Epidermal and Adnexal Proliferations and Tumors

Nima Mesbah Ardakani

Ellen Koch

Jonathan J. Lee

Alejandro A. Gru

Benjamin Wood

Epidermal Proliferations

EPIDERMAL NEVUS

Definition and Epidemiology

“Epidermal nevus” refers to a benign developmental malformation of the epidermis. These lesions may present in isolation or in association with other developmental anomalies, thereby constituting an “epidermal nevus syndrome.” Six major clinically distinct syndromes, with systemic anomalies that most frequently affect the musculoskeletal and neurologic systems, are currently recognized (Table 23-1).

Epidermal nevus may be present at birth or become more noticeable during early childhood (80% within the first year of life) with an estimated incidence of 1 in 1000 infants.¹ Initial recognition in adulthood has been reported.² Males and females appear to be equally affected, and there is no racial predilection. Familial cases with autosomal dominant inheritance patterns have been reported.³,⁴,⁵

Etiology

Mosaicism at specific genetic loci may underlie particular clinicopathologic subtypes of epidermal nevi. Genetic mosaicism, with activating FGFR3 mutations at codon 248 (R248C) in the epidermis, caused by postzygotic mutations early in embryonic development are thought to cause the “common,” nonorganoid, nonepidermolytic epidermal nevi.¹ In contrast, mosaicism in the genes encoding suprabasilar keratins 1 and 10 (KRT1, KRT10) has been shown to underlie the epidermolytic, hyperkeratotic subtype of epidermal nevi.⁶ Importantly, the offspring of affected individuals may develop generalized epidermolytic ichthyosis (bullous congenital ichthyosiform erythroderma). Additional genetic abnormalities associated with epidermal nevi include activating mutations in PIK3CA (phosphoinositide-3-kinase, which functions downstream of FGFR3), as well as mutations in KRAS.⁷,⁸

Clinical Presentation

Epidermal nevus presents as an asymptomatic, occasionally pigmented, well-circumscribed papillomatous linear plaque comprised of numerous densely grouped fleshy papules (Figure 23-1). There is a predilection for the trunk, extremities, and neck, but any cutaneous surface can be affected. They most commonly occur as an isolated lesion, but multiple unilateral or bilateral plaques may be seen. Not infrequently, the lesion follows Blaschko’s lines, and there may be midline demarcation. Importantly, early epidermal nevi may present with macular morphology and can mimic linear and whorled nevoid hypermelanosis. Over time, they may thicken and develop a verrucous surface texture, particularly in intertriginous areas. The nevus verrucosus subtype refers to localized epidermal nevus (EN) with a wart-like appearance. Nevus unius lateris is typified by a large epidermal nevus with extensive unilateral involvement of the trunk. The ichthyosis hystrix subtype refers to the clinical subtype with extensive bilateral involvement, typically on the trunk.

TABLE 23-1. Key Features of the Major Epidermal Nevus Syndromes

EN-Associated Condition	Key Features
Schimmelpenning syndrome	Unilateral nevus sebaceus of head and neck Cerebral, ocular, cardiac, vascular, skeletal abnormalities Coloboma and lipodermoid of conjunctiva Vitamin D-resistance hypophosphatemic rickets
Nevus comedonicus syndrome	Nevus comedonicus Electroencephalogram abnormalities, cataracts and skeletal defects
Becker’s nevus syndrome	Becker’s nevus Ipsilateral hypoplasia of breast, skeletal anomalies
Proteus syndrome	Nonepidermolytic keratinocytic epidermal nevi Asymmetric overgrowth syndrome due to activating mutations in AKT1 Limb gigantism, asymmetric macrodactyly, scoliosis Visceral overgrowth (spleen) Vascular malformations, palmoplantar cerebriform hyperplasia Lipomas, regional lipohypoplasia
CHILD syndrome	X-linked dominant disorder due to inactivating mutations in NSDHL Congenital or neonatal unilateral erythema with sharp midline demarcation and facial sparing, closely resembling ILVEN (see Section “Inflammatory Linear Verrucous Epidermal Nevus”) Linear alopecia, claw-like nail dystrophy
Phakomatosis pigmentokeratotica	Nevus sebaceous (with relatively increased risk of basal cell carcinoma) Papular nevus spilus CNS anomalies, hyperhidrosis, weakness Vitamin D-resistant, hypophosphatemic rickets
CHILD, congenital hemidysplasia with ichthyosiform nevus and limb defects; CNS, central nervous system.

