Keratinocytic Epidermal Nevi

Keratinizing epidermal nevi are the most common type of epidermal nevus and are described by a great variety of terms, such as linear epidermal nevus, hard nevus of Unna, soft epidermal nevus, and nevus verrucosus (verrucous nevus). If the lesion is widespread on half the body, the term nevus unius lateris has been used. The term ichthyosis hystrix is used if the lesions are bilateral and widespread.

The most common pattern of keratinocytic epidermal nevus is linear epidermal nevus. The individual lesions are verrucous, skin-colored, dirty-gray, or brown papules, which coalesce to form a serpiginous plaque ( Fig. 29.1 ). Interspersed in the localized patch may be horny excrescences and rarely comedones. The age of onset of epidermal nevi is generally at birth, but they may also develop within the first 10 years of life. They follow the lines of Blaschko.

Linear epidermal nevus.

The histologic changes in the epidermis are hyperplastic and affect chiefly the stratum corneum and stratum malpighii. There is variable hyperkeratosis, acanthosis, and papillomatosis. Up to 62% of biopsies of epidermal nevi have this pattern, so-called nonepidermolytic epidermal nevi. About 16% show epidermolytic hyperkeratosis. At times, other histologic patterns may be found, including a psoriatic type, an acrokeratosis verruciformis–like type, and a Darier disease–like type. It is assumed that each of these types would be associated with a specific mutation in the affected skin that, if widespread, would give rise to the cutaneous disorder with the same histology. For example, epidermal nevi that show epidermolytic hyperkeratosis would have the same gene mutation as the disorder of cornification, bullous congenital ichthyosiform erythroderma (i.e., keratins K1 and K10). In fact, patients with this type of epidermal nevus may have gonadal mosaicism that can result in offspring with the full-blown disorder. In a significant portion of the classic and common keratinocytic epidermal nevi that simply shows hyperkeratosis, papillomatosis, and acanthosis histologically, there is an activating gene mutation in fibroblast growth factor receptor 3 (FGFR3), HRAS, or PIK3CA, a downstream effector of FGFR signaling. FOXN1 is highly expressed in these lesions. These same gene mutations are found in sporadic seborrheic keratoses, which, not surprisingly, have the same histology.

Keratinocytic epidermal nevi may be associated with skeletal abnormalities and central nervous system (CNS) manifestations. CNS manifestations appear to be more common when the lesions are large and located on the head and neck. Large keratinocytic epidermal nevi of the trunk and extremities are more frequently associated with skeletal abnormalities. Because both nevus sebaceus and keratinocytic epidermal nevi were included in the original and large reports of epidermal nevus syndrome, the precise characterization of the “keratinocytic epidermal nevus syndrome” remains to be defined.

Both Proteus syndrome and CLOVE syndrome (congenital lipomatous overgrowth, vascular malformations, and epidermal nevi) can have skin lesions of epidermal nevus. CLOVE is distinguished from Proteus syndrome by congenital overgrowth of a ballooning nature, which grows proportionately with the patient and typically affects the feet.

The CHILD syndrome and verruciform xanthoma are both characterized by the presence histologically of elongated and widened dermal papillae filled with xanthoma-like cells. Epidermal hyperplasia, with acanthosis, papillomatosis, parakeratosis, and hyperkeratosis, is also present (the features of a keratinocytic epidermal nevus). In rare cases, instead of half the body being affected, large quadrants of the body, favoring folds, are the sites of the epidermal growths (ptychotropism). CHILD and verruciform xanthoma (in some cases) contain mutations in the NSDHL gene, located on the X chromosome and required for cholesterol biosynthesis.

Epidermal nevus syndrome associated with FGFR3 mutation is characterized by widespread epidermal nevus and developmental brain defects. Epidermal nevus syndrome may also be associated with vitamin D–resistant hypophosphatemic rickets, perhaps from circulating fibroblast growth factor 23 (FGF-23) acting as a phosphaturic.

