is inconsistent,and the lasers used have individual differences.54,71-74It is acknowledged that diverse joint therapies displayed the most notable improvement for a BN.63,72,75

5.Smooth muscle hamartoma

An SMH is a benign tumor caused by the proliferation of smooth muscle bundles in the dermis.Stokes first reported this disease in 1923,dividing it into congenital,acquired,and familial cases.A congenital smooth muscle hamartoma(CSMH)is a rare skin disease with four types:localized,hair follicle,multiple,and diffuse.To date,there are only a few reports on the disease worldwide,and only 15 cases have been reported in China.A CSMH usually develops in the neonatal period,with an incidence of approximately 1/26 000 to 1/1 000 births and a male-tofemale sex ratio of approximately 1.5:1.76Most patients are affected in the trunk and two-thirds in the lumbosacral area.Some patients are also likely to be affected in the scrotum,foreskin,thigh,sacrum,nose,upper arm,and other parts of the body.The typical characteristics of the localized type are skin tone or mildly pigmented patches or plaques with hirsutism.Approximately 80%of patients experience temporary bulging or subtle peristalsis after exposure to cold or friction.This phenomenon is called pseudo-Darier’s sign and is caused by contraction of the inner trichome or smooth muscle of the skin lesion after stimulation.

A CSMH is not likely to be malignant;thus,treatment is not necessary in most cases.77For cosmetic purposes,surgical excision and reconstruction,as well as laser therapy,are appropriate treatments.A large lesion may leave an unacceptable scar after surgery,which is a significant challenge for surgeons to reconstruct at once.Some studies have reported that PDL partially decreased the erythema of SMH but did not directly affect hamartoma.16,78

6.Nevus comedonicus

An NC is also known as nevus follicularis keratosus,nevus acneiformis,unilateral comedo nevus,or keratotic follicular nevus.Its concept was first proposed by Kofmann in 1895.79The disease is caused by congenital hair follicle malformations.Symptoms mostly occur at birth;however,some have an onset before the age of 10 years.In the early adolescence stage,the condition tends to worsen,while in adulthood,the development of skin lesions slows down gradually and becomes stable.Generally,the nevus does not fade on its own.The clinical manifestations are blackhead-like papules arranged in bands and distributed on one side of the body.The commonly affected regions are the face,neck,upper arms,chest,and abdomen.Keratinization of the sebaceous glands and hair follicles on the skin surface forms black keratinous plugs.This type of horny plug is thick and large,confined to the normal part of the skin,and scattered with blackheads.

Similar therapies have been applied to cure an NC as in other types of EN,such as topical medicines,ablative laser,surgery,and biologic therapy.80Conservative options include corticosteroids,tretinoin/clindamycin gel,keratolytics(e.g.,salicylic acid),retinoic acid,ammonium lactate solution,and vitamin D derivatives.81-85Chemotherapy drugs might be helpful but could not prevent relapses.86-89For wildly spreading lesions,staged surgical excision and reconstruction could yield great outcomes.90It has been reported that 2 940-nm erbium:YAG and 10 600-nm ultrapulsed CO2laser treatments were beneficial for some patients;however,there was a possibility of recurrence and scarring.91-95Non-ablative lasers,including 1 450-nm diode lasers combined with 1 550-nm erbium-doped fiber lasers,are potentially effective because 1450-nm laser targets the sebaceous glands and consequently decreases seborrhea.96,97Recently,a novel method for treating an NC using a microneedling fractional radiofrequency(MFR) device or microneedling alone yielded promising results with no relapse.98,99

7.Porokeratotic eccrine nevus

A porokeratotic eccrine nevus,also known as a porokeratotic eccrine ostial and dermal duct nevus (PEODDN),is a rare type of eccrine hamartoma.No significant difference has been observed in the incidence of this disease between men and women.It most commonly occurs at birth or during childhood and is very rare in adults.The skin lesions are mainly located on the extremities,especially the palms and soles,and can involve the face,neck,limbs,trunk,armpits,and buttocks.The majority are distributed along the Blaschko line.A minimal number of patients may have generalized skin lesions.The nevi on the skin can be scattered or densely distributed keratinizing papules,with a small pit in the center.Some acne-like horny plugs in the center of the papules merge into plaques.Others may manifest as filamentous or wart-like lesions that do not merge.The color of the lesions varies from complex to dark brown,with clear boundaries.Patients rarely complain of discomfort regarding the nevus and only occasionally of mild itching.Patients with a PEODDN may also have abnormalities,such as hemiplegia,scoliosis,anhidrosis,alopecia areata,deafness,growth retardation,nail dystrophy,unilateral calcification,and linear psoriasis.