FIGURE 23-1. An epidermal nevus on the inner aspect of the arm presenting as a linear plaque formed by confluent fleshy papules.

Histologic Findings

Epidermal nevus typically demonstrates orthokeratosis, papillomatosis, acanthosis, and elongation of the epidermal rete (Figure 23-2). The histology is often subtle and not infrequently mimics that of acanthosis nigricans or seborrheic keratosis.⁹ Occasionally, epidermal nevus may show cornoid lamella formation. In addition, epidermal nevi may contain areas demonstrating features of epidermolytic hyperkeratosis. This finding should prompt the clinician to counsel the patient regarding the possibility of transmission of bullous congenital ichthyosiform erythroderma, as noted earlier.¹⁰,¹¹ Several reports have described focal acantholytic dyskeratosis within epidermal nevi, which some
consider as a manifestation of segmental or zosteriform Darier disease.¹²,¹³,¹⁴ Rare cases display a distinctive pattern of rectangular elongation of the rete ridges with palisading of basal keratinocytes and are referred to as papular epidermal nevus with skyline basal cell layer (PENS).¹⁵ These are associated with extracutaneous findings (neurologic, in particular) in approximately 50% of cases.¹⁶

FIGURE 23-2. Epidermal nevus frequently resembles seborrheic keratosis histologically, with orthokeratotic hyperkeratosis, papillomatosis, and epidermal acanthosis.

Basal cell carcinomas (BCCs), squamous cell carcinomas (SCCs), and keratoacanthomas are rarely reported in association with epidermal nevi, with a lower frequency than in the related nevus sebaceus.

Differential Diagnosis

The clinical differential diagnosis for nonorganoid, keratinocytic epidermal nevi includes nevus sebaceus, lichen striatus, porokeratotic eccrine ostial and dermal duct nevus, and other nevoid conditions distributed along Blaschko’s lines. Linear lichen planus might also be considered. Histologically, seborrheic keratosis, acanthosis nigricans, verruca vulgaris, and other conditions characterized by hyperkeratosis and papillomatosis may enter the differential diagnosis. These latter conditions are usually clinically distinct.

INFLAMMATORY LINEAR VERRUCOUS EPIDERMAL NEVUS

Definition and Epidemiology

Inflammatory linear verrucous epidermal nevus (ILVEN) was first described in 1971 by Altman and Mehregan and is thought to represent a distinct variant of epidermal nevus.¹⁷

ILVEN is uncommon, representing approximately 6% of epidermal nevi.¹⁸ The majority arise in individuals before the age of 5 years and most commonly before the age of 6 months. There is a slight female predilection. Onset in adulthood has been reported, which may be associated with a familial predisposition.⁵,¹⁹

Etiology

The cause of ILVEN is not known. Some authors propose that this linear psoriasiform eruption may be due to clonal dysregulation of keratinocyte growth.²⁰ Distinction of IL-VEN from linear psoriasis may be difficult. Proposed distinguishing biologic features include differential expression of involucrin, which is limited to the orthokeratotic stratum corneum in the former, whereas it is increased in all layers of the epidermis but the basal layer in the latter.²⁰ In addition, quantitative immunohistochemical studies indicate a significantly lower number of T-cell subpopulations relevant to the pathogenesis of psoriasis in ILVEN.²¹

Clinical Presentation

ILVEN presents as pruritic, erythematous, scaly, occasionally verrucous papules that often coalesce into a linear plaque, often following the lines of Blaschko (Figure 23-3).²² It most frequently occurs on an extremity, with a propensity for the thigh and buttock. Given its pruritic nature, superimposed lichenification and excoriation are frequently present. On occasion, ILVEN coexists with psoriasis, may present as a part of an epidermal nevus syndrome, or may exceptionally be associated with underlying arthritis.²³,²⁴,²⁵

Histologic Findings

ILVEN is characterized by psoriasiform acanthosis, with overlying alternating orthokeratotic and parakeratotic hyperkeratosis (Figure 23-4). Underneath the orthokeratosis, there is hypergranulosis, which alternates with hypogranulosis below the parakeratotic areas. There is typically mild spongiosis and a moderate superficial perivascular lymphocytic infiltrate.

FIGURE 23-3. Inflammatory linear verrucous epidermal nevus (ILVEN) presents as an erythematous and scaly linear plaque, resembling linear psoriasis.

FIGURE 23-4. Horizontal alternation of orthokeratotic and parakeratotic hyperkeratosis is characteristic of inflammatory linear verrucous epidermal nevus (ILVEN), although the histologic features can be difficult to separate from psoriasis.

