Are You Confident of the Diagnosis?
What to be alert for in the history
Epidermal nevi are typically diagnosed by their characteristic clinical appearance and supporting history.
An epidermal nevus is a hamartoma of the epidermis and papillary dermis that is present at birth or typically appears within the first year of life. Occasionally, epidermal nevi may not be recognized until later in childhood.
Characteristic findings on physical examination
An epidermal nevus presents as a single, linear or whorled plaque composed of well circumscribed, discrete or confluent hyperpigmented warty papules that follow the lines of Blaschko. Epidermal nevi may look pale white just after delivery (Figure 1), but they take on a pink to skin-colored or darker brown hue due to the transition from intrauterine to a terrestrial dry environment. The lesions become thickened, darker, and more verrucous over time (Figure 2). Rarely, epidermal nevi remain hypopigmented.
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Figure 1.
The pale white color of this epidermal nevus seen at birth is due to corneocyte hydration from amniotic fluid.
Figure 2.
This verrucous papular band is characteristic of epidermal nevi in older children.
Epidermal nevi may occur on the trunk, extremities, or neck. They are typically asymptomatic, but some variants are pruritic. Epidermal nevi are typically unilateral; but sometimes, multiple unilateral or bilateral lesions may occur. They may be small and localized or quite extensive.
Expected results of diagnostic studies
If clinical examination is in question, a skin biopsy can confirm the diagnosis. At least ten different histologic patterns have been described in epidermal nevi (Table I). The most common type is a keratinocytic epidermal nevus that demonstrates epidermal hyperplasia with hyperkeratosis, papillomatosis, acanthosis with elongation of the rete ridges, and variable parakeratosis histologically. These findings explain the alternative nosology of nevus verrucosus or verrucous nevus. Other findings such as focal acantholytic dyskeratosis or epidermolytic hyperkeratosis may be present.
Table I.
| Hyperkeratosis, papillomatosis, and acanthosis (common type) |
| Acrokeratosis verruciformis-like |
| Epidermolytic hyperkeratosis |
| Seborrheic keratosis-like |
| Psoriasiform (ILVEN) |
| Verrucoid |
| Porokeratosis-like |
| Focal acantholytic dyskeratosis (Darier’s disease-like) |
| Nevus comedonicus |
| Acanthosis nigricans-like |
*Adapted from Su WPD. Histopathologic varieties of epidermal nevus: A study of 160 cases. Am J Dermatopathol 1982;4:161-70.
Epidermal nevi may display a mixture of components of epidermal origin; however, they are best classified according to their predominant component. Hence, epidermal nevi may be classified as keratinocytic (nonorganoid) epidermal nevi or as organoid (sebaceous, follicular, sweat gland) nevi.
The inflammatory linear verrucous epidermal nevus (ILVEN), also known as dermatitic epidermal nevus, accounts for approximately 6% of all epidermal nevi. ILVEN is a variant or subtype of keratinocyte nevus that appears pink or red and has a psoriasiform appearance on histopathology. ILVEN is clinically characterized by scaly, linear, erythematous to hyperpigmented, hyperkeratotic papules coalescing into plaques that follow the lines of Blaschko (Figure 3). It is almost always unilateral and often occurs on the lower half of the body.
Figure 3.
This pruritic band of psoriasiform patches is characteristic of an ILVEN.
Pruritus, which may sometimes be unrelenting and extreme, is a hallmark as is its recalcitrance to most therapies. The lesions are persistent with no tendency to remit or improve with time. Some reports claim that ILVEN is more common in girls, however, other reports question this finding and state that it likely occurs either with a male predominance or equally in both sexes. Skin biopsy distinguishes ILVEN from linear psoriasis.
Histology shows psoriasiform hyperplasia, alternating orthokeratosis with underlying hypergranulosis and parakeratosis with underlying hypogranulosis. There is also decreased expression of involcrin within keratinocytes underlying areas of parakeratosis.
An organoid epidermal nevus contains one or more types of epidermal appendages. The nevus sebaceus or sebaceous nevus is not uncommon and represents approximately half of all epidermal nevi. Sebaceous nevi typically occur on the head and clinically appear as a yellow-salmon colored waxy, hairless plaque that becomes more prominent during puberty. This organoid nevus contains harmartomatous components of sebaceous and apocrine glands in addition to the papillomatous epidermis.