A PEODDN has been reported to respond poorly to topical corticosteroids,tar,PUVA,UVB,and anthralin but quite positively to topical dithranol,tazarotene,and calcipotriol.100-103Further,10% urea ointment and sun exposure seemed to have improved the lesion mildly.104A PEODDN has also been found to be treated successfully by erbium and CO2lasers;however,further observation is still required to evaluate the outcomes.105-111Meanwhile,PDL failed to have any effect on this lesion.112CO2laser combined with topical retinoids and PDT with topical 5-aminolevulinic acid were both partially effective.113,114

8.Epidermal nevus syndrome

ENS was first proposed by Solomon Equals in 1968.4It is defined as an EN associated with deformity or abnormality of any organ of any system other than the skin.The lesions are collectively referred to as ENS,including deformities or abnormalities of the skin,eyes,nerves,bones,cardiovascular system,or genitourinary system.There are four major dissimilar types of ENS:linear sebaceous nevus,linear NC,linear EN,and ILVEN.115However,the onset of this disease remains unclear.Some doctors have speculated that it may be a chimeric skin disease caused by post-zygotic mutations in embryonic cells.The earlier gene mosaicism occurs,the more extensive the systems are affected by the mutation.115,116With advancements in modern genomics research,this field has developed rapidly,and many discoveries have changed the understanding of these syndromes caused by somatic mosaicism.The underlying causes of the various clinical manifestations of ENS may be multifactorial,including but not limited to the functional role of specific gene defects,level of expression in specific cell types,epigenetic factors,and timing of fetal mutations in development.

For skin abnormalities,vitamin D analogs may partially regress some plaques.117,118Lactic acid,salicylic acid,anthralin,intralesional steroids,and retinoids have all been successful to some degree.1Electrocautery,cryotherapy,dermabrasion,and excision with phenol peel each showed inconsistent results.119Currently,it is already known that ablative lasers are effective in treating an EN.Evidence has proven that erbium:YAG laser is useful for the skin lesion of ENS.120In the early 1990s,Losee et al.121already utilized two different techniques of CO2laser to ablate lesions and observed no recurrence.Given that ENS is a disease involving multiple systems,medicines that work on the entire body should be the first choice.Research has shown that the symptoms of patients with PIK3CA-related overgrowth syndrome can be reduced by BYL719 clinically and safely.122Besides,alpelisib,a specific alpha fraction inhibitor,and rapamycin,an mTOR inhibitor,have shown satisfactory results.123,124Further studies are urgently needed in this field to promote the precise and efficacious treatment of ENS.

9.Conclusion

In conclusion,an EN is a common disease;however,its pathogenesis remains unclear.Various types of EN not only share regular symptoms and phenotypes but also have unique characteristics,making this disease more complicated to manage.The most frequently used therapies,including surgical excision and ablative laser,are quite similar.It is important to determine the most appropriate parameters for laser and light therapies.As mentioned above,CO2and erbium:YAG lasers are favorable for the majority in a different manner,such as the fractional mode,which is supposed to reduce adverse effects.Pigmented lasers with dissimilar fluences and modes are also essential parts of the treatment for an EN (short-wavelength lasers for superficial lesions and longwavelength lasers for lesions that invade deeper tissues).PDT is also a practical method that yields promising treatment results.

In addition,numerous potential drugs are required.With the development of photoelectric techniques,minimally invasive or noninvasive therapies have become an unstoppable trend in this field.However,there are many unknown problems that remain unsolved.Therefore,an EN requires more attention,and further research is needed to provide appropriate,timely,and effective treatments for each patient.

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.

Authors’ contributions

Liu L:Investigation,Writing-Original draft.Wang H:Investigation,Writing-Original draft.Dong J:Conceptualization,Supervision,Writing-Review and Editing,Validation.