Differential Diagnosis

On routine dermatopathologic examination, ILVEN may be indistinguishable from psoriasis. Alternating orthokeratotic and parakeratotic areas may be a clue to the former diagnosis, but clinicopathologic integration is critical, because similar features may be seen in the eruption of pityriasis rubra pilaris. Dermatophyte infection and a wide range of spongiotic and psoriasiform dermatoses may also be considered on microscopic examination.

ACANTHOSIS NIGRICANS

Definition and Epidemiology

Acanthosis nigricans presents as symmetric, hyperpigmented areas of velvety skin thickening that typically affects the dorsolateral neck and flexural areas and is commonly associated with an underlying metabolic disorder. Less common associations include an underlying malignancy, genetic predisposition, or association with medications.

The prevalence of acanthosis nigricans in children is not precisely known, but this condition is found in a significant fraction of those with obesity or insulin resistance. Acanthosis nigricans is more commonly seen among Native American, African American, and Hispanic individuals than in those of Caucasian or Asian descent. A cross-sectional study of 1730 patients aged 7 to 65 years in the primary care setting across various sites in the United States found a 19% prevalence of acanthosis nigricans.²⁶ The incidence of acanthosis nigricans associated with other less common conditions, as discussed below, is not known.

Etiology

Acanthosis nigricans is most commonly associated with an underlying metabolic disease, inherited predisposition, or malignancy. However, other important associations must be recognized, including medications,²⁷ connective tissue disease,²⁸,²⁹,³⁰ and rare genetic syndromes.³¹ Table 23-2 summarizes the underlying associated conditions.

The precise pathogenic pathways that lead to acanthosis nigricans are not well understood, but abnormalities related to tyrosine kinase receptors, including insulin-like growth factor receptor-1 (IGFR1), fibroblast growth factor receptors (FGFR), and epidermal growth factor receptor (EGFR), may be contributing factors. Of interest, activating mutations in FGFR3 have been linked to several inherited syndromes that present with acanthosis nigricans, such as Crouzon syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia dwarfism.³² In the setting of malignancy, elevated levels of transforming growth factor-α, which exerts proliferative effects on the epidermis via EGFR, may contribute to acanthosis nigricans.

Clinical Presentation

Acanthosis nigricans presents as a symmetric eruption, consisting of brown to gray, hyperpigmented, velvety
plaques that primarily involves skin folds. The posterior and lateral folds of the neck are commonly affected. Early acanthosis nigricans may be heralded by slight hyperpigmentation that later eventuates into thickening of the skin. Other affected areas include the dorsal knuckles, genitalia, perineum, face, thighs, breast, and axillae. Generalized acanthosis nigricans may occur, which can present with involvement of the oral mucosa, lips, and eyelids and may herald an underlying malignancy.³³ Similarly, the finding of “tripe palms,” or velvety thickening of the palms and dorsal hand, may also be paraneoplastic.³⁴ Rarely, acanthosis nigricans may present in the form of an epidermal nevus, which may be heritable in autosomal dominant fashion and can present at birth, childhood, or puberty.³⁵

TABLE 23-2. Conditions Associated With Acanthosis Nigricans

Hereditary benign	Epidermal nevus variant; may be inherited in autosomal dominant fashion
Metabolic or endocrinologic	Most common; insulin-resistant states, including metabolic syndrome and type II diabetes mellitus, polycystic ovarian syndrome
Malignancy	Underlying gastrointestinal adenocarcinoma, head and neck malignancy, carcinoma of the lung
Genetic syndromes	Bloom syndrome, Crouzon syndrome, Prader-Willi syndrome, Lawrence-Seip syndrome, Bear-Stevenson syndrome
Medications	Niacin, corticosteroids, oral contraceptives, others
Connective tissue (collagen vascular) disease	Systemic lupus erythematosus, dermatomyositis, scleroderma; note: may be medication related

Histologic Findings

Despite the name, acanthosis nigricans is characterized by fine epidermal papillomatosis (rather than acanthosis), with overlying orthokeratotic hyperkeratosis (Figure 23-5). Basal keratinocyte pigmentation is typically readily identifiable, but there is no obvious increase in melanin pigmentation throughout the epidermis.

Differential Diagnosis

The histologic features of acanthosis nigricans show significant overlap with those of some epidermal nevi and confluent and reticulated papillomatosis (CARP). The prototypical clinical presentation of each of these conditions is distinct, but in some cases overlap may occur. Similar histologic features may be seen in conditions such as nevoid hyperkeratosis of the nipple and some examples of seborrheic keratosis.