The nevus comedonicus is a localized collection of dilated follicles containing keratin that typically occurs on the face, trunk, or upper extremities. Nevus comedonicus has a different clinical appearance from epidermal nevi; however, it may be considered a variant of epidermal nevi.
Porokeratotic eccrine nevus is another variant of an epidermal nevus that is characterized by verrucous, keratotic papules with keratin-filled invaginations of eccrine ducts on the palms and soles.
Diagnosis confirmation
The differential diagnosis of epidermal nevi can be broad and includes many other cutaneous lesions that follow the lines of Blaschko. Lichen striatus is an acquired lesion that typically self-resolves. Linear lichen planus, linear psoriasis, Becker nevus, verruca vulgares with autoinnoculation, congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome, and X-linked dominant chondrodysplasia punctata are other differentials that must be considered. A biopsy may be necessary to distinguish these conditions from epidermal nevi since many become apparent during infancy at the same time as the discovery of an epidermal nevus.
Who is at Risk for Developing this Disease?
The incidence of epidermal nevi is estimated to range from 1 to 3 per 1000 live births. The majority of cases occur sporadically; however, familial cases have been reported. It appears that males and females are equally affected.
What is the Cause of the Disease?
Etiology
Pathophysiology
Epidermal nevi are hamartomas that arise from the embryonic ectoderm, which later differentiates into keratinocytes and other cells making up the epidermal appendages. Most epidermal nevi are thought to occur as a result of genomic mosaicism that follows Blaschko’s lines. In some instances, specific genetic mosaic defects have been identified. Some nevi with classic histologic findings are sometimes due to a mosaic-activating mutation in the fibroblast growth factor receptor 3 gene (FGFR3).
Epidermal nevi with histologic acantholytic dyskeratosis are due to a mosaic mutation in the ATP2A2 gene. This can represent a mosaic form of Darier disease.
Epidermal nevi with histologic findings of epidermolytic hyperkeratosis are due to postzygomatic mosaic mutations in keratin 1 or keratin 10. If the mosaic defect in keratin 1 or keratin 10 is present in germline cells, carriers of this gonadal mosaic mutation may transmit this mutation to their offspring. If this occurs, the offspring would be born with generalized bullous congenital ichythyosiform erythroderma (epidermolyic hyperkeratosis).
Deletions in the PTCH gene have been demonstrated in a few cases of sebaceous nevus. Although hypothesized, it has not yet been proven that the presence of a PTCH deletion could be associated with the development of basal cell carcinomas or other appendageal tumors within sebaceous nevi.
ILVEN has been reported to be associated with an upregulation of interleukin 1, interleukin 6, tumor necrosis factor-alpha, and intercellular adhesion molecule 1, similar to cytokine patterns that can be seen in psoriasis. Although ILVEN and psoriasis are two distinct entities, their similarity in some histologic features and cytokine patterns may indicate common pathways in pathogenesis. This idea, however, is yet to be fully elucidated.
Systemic Implications and Complications
At puberty or perhaps earlier during adrenarche, many epidermal nevi become thickened, dark and rugose as they approach or course through the groin, axillary vaults or folds of the neck. These changes can lead to maceration, pain, and malodorous microbial overgrowth that requires treatment.
Extensive epidermal nevi can occur in association with abnormalities of other organ systems, called the epidermal nevus or organoid nevus syndrome. See the chapter on Epidermal nevus syndromes.
A possible association of ILVEN with arthritis has been described. If ILVEN is associated with severe skeletal defects, it is likely that the proper diagnosis is in fact CHILD syndrome rather than ILVEN.
Treatment Options
Treatment options are summarized in Table II.
Table II.
| Medical Treatment | Surgical Procedures | Physical Modalities |
|---|---|---|
| Topical corticosteroids, high potency | ||
| Topical retinoic acid | Shave excision | Cryotherapy |
| Topical calcipotriol | Curettage | Phenol peel |
| Topical 5-fluorouracil | Dermabrasion | Laser (CO2, pulsed dye laser, argon, Er:YAG) |
| Topical tar | Full-thickness excision | |
| Topical anthralin | ||
| Topical podophyllin | ||
| Intralesional steroids | ||
| Systemic retinoids |
Optimal Therapeutic Approach for this Disease
Treatment of epidermal nevi can be quite challenging as numerous modalities have been tried with varying results. Although medical management is often unsatisfactory as results are often temporary, it may still be considered first line for treating epidermal nevi. Potent topical corticosteroids with or without occlusion, topical retinoic acid, topical tars, anthralin, topical 5-fluorouracil and podophyllin have all been used but appear to have limited benefit or variable results. Topical 0.005% calcipotriol has been reported to improve pruritus and erythema and decrease hyperkeratosis in ILVEN.