Rarely, malignancies occur in keratinocytic epidermal nevi or in other organs. Any newly appearing lesion within a stable epidermal nevus should be biopsied to exclude this possibility. Management of keratinocytic epidermal nevi is difficult because, unless the treatment extends into the dermis (and thus may cause scarring), the lesion recurs. The use of a combination of 5% 5-fluorouracil (5-FU) plus 0.1% tretinoin creams once daily may be beneficial, and the response may be enhanced by occlusion. Cryotherapy can be quite effective, with good cosmetic results. Corticosteroids or a combination of a topical corticosteroid and calcipotriene may be beneficial. Carbon dioxide (CO ₂ ) and erbium:yttrium-aluminum-garnet (Er:YAG) laser treatment may also be effective. If the lesion is small, simple excision can be considered.

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  Akingboye A, et al: Papillary transitional cell bladder carcinoma and systematized epidermal nevus syndrome. Cutis 2017; 99: 61.

  
  
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  Gantner S, et al: CHILD syndrome with mild skin lesions. J Cutan Pathol 2014; 41: 787.

  
  
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  Koh MJ, et al: Systematized epidermal nevus with epidermolytic hyperkeratosis improving with topical calcipotriol/betametasone dipropionate combination ointment. Pediatr Dermatol 2013; 30: 370.

  
  
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  Om A, et al: Phacomatosis pigmentokeratotica. Pediatr Dermatol 2017; 34: 352.

  
  
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  Yarak S, et al: Squamous cell carcinoma arising in a multiple verrucous epidermal nevus. An Bras Dermatol 2016; 91: 166.

Nevus Comedonicus

Nevus comedonicus is characterized by closely arranged, grouped, often linear papules that have at their center dilated follicular openings with keratinous plugs resembling comedones. Cysts, abscesses, fistulas, and scars develop in about half the cases, which have been described as “inflammatory” nevus comedonicus. As with other epidermal nevi, lesions may be localized to a small area or may have an extensive distribution. They are most frequently unilateral, although bilateral cases are also seen. Lesions occur mostly on the trunk and follow the lines of Blaschko. The lesions may develop any time from birth to age 15 but are usually present by age 10. Follicular tumors, including trichofolliculoma and pilar sheath acanthoma, can appear within the lesion. An “epidermal nevus syndrome” or “nevus comedonicus syndrome” has been reported with electroencephalogram (EEG) abnormalities, ipsilateral cataract, corneal changes, and skeletal anomalies (hemivertebrae, scoliosis, and absence of fifth ray of hand).

The pilosebaceous follicles are dilated and filled with keratinous plugs ( Fig. 29.2 ). On the palms, pseudocomedones are present. Histologic examination reveals large dilated follicles filled with orthokeratotic horny material and lined by atrophic squamous epithelium. The interfollicular epidermis is papillomatous, as seen in typical epidermal nevi. Hair follicle differentiation, well-formed follicular structures, and normal sebaceous glands are not common in well-formed lesions.

Nevus comedonicus.

Somatic mutations in NEK9 are frequently associated. Apert syndrome is characterized by skeletal anomalies and acne. It is caused by a mutation in FGFR2. A mutation has also been found in FGFR2 in at least one case of nevus comedonicus, suggesting that nevus comedonicus may be a mosaic form of Apert syndrome.

Treatment of lesions not complicated by inflammatory cysts and nodules is primarily cosmetic. Pore-removing cosmetic strips and comedone expression may improve the cosmetic appearance. Topical tretinoin may be beneficial, as may Er:YAG or CO ₂ laser. Patients with inflammatory lesions are much more difficult to manage. If the area affected is limited, surgical excision may be considered. Oral isotretinoin, chronically at the minimum effective dose (0.5 mg/kg/day, or less if possible), may partially suppress the formation of cysts and inflammatory nodules; however, many cases of nevus comedonicus fail to respond. The comedonal lesions do not improve with oral isotretinoin.

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  Chiriac A, et al: Extensive unilateral nevus comedonicus without genetic abnormality. Dermatol Online J 2016 Sep 15; 22.

  
  
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  Ferrari B, et al: Nevus comedonicus. Pediatr Dermatol. 2015; 32: 216.

  
  
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  Levinsohn JL, et al: Somatic mutations in NEK9 cause nevus comedonicus. Am J Hum Genet 2016; 98: 1030.

  
  
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  Polat M, et al: Bilateral nevus comedonicus of the eyelids associated with bladder cancer and successful treatment with topical tretinoin. Dermatol Ther 2016; 29: 479.