FIGURE 23-5. Acanthosis nigricans is characterized by hyperkeratosis and papillomatosis. The appearances are similar to those of confluent and reticulated papillomatosis (CARP) and some cases of epidermal nevus.

CONFLUENT AND RETICULATED PAPILLOMATOSIS

Definition and Epidemiology

CARP of Gougerot and Carteaud was first described in 1927 and represents an idiopathic condition that clinicopathologically resembles acanthosis nigricans.

Although its precise incidence is unknown, CARP is a disorder seen primarily in adolescents and young adults, with females affected more than twice as often as males. It may be more common among African American as well as East and South Asian populations.³⁶ The vast majority of cases are sporadic, with familial occurrence limited to isolated case reports.³⁷,³⁸

Etiology

The etiopathogenesis of CARP is unknown, but several hypotheses have been proposed. Given its resemblance to acanthosis nigricans, an underlying endocrine imbalance has been postulated, which is supported by isolated case reports in patients having underlying obesity and insulin resistance.³⁹,⁴⁰,⁴¹,⁴² Of interest, the majority of these cases occurred in individuals of East Asian descent. Historically, CARP was thought to be caused by an abnormal host response to Malassezia furfur, given its superficial clinical resemblance to tinea versicolor, reports of response to topical or oral antifungals, and the presence of yeast-like spores within the stratum corneum noted histologically.⁴³ However, recent reports have implicated a newly discovered and described Actinomycete species known as Dietzia papillomatosis in the pathogenesis of CARP.⁴⁴,⁴⁵,⁴⁶ This latter, novel hypothesis is consistent with clinical response to minocycline as well as other tetracyclines and macrolide antibiotics.⁴⁷

Clinical Presentation

Early lesions of CARP consist of 1 to 2 mm hyperpigmented papules favoring the intermammary, interscapular, or epigastric skin that enlarge and coalesce into large brown, hyperkeratotic, reticulate patches or thin plaques (Figure 23-6). Other less common areas of involvement include the neck and shoulders. This benign dermatosis is usually asymptomatic, but can be associated with mild pruritus.

FIGURE 23-6. Confluent and reticulated papillomatosis (CARP) frequently presents in adolescent patients as hyperpigmented papules in the inframammary region, which coalesce to form thin reticulate plaques.

Histologic Findings

CARP shows orthokeratotic hyperkeratosis, slight papillomatosis, and delicate elongation of the rete ridges (Figure 23-7). Malassezia and gram positive bacteria are frequently identified on the surface.⁴⁸,⁴⁹

Differential Diagnosis

The histologic appearances of CARP can closely mimic epidermal nevus and acanthosis nigricans. Although acanthosis nigricans is described as showing more basal pigmentation, and more prominent epidermal acanthosis and papillomatosis, the discriminatory value in many cases is likely to be limited. Clinicopathologic correlation represents the mainstay of distinction.⁴⁹

FIGURE 23-7. The histologic features of confluent and reticulated papillomatosis (CARP) include orthokeratotic hyperkeratosis and slight papillomatosis. Fungal yeast forms are often identifiable on the surface.

PEDIATRIC BASAL CELL CARCINOMA AND HERITABLE BASAL CELL CARCINOMA SYNDROMES

Definition and Epidemiology

Basal cell carcinoma (BCC) is a typically nonmetastasizing, slowly growing, invasive, malignant neoplasm of the skin primarily caused by mutations acquired through exposure to ultraviolet radiation. Although the vast majority of cases are sporadic (nonsyndromic), a small subset arises in familial form (basal cell nevus syndrome, BCNS, or Gorlin syndrome).

BCC is the most frequent cancer diagnosed in the United States. Although older adults are typically afflicted, younger adults are increasingly being diagnosed with sporadic BCC.⁵⁰ Moreover, there are over 100 individual case reports of de novo BCC arising in children and adolescents, in whom there was no evidence of an underlying heritable, cancer predisposition syndrome or immunosuppressive disorder.⁵¹ Age of onset of childhood BCC ranges from 2 to 18 years (median age of 12 years), with most cases occurring in fair-skinned patients, although occurrence in Hispanic and African-American patients, in whom pigmented variants are more common, is recognized.⁵¹ Well-established risk factors for the development of sporadic, nonsyndromic BCC include extensive recreational and occupational exposure to ultraviolet radiation (UVR),⁵² chemical exposures (ie, arsenic), immunosuppression with or without solid organ transplant, and smoking.⁵³ In addition to basal cell nevus syndrome (BCNS), or Gorlin syndrome, see Etiology), several heritable disorders also predispose to the development of BCC, including Bazex and Rombo syndrome, nevus sebaceus, xeroderma pigmentosum, and oculocutaneous albinism.⁵¹