Combination therapies such as topical 0.1% tretinoin cream and 5% 5-fluorouracil have improved linear epidermal nevi. Topical tazarotene coupled with topical steroids has been reported to be successful in the treatment of ILVEN. Also, 3 to 4 months of combination treatment with 0.05% clobetasol propionate and 5% salicylic acid ointment under occlusion has been reported to result in long-term improvement of ILVEN.
Intralesional steroids, either via injections or via Dermojet with 1.0cc triamcinolone biweekly treatments have also been tried with some positive, but mixed results. Nevus comedonicus is reported to have a good response to once daily topical application of 12% ammonium lactate solution. The use of a cosmetic pore strip may decrease the keratin plugs.
Systemic treatment with oral retinoids has been reported to be effective in decreasing the thickness of the epidermal nevi; however, it does not result in resolution of the lesions. The known risks of systemic retinoids (isotretinoin or acetretin) must be weighed when considering this treatment. There are anecdotal reports of improvement with etanercept.
Cryotherapy is another treatment option that has been reported to be effective. Phenol peels in combination with shave excisions has been reported to have beneficial results. Laser ablation with CO2 may also be tried; however, to be effective, scarring of the papillary dermis must take place. CO2 lasers may also lead to pigmentary changes. Pulsed dye laser and argon lasers have been reported to be useful in some cases.
Recently, Er:YAG laser treatments were reported to be an effective, nonscarring method for the treatment of verrucous epidermal nevi. Postinflammatory hyperpigmentation and transient hypopigmentation along with acne flares were reported to be adverse effects from the Er:YAG laser treatments.
If patients fail medical therapy, surgical procedures should be considered. Shave excision, curettage, and superficial dermabrasion will likely result in recurrence of the epidermal nevi if only the epidermis is removed. However, in the experience of one of the authors, deep shave with electrodessication and curettage to the mid-dermis can produce favorable results. This can be performed in stages if the epidermal nevus is extensive.
Full-thickness surgical excision can be curative and has been advocated as the most reliable therapy, however, this results in a permanent scar. Full-thickness surgical excision has been reported to be successful even with extensive ILVEN when performed in a staged manner, with the use of tissue expanders or skin grafting.
Patient Management
Epidermal nevi are often resistant to a variety of treatment modalities; hence, patients should be made aware that numerous treatment approaches may be necessary.
Sebaceous nevi may rarely be associated with the development of neoplasms that are usually benign such as syringocystadenoma papilliferum or basaloid follicular hamartomas. Isolated cases of true basal cell carcinomas, squamous cell carcinomas, adnexal carcinomas, and keratoacanthomas have been reported, but the risk for development in any one lesion is extremely small. If such a malignancy is to develop, it usually occurs after puberty.
Benign and malignant neoplasms are not considered to be sequelae of other forms of epidermal nevi. However, skin biopsies should be performed not only in cases where the diagnosis is uncertain but also in cases where the lesion is changing in a suspicious manner to rule out any possibility of malignancy.
Skin biopsies may also be considered to evaluate the lesions for the presence of epidermolytic hyperkeratosis, as this can suggest a mosaic defect in keratin 1 or 10. This is particularly true when the lesion is large and segmental and involving the torso or is systematized and bilateral. If epidermolytic hyperkeratosis is found in this setting, then referral for additional immunostains for keratins 1 or 10 should be pursued.
If a patient’s epidermal nevus is known to be due to a mosaic defect in keratin 1 or keratin 10, genetic counseling should be considered. If the defect is present in germline cells, carriers of this mosaic mutation may transmit this mutation to their offspring. If that occurs, the offspring would be born with generalized bullous congenital ichythyosiform erythroderma (epidermolyic hyperkeratosis).