  
  
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  Tchernev G, et al: Nevus comedonicus. Dermatol Ther (Heidelb) 2013; 3: 33.

  
  
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  Zhu C, et al: Ultrapulse carbon dioxide laser treatment for bilateral facial nevus comedonicus. Dermatol Ther 2017; 30.

Epidermal Nevus Syndrome

Epidermal nevus syndrome does not represent a single entity, but rather multiple syndromes characterized by keratinocytic or organoid nevi, at times associated with internal organ involvement. Each variant has characteristic cutaneous findings and at times relatively specific internal findings. There are at least five variants of organoid epidermal nevus syndrome:

• 1.
  

  Schimmelpenning syndrome ( Fig. 29.3 ). Nevus sebaceus coexists with cerebral, ocular, and skeletal defects. Lesions of the head and neck may lack prominent sebaceous hyperplasia. Coloboma and lipodermoid of the conjunctiva can occur. Vitamin D–resistant hypophosphatemic rickets may be present.

  
  

  
  

  
  

  

  
  

  
  

  Schimmelpenning syndrome.

  
  
  
  
• 2.
  

  Phacomatosis pigmentokeratotica. Nevus sebaceus and papular nevus spilus coexist. The nevus sebaceus may have a flat, erythematous central area with an elevated margin showing features of a nonorganoid epidermal nevus. Multiple angiomas may be found in the nevus spilus component. True basal cell carcinomas develop in the nevus sebaceus of this syndrome. CNS complications can occur, along with hyperhidrosis, weakness, and sensory or motor neuropathy. Vitamin D–resistant rickets may also be present.

  
  
• 3.
  

  Nevus comedonicus syndrome. Nevus comedonicus with ipsilateral ocular, skeletal, or neurologic defects defines this syndrome.

  
  
• 4.
  

  Angora hair nevus syndrome. A linear epidermal nevus is covered with long, white hair growing from dilated follicular pores. CNS, eye, and skeletal abnormalities may be found.

  
  
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  Becker nevus syndrome. Becker nevus is associated with ipsilateral hypoplasia of the breast.

Keratinocytic nevi are seen in at least four epidermal nevus syndromes:

• 1.
  

  Proteus syndrome.

  
  
• 2.
  

  Type 2 segmental Cowden disease. A linear soft, thick, papillomatous keratinocytic nevus in the absence of cerebriform hyperplasia of the palms and soles, but with segmental glomerulosclerosis. It is caused by loss of heterozygosity in an embryo carrying a PTEN germline mutation. Associated anomalies include lipomas, connective tissue nevi, vascular nevi, hemihypertrophy, seizures, hydrocephalus, and gastrointestinal (GI) polyps.

  
  
• 3.
  

  CHILD syndrome. X-linked dominant, male lethal trait. It is caused by a mutation in NSDHL. Chondrodysplasia punctata is characteristic. There is a marked affinity of the nevus for the body folds (ptychotropism). There is a tendency to spontaneous involution.

  
  
• 4.
  

  Fibroblast growth factor receptor 3 epidermal nevus syndrome (Garcia-Hafner-Happle syndrome). A velvety-type nonepidermolytic epidermal nevus and cerebral defects identify this syndrome.

Less well-defined syndromes include the following:

• 1.
  

  Nevus trichilemmocysticus. Multiple trichilemmal cysts along Blaschko’s lines are associated with osteomalacia and fractures.

  
  
• 2.
  

  Didymosis aplasticosebacea. Sebaceous nevus coexists with aplasia cutis, usually in close proximity to each other.

  
  
• 3.
  

  SCALP syndrome: sebaceous nevus, CNS malformations, aplasia cutis congenital, limbal dermoid, and pigmented nevus. It is a combination of didymosis aplasticosebacea and a large melanocytic nevus.

  
  
• 4.
  

  Gobellos syndrome: systematized, linear, velvety, orthokeratotic nevus with hypertrichosis and follicular hyperkeratosis. Multiple bony defects are present.

  
  
• 5.
  

  Bafverstedt syndrome: horny excrescences in a linear pattern with mental retardation and seizures. Diffuse ichthyosis-like hyperkeratosis covers the entire body, including the palms and soles.