Etiology

BCCs are thought to arise from the malignant transformation of basal keratinocytes. Several lines of evidence support the role of intermittent, recreational UVR exposure in pathogenesis.⁵⁴ In particular, activation of the sonic hedgehog (SHH)-Patched (PTCH) signaling pathway is thought to play a role, which may be achieved by homozygous inactivation of PTCH (9q22) or activating mutations
of its target Smoothened (SMO, 7q32). Germline mutations in PTCH1 are associated with autosomal dominantly inherited basal cell nevus syndrome (BCNS).⁵⁵,⁵⁶ Mutations in the gene encoding tumor suppressor p53 (17p13.1) as well as CDKN2A (9p21) may also play a role. Recent data suggest that a single-nucleotide polymorphism in mismatch repair genes MSH2 (2p) and MLH1 (Chr. 3) as well as variants in the melanocortin 1 receptor (MC1R, 16q) gene may predispose individuals to BCC.⁵⁷,⁵⁸ A novel hereditary BCC syndrome, wherein patients develop multiple hereditary infundibulocystic variant BCCs, has recently been attributed to heterozygous splice site mutations in one copy of the tumor suppressor known as suppressor of fused gene (SUFU, 10q), a component of the sonic hedgehog pathway.⁵⁹,⁶⁰

Clinical Presentation

Sporadic pediatric BCC is rare.⁵¹,⁶¹ Clinically, they present as a pink to flesh-colored, occasionally pigmented papule or nodule having a smooth surface with or without ulceration favoring the head (>90%), followed by the back, chest, and neck.⁵¹ On the face, in order of decreasing frequency, childhood BCCs are more commonly identified on the cheek, nose, eyelid, scalp, chin, and lip.⁵¹ Afflicted patients may note a recent increase in size, tenderness, bleeding, or change in color to the lesion.⁵¹

Individuals with the BCNS develop childhood onset of numerous BCCs, in addition to keratocystic odontogenic tumor of the jaw, bifid ribs, calcifications of the falx cerebri, and palmar or plantar pits.⁶² Additional findings include childhood medulloblastoma, cardiac or ovarian fibromas, ocular abnormalities, macrocephaly, and polydactyly.⁶² Afflicted individuals develop, on average, approximately 100 to 300 BCCs, although many more can occur, that tend to favor the face, neck, back, trunk, and upper extremities.⁶³ Over a 2-year period, these patients may develop from zero to 250 new BCCs (on average, approximately 10-25).⁶³ They present as variably sized flesh to pink dome-shaped papules, which less commonly demonstrate secondary features such as ulceration, crusting, or bleeding. Additional clues to diagnosis include coarse facies with broad nasal root, hypertelorism, milia, comedones, epidermal cysts, lipomas, fibromas, and café-au-lait macules.

Multiple hereditary infundibulocystic BCC syndrome (MHIBCC) has to date demonstrated a striking female predominance of middle age in whom multiple dome-shaped flesh-colored asymptomatic papules present on the face and vulva. Its predilection for the nasolabial folds may clinically mimic facial trichoepitheliomas, trichilemmomas, or adenoma sebaceum.⁵⁹,⁶⁰

Histologic Findings

The histologic appearances of BCC in children are similar to those in adults (Figure 23-8). Common patterns include superficial, nodular, and infiltrative growth of basaloid epithelial cells. There is typically peripheral palisading, with clefting separation from the adjacent stroma and extracellular connective tissue mucin. Apoptosis, mitoses, and mucin deposition are also characteristic findings.

FIGURE 23-8. Basal cell carcinoma in children shows similar features to those seen in adults, although background solar elastosis is typically absent. This sporadic lesion arose on the shoulder of a 14-year-old patient.