Unusual Clinical Scenarios to Consider in Patient Management
Unusual variants of epidermal nevi exist. Nevus unius lateris is a variant of an epidermal nevus where there are multiple, extensive lesions present unilaterally. Ichthyosis hystrix is a bilateral variant of an epidermal nevus.
What is the Evidence?
Moss, C, Bolognia, JL, Jorizzo, JL, Rapini, RP. “Mosaicism and linear lesions”. Dermatology. 2008. pp. 821(This is a comprehensive dermatology reference with an excellent overview on mosaicism and linear lesions.)
Sugarman, JL. “Epidermal nevus syndromes”. Semin Cutan Med Surg. vol. 23. 2007. pp. 221-30. (This is a detailed review on epidermal nevi including clinical manifestations, subtypes of epidermal nevi, and neoplasms associated with epidermal nevi.)
Happle, R, Rogers, M. “Epidermal nevi”. Advances in dermatology. 2002. pp. 175-201. (This is an excellent, detailed review on epidermal nevi that discusses the pathogenesis, clinical features, pathology, and management of numerous types of epidermal nevi. )
Park, JH, Hwang, ES, Kim, SN, Kye, YC. “Er:YAG laser treatment of verrucous epidermal nevi”. Dermatol Surg. vol. 30. 2004. pp. 378-81. (Fifteen of 20 patients were successfully treated with this ablative technology at one session; however there was a 25% recurrence rate at 1 year. Follow-up was not longer than 2 years and results of re-treatment were not reported.)
Lee, BJ, Mancini, AJ, Renucci, J, Paller, AS, Bauer, BS. “Full-thickness surgical excision for the treatment of inflammatory linear verrucous epidermal nevus”. Ann Plast Surg. vol. 47. 2001. pp. 285-92. (Four cases of extensive ILVEN are successfully treated with full-thickness surgical excision. Other less successful medical and surgical approaches to this extremely pruritic lesion are reviewed.)
Morag, C, Metzker, A. “Inflammatory linear verrucous epidermal nevus: Report of seven new cases and review of the literature”. Pediatr Dermatol. vol. 3. 1985. pp. 15-8. (This is a case series of seven patients with ILVEN and review of the literature. Clinical and histologic features are detailed. Additionally, revised criteria for the classification of ILVEN are proposed.
Lee, SH, Rogers, M. “Inflammatory linear verrucous epidermal naevi: A review of 23 cases”. Australas J Dermatol. vol. 42. 2001. pp. 252-6. (Most of the cases in this 13-year retrospective review were located unilaterally on the buttocks or legs. They were usually present in the first 6 months of life, and extension beyond the original borders was not uncommon. Boys were more affected than girls.)
Su, WPD. “Histopathologic varieties of epidermal nevus: A study of 160 cases”. Am J Dermatopathol. vol. 4. 1982. pp. 161-70. (This is a detailed review analyzing the histopathologic features of 160 cases of epidermal nevi. The frequency and categorization of various histologic features is detailed.)
Zvulunov, A, Grunwald, MH, Halvy, S. “Topical calcipotriol for the treatment of inflammatory linear verrucous epidermal nevus”. Arch Dermatol. vol. 133. 1997. pp. 567-8. (This short case series describes the use and effectiveness of topical calcipotriol for the treatment of ILVEN.)
Xin, H, Matt, D, Qin, JZ, Burg, G, Böni, R. “The sebaceous nevus: a nevus with deletions of the PTCH gene”. Cancer Res. vol. 59. 1999. pp. 1834-6. (This study tested sebaceous nevi for the presence of allelic deletions of the tumor suppressor gene PTCH. Forty percent [8/20] of micro-dissected paraffin-embedded sections from sebaceous nevi exhibited loss of heterozygosity of at least one PTCH gene polymorphic markers. Although this study provides preliminary evidence of the involvement of PTCH gene in sebaceous nevi, one cannot conclude that the presence of this tumor suppressor gene defect will identify those lesions that are predisposed to develop basal cell carcinoma or other neoplasms.)
Cockerell, CJ, Larsen, F, Bolognia, JL, Jorizzo, JL, Rapini, RP. “Benign epidermal tumors and proliferations”. Dermatology. 2008. pp. 1671-4. (This is an extensive review on general dermatology that specifically discusses the history, pathogenesis, clinical features, and treatment options of epidermal nevi, including ILVEN.)
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