  
  
• 6.
  

  NEVADA syndrome: keratinocytic, verrucous nevus with angiodysplasia.

  
  
• 7.
  

  CLOVE syndrome: congenital lipomatous overgrowth, vascular malformation, and epidermal nevus. Extensive truncal vascular malformations and overgrown feet are characteristic.

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  Asch S, Sugarman JL: Epidermal nevus syndromes. Handb Clin Neurol 2015; 132: 291.

  
  
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  Happle R: The group of epidermal nevus syndromes. J Am Acad Dermatol 2010; 63: 25.

Inflammatory Linear Verrucous Epidermal Nevus

The term inflammatory linear verrucous epidermal nevus (ILVEN) may encompass as many as four separate conditions, with some representing mosaicism for erythrokeratodermia variabilis et progressiva. The most common form is the classic ILVEN, or “dermatitic” epidermal nevus. At least three quarters of these cases appear before age 5 years, most before age 6 months. Later onset in adulthood has been reported. ILVEN is characteristically pruritic and pursues a chronic course. Lesions follow the lines of Blaschko. The individual lesions comprising the affected region are erythematous papules and plaques with fine scale ( Fig. 29.4 ). The lesions are morphologically nondescript and, if the distribution is not recognized, could be easily overlooked as an area of dermatitis or psoriasis. Multiple, widely separated areas may be affected, usually on only one side of the body; this may also be bilateral, analogous to other epidermal nevi. Familial cases have been reported. Rarely, systemic involvement, with musculoskeletal and neurologic sequelae (developmental delay, epilepsy), has been reported.

Inflammatory linear verrucous epidermal nevus.

Histologically, classic ILVEN demonstrates abruptly alternating areas of hypergranulosis with orthokeratosis, and parakeratosis with agranulosis. An inflammatory infiltrate of lymphocytes is present in the upper dermis. At times, the histology may simply be that of a subacute dermatitis. Although the histologic diagnosis of psoriasis can be considered, the correct diagnosis can be established if the dermatopathologist is made aware of ILVEN as a consideration. If there is a question, the presence of involucrin expression in the parakeratotic areas can distinguish ILVEN from psoriasis.

Three other types of inflammatory nevus have been included in this group. Some cases of “linear” lichen planus have been considered as “epidermal nevi,” because they typically follow lines of Blaschko. CHILD syndrome, also considered a type of “inflammatory” epidermal nevus, is usually clinically distinct, demonstrating its characteristic hemidysplasia. The most confusing entity has been the “nevoid” or “linear” psoriasis. These cases are of two types. The first type is a child with a family history of psoriasis who has a nevoid lesion at or near birth. The child later develops psoriasis that “koebnerizes” into the ILVEN lesion, suggesting it is a “locus minoris resistensiae” for psoriasis. Treatment of the psoriasis clears the psoriasis overlying the ILVEN, but not the ILVEN. Arthritis developed in one such patient. In the second type, psoriasis initially presents in one band or area. Histologically, it resembles psoriasis. Most of these patients develop typical psoriasis later in life, suggesting a mosaicism that allowed expression of the psoriasis earlier in the initially affected area.

Inflammatory LVEN is differentiated from other epidermal nevi by the presence of erythema and pruritus clinically and by histologic features. Lichen striatus can be distinguished by its histology and natural history. Topical corticosteroids and topical retinoids appear to have limited benefit in ILVEN. However, topical vitamin D (calcipotriol and calcitriol) and topical anthralin have been beneficial. Surgical modalities include excision, cryotherapy, and laser. In cases of “nevoid,” “linear,” or “blaschkolinear” psoriasis, acitretin, narrow-band (NB) ultraviolet (UV) B therapy, and calcipotriene have been beneficial, but etanercept has failed.

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  Conti R, et al: Inflammatory linear verrucous epidermal nevus. J Cosmet Laser Ther 2013; 15: 242.

  
  
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  Hammami Ghorbel H, et al: Treatment of inflammatory linear verrucous epidermal nevus with 2940 nm erbium fractional laser. J Eur Acad Dermatol Venereol 2014; 28: 824.