The palmar pits in the BCNS show hypokeratosis with crowding of the underlying basal cells, in some examples resembling superficial BCC, although the development of authentic BCC at this site is very uncommon.⁶⁴

The infundibulocystic BCCs of MHIBCC syndrome often demonstrate hybrid morphology composed of conventional features of nodular BCC admixed with numerous, occasionally dilated infundibular cysts.⁶⁰

Differential Diagnosis

In the pediatric setting, the principal differential diagnostic consideration is with trichoepithelioma/trichoblastoma. These lesions are discussed in greater detail below. Trichoepithelioma/trichoblastoma typically shows a symmetrical and noninfiltrative growth pattern, with a prominent stromal component and stromal-stromal clefting. The distinction of desmoplastic trichoepithelioma from infiltrating BCC can be problematic, particularly in small biopsy samples. Although the clinical presentation and relatively subtle morphologic features (eg, the characteristic “wrapping” of epithelial nests by thickened collagen; the presence of CK20-positive Merkel cells) may be helpful, in practice it is usually wise to ensure that lesions in which there is differential diagnostic difficulty are completely excised. Another problematic differential diagnosis with infiltrative BCCs is with microcystic adnexal carcinomas (MACs), also reported in the pediatric age group. As opposed to BCCs, MAC are negative for Ber-EP4 immunostain.

SQUAMOUS CELL CARCINOMA

Definition and Epidemiology

SCC is a malignant tumor of squamous keratinocytes that can arise on both cutaneous and mucosal surfaces.

Pediatric cutaneous or mucosal SCCs are exceedingly rare,⁶⁵ with most reported cases identified in children or adolescents with an underlying predisposition. Conditions with marked photosensitivity, such as xeroderma pigmentosum, oculocutaneous albinism,⁶⁶ PIBIDS (photosensitivity, ichthyosis, brittle hair, impaired physical and mental development, decreased fertility, and short stature) syndrome,⁶⁷ as well as medication-induced photosensitivity (particularly with voriconazole⁶⁸) put the pediatric patient at the greatest risk for developing SCC. Those with a history of epidermolysis bullosa,⁶⁶ particularly dystrophic epidermolysis bullosa, and individuals with the related Kindler syndrome (FERMT1, 20p)⁶⁹ are also at increased risk. Pediatric SCCs may rarely arise from chronic wounds, including adjacent to gastrostomy tube sites,⁷⁰ in addition to scars, including within lesions of pansclerotic morphea.⁷¹ Immunosuppression associated with organ transplantation,⁷² chemotherapy treatment, or an underlying heritable immunodeficiency syndrome, such as the interferon-γ receptor-2 (IFNGR2, 21q) deficiency may also confer increased risk.⁷³ A higher incidence of pediatric SCC may also be seen in individuals predisposed to human papillomavirus (HPV) infection.⁷⁴

Etiology

The precise etiology of SCC in the pediatric patient population is poorly understood. On the basis of studies of patients known to be at risk, such as those with photosensitivity conditions as well as epidemiologic and molecular studies of adult patients with SCCs, ultraviolet radiation exposure likely plays a key role in the pathogenesis of pediatric SCC.⁷⁵,⁷⁶ The role of HPV has not been clearly delineated but is an active area of investigation. Although observed in the adult transplant patient population, diversity of β-HPV strains and greater β-HPV viral DNA load was found to predispose individuals to cutaneous SCCs.⁷⁷

Clinical Presentation

Pediatric SCC most commonly arises on sun-exposed areas of the face, head, and neck region (particularly the lower lip and pinna of ear) as well as the hands and forearms. An indurated, scaly red papule or plaque may be observed, with or without associated telangiectasia, ulceration, and/or hemorrhagic crust. Lesions are usually solitary but rarely, particularly in the immunocompromised, may be multiple.⁷³

Histologic Findings

The histologic appearances of SCC in children are similar to those seen in adults. Infiltrative growth of squamous keratinocytes displaying cytologic atypia is sine qua non for the diagnosis. Because of the extreme rarity of this neoplasm, careful consideration should be given to alternative diagnoses, as discussed later, particularly in the absence of a clear precipitating risk factor.

Differential Diagnosis

The differential diagnosis of SCC in the pediatric patient includes benign proliferations such as verruca vulgaris and adnexal tumors. In regard to the latter, lesions such as proliferating trichilemmal tumor and benign adnexal tumors with a “desmoplastic” pattern (eg, desmoplastic tricholemmoma, desmoplastic trichoepithelioma) or with squamous metaplasia and “pseudoinfiltrative” growth (eg, hidradenoma) should be considered. Extensive pseudoepitheliomatous (pseudocarcinomatous) epidermal hyperplasia can be seen secondary to infections, in the context of inflammatory conditions or associated with other neoplasms such as granular cell tumor and may closely mimic SCC. In general, the diagnosis of pediatric cutaneous SCC should be made with great caution, even more so in the absence of a predisposing risk factor.

WHITE SPONGE NEVUS

Definition and Epidemiology

White sponge nevus, also known as leukoedema exfoliativum mucosae oris or familial white folded dysplasia of mouth, is a rare, heritable dermatologic condition that afflicts nonkeratinized stratified squamous epithelium and is clinically characterized by mucosal overgrowth.

This is a rare condition limited to individual case reports and pedigree series.⁷⁹,⁸⁰,⁸¹ All ethnicities may be affected.

Etiology

White sponge nevus is autosomal dominantly inherited. The underlying genetic cause has been traced to mutations in the helical domain of mucosa-specific keratins K4 (12q) and K13 (17q).⁸²,⁸³ Specifically, heterozygous deletions, missense mutations, and insertions involving these genes have been described.⁸⁴ Given the importance of keratins 4 and 13 to the epithelia of the oropharynx, anogenital, and esophageal mucosa, involvement of these sites is most commonly seen.

Clinical Presentation

White sponge nevus presents as an asymptomatic, exuberant diffuse, spongy, ragged-appearing white-to-gray folded plaque that affects the oral buccal mucosa but can also affect the tongue, gingiva, palate, floor of mouth, as well as the anogenital, nasal, esophageal, and conjunctival mucosa. The latter may be associated with coloboma.⁷⁵ Lesions may be noted at birth or develop anytime during childhood and adolescence.

Histologic Findings

White sponge nevus shows parakeratosis, acanthosis, and vacuolation of keratinocytes above the basal layer (Figure 23-9).⁸⁵ There are perinuclear accumulations of eosinophilic material, which correspond to tonofilament aggregation.⁸⁶

Differential Diagnosis

The histologic features are quite striking, but other disorders with similar clinical appearances (eg, hereditary benign intraepithelial dyskeratosis) may enter the differential diagnosis. Much more common nonspecific reactive changes, as seen in leukoedema and/or chronic bite injury, include prominent clear cell change. Infectious conditions such as oral hairy leukoplakia or Heck disease may enter the differential diagnosis. The combination of clinical presentation, vacuolization, and abnormal keratinization should allow separation.

FIGURE 23-9. White sponge nevus displays parakeratosis, acanthosis, and prominent clearing of suprabasal keratinocytes.

Adnexal Proliferations

NEVUS SEBACEUS

Definition and Epidemiology

Nevus sebaceus (of Jadassohn), also known as organoid nevus, is a common congenital hamartoma composed of epidermal, sebaceous, and apocrine elements that can, on occasion, give rise to secondary benign and malignant neoplasms. Nevus sebaceus has been described in up to 0.3% of neonates with an equal incidence in males and females.⁸⁷ Lesions are often noted at birth, but patients may not seek medical attention for decades.⁸⁸ Although most cases are sporadic, familial cases,⁸⁹ including with Schimmelpenning syndrome, have been reported.

Etiology

Recent molecular studies have identified postzygotic activating mutations, predominantly in HRAS as well as in KRAS, in lesional keratinocytes of nevus sebaceus.⁹⁰,⁹¹ These cause constitutive activation of the MAPK and PI3K-Akt signaling pathways, which lead to the clinical phenotype. Consistent with these findings, mosaicism in HRAS and KRAS was found in individuals with Schimmelpenning syndrome.⁹¹

Clinical Presentation

Nevus sebaceus most commonly presents on the head and neck region, favoring the scalp and, less commonly, involving the face (Figure 23-10). Lesions can also occur on the ears, trunk, extremities, oral, perianal, and genital (labial)
mucosa.⁹²,⁹³,⁹⁴,⁹⁵,⁹⁶ A single, round to oval, sharply circumscribed, yellow to flesh-colored, pebbly thin plaque is often noted at birth and slowly thickens during childhood, while also assuming a more yellow-orange hue. Around adolescence, as a result of hormonal stimulation of lesional sebaceous glands, a more prominent thickening occurs, leaving a verrucous to cerebriform waxy smooth surface. Behind the ear, a linear configuration is often noted. Importantly, multiple lesions accompanied by seizures; intellectual impairment; and ocular, craniofacial, or skeletal abnormalities should raise suspicion for Schimmelpenning syndrome. The additional presence of a speckled lentiginous nevus along with skeletal and neurologic defects should raise concern for phakomatosis pigmentokeratotica.

FIGURE 23-10. Nevus sebaceus presenting as a plaque with a pebbled appearance on the face of an adolescent patient.

Histologic Findings

Nevus sebaceus exhibits disorganized hamartomatous growth of both the epidermal and the adnexal structures (Figure 23-11). The epidermis is papillomatous and may contain distinctive areas of clear cell change. The sebaceous glands are usually hyperplastic, particularly in early infancy and puberty, but may be attenuated later in life. In addition, there is disorganization of sebaceous units, including superficial location of the glands, with incomplete lipidization and direct opening to the epidermal surface. The hair follicles are often decreased in number and miniaturized. An area of follicular absence in a scalp biopsy is an important low-power clue to the diagnosis. Abortive hair papillae are commonly present. Eccrine coils may be attenuated and occasionally cystically dilated. Ectopic apocrine glands may be seen in the deep dermis, particularly in adolescence and beyond. The dermis may be thickened and contains a mild lymphoplasmacytic inflammatory infiltrate. Benign proliferations known as “basaloid follicular hamartoma” are frequently present, manifesting as strands and islands of basaloid cells with minimal cytologic atypia and low mitotic activity, associated with a loose follicular stroma with no retraction artifact.

FIGURE 23-11. Nevus sebaceus displaying papillomatous epidermal hyperplasia and abnormal sebaceous glands. Note the absence of terminal hairs in this biopsy from the scalp, which can be a useful diagnostic clue.

Secondary benign or malignant neoplasms arise in approximately one fifth of cases of nevus sebaceus.⁹⁷,⁹⁸,⁹⁹ In decreasing order of frequency, trichoblastoma, syringocystadenoma papilliferum (SCP), and trichilemmoma are the most common benign secondary neoplasms. Others include poroma as well as both sebaceous and apocrine adenomas. Multiple neoplasms or overlapping lesions that are difficult to classify may be seen. Malignant neoplasms such as BCC, SCC, and sebaceous carcinoma are very rarely encountered in children.⁹⁹,¹⁰⁰

Differential Diagnosis

Epidermal nevus shows similar epidermal alterations; however, the abnormalities of pilosebaceous units are not present. Other than as a transient physiologic response to maternal hormones in the neonate, sebaceous proliferations are seldom seen in children. Sebaceous hyperplasia is characterized by lobular hyperplasia of normal-appearing sebaceous glands, without the other components of nevus sebaceus. Sebaceous adenoma is a lobular proliferation of abnormal sebaceous glands with expanded peripheral immature sebocytes with a basaloid appearance, and direct opening of the glands onto the epidermal surface. It also lacks the additional follicular and epidermal alterations seen in a nevus sebaceous. Rudimentary meningocele often occurs on the scalp. The morphologic features can show similarities to nevus sebaceous, with the additional feature of a proliferation of meningothelial cells.

NEVUS COMEDONICUS

Definition and Epidemiology

Also known as “comedo nevus,” the nevus comedonicus is an uncommon, benign hamartoma of the folliculosebaceous unit, presenting as a plaque composed of numerous, dilated, keratin-filled comedones.

There does not appear to be any racial or sexual predilection. Approximately half of nevi comedonicus are present at birth, with the remaining cases noted during childhood before the age of 10. Adult onset is noted and, in such cases, may be related to cutaneous friction and/or trauma or, rarely, paraneoplastic.¹⁰¹

Etiology

Recent genomic analysis of nevus comedonicus demonstrated somatic mutations in the gene encoding the serine/threonine protein kinase Nek9 (NEK9), which may serve as an important regulator of follicular homeostasis and give rise to the clinical and histologic findings.¹⁰² Somatic mutations in keratin 10 (KRT10) have been associated with epidermolytic nevus comedonicus associated with extensive lentigo simplex and linear epidermolytic nevus.¹⁰³ Mutations in FGFR2 have also been described.¹⁰⁴

Clinical Presentation

Nevus comedonicus presents as an asymptomatic, curvilinear plaque composed of hyperkeratotic papular comedones, some containing horny keratin plugs, with varying degrees of surrounding erythema (Figure 23-12). Lesions typically involve the face, neck, or upper trunk but can also extensively involve the hands bilaterally, with a predilection for the palms and wrists.¹⁰⁵,¹⁰⁶,¹⁰⁷ Occasionally, nevus comedonicus can assume a zosteriform configuration or present along the lines of Blaschko. Exceptional cases of secondary neoplasms, including SCC, keratoacanthoma, and BCC arising within nevus comedonicus have been described in adult patients.¹⁰⁸,¹⁰⁹,¹¹⁰

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