  
  
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  Umegaki-Arao N, et al: Inflammatory linear verrucous epidermal nevus with a postzygotic GJA1 mutation is a mosaic erythrokeratodermia variabilis et progressiva. J Invest Dermatol 2017; 137: 967.

  
  
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  Wollina U, et al: ILVEN—Complete remission after administration of topical corticosteroid. Georgian Med News 2017; 263: 10.

Clinical Features

There are four types of keratoacanthoma: solitary, multiple, eruptive, and keratoacanthoma centrifugum marginatum. The exact biologic behavior of keratoacanthoma remains controversial. In the past, it had been considered a reactive condition or pseudomalignancy that could be treated expectantly. Now, the favored view is that keratoacanthomas are low-grade SCCs, which in many cases will regress. The regression may be partially mediated by immunity but takes the form of terminal differentiation. The course of these tumors is unpredictable. Even those that ultimately involute can cause considerable destruction before they regress. Any lesions that have the histologic features of keratoacanthoma and appear in an immunosuppressed host should be managed as an SCC, with complete eradication.

Sunlight appears to play an important role in the etiology, especially in the solitary types, with light-skinned persons being predominantly affected. Cases of keratoacanthoma after trauma, hypertrophic lichen planus, discoid LE, tattoos, fractional thermolysis, and imiquimod erosions, and along the distal ends of surgical excisions, suggest that an isomorphic phenomenon is common. The keratoacanthomas appear about 1 month after the traumatic injury. All these associated conditions result in damage to the dermis, especially along the DEJ, and necessitate wound healing. The biologic behavior of these lesions is unknown, but they have added to the controversy of keratoacanthoma as a reactive versus a malignant process. Eruptive keratoacanthomas and SCCs have appeared during treatment for metastatic melanoma with the BRAF inhibitor vemurafenib as well as with anti-PD1 agents such as pembrolizumab. In Muir-Torre syndrome, sebaceous tumors and keratoacanthomas occur in association with multiple internal malignancies. A second, less common cancer scenario is the keratoacanthoma–visceral carcinoma syndrome (KAVCS); only a handful of cases have been reported. Patients have multiple or large keratoacanthomas that appear at the same time as an internal malignancy, always of the genitourinary tract. The relationship of Muir-Torre syndrome (MTS) to KAVCS awaits identification of the genetic basis of both syndromes.

Solitary Keratoacanthoma

The solitary keratoacanthoma is a rapidly growing papule that enlarges from a 1-mm macule or papule to as large as 25 mm in 3–8 weeks. When fully developed, it is a hemispheric, dome-shaped, skin-colored nodule that has a smooth crater filled with a central keratin plug ( Fig. 29.13 ). The smooth shiny lesion is sharply demarcated from its surroundings. Telangiectases may run through the lesion. Subungual keratoacanthomas are tender subungual tumors that usually cause significant nail dystrophy. Subungual lesions often do not regress spontaneously and induce early underlying bony destruction, characterized on radiograph as a crescent-shaped lytic defect without accompanying sclerosis or periosteal reaction.

Keratoacanthoma.

(Courtesy Steven Binnick, MD.)

The solitary keratoacanthoma occurs mostly on sun-exposed skin, with the central portion of the face, backs of the hands, and arms most often involved. Less frequently, other sites are involved, such as the buttocks, thighs, penis, ears, and scalp. Elderly fair-skinned individuals most frequently develop keratoacanthomas. Lesions of the dorsal hands are more common in men, and keratoacanthomas of the lower legs are more common in women. The most interesting feature of this disease is the rapid growth for 2–6 weeks, followed by a stationary period for another 2–6 weeks, and finally a spontaneous involution over another 2–6 weeks, leaving a slightly depressed scar. The stationary period and involuting phase are variable; some lesions may take 6 months to 1 year to resolve completely. An estimated 5% of treated lesions recur. Invasion along nerve trunks has been documented and may result in recurrence after a seemingly adequate excision.

Eruptive Keratoacanthomas of the Lower Leg

In older patients, especially older women, keratoacanthomas on the lower legs are often multiple and erupt in great numbers when one is treated surgically. The old quip is that “you kill one and five come to the funeral.” An effective approach is to treat the lesions with 5-FU cream under Unna boot occlusion. Topical imiquimod, intralesional 5-FU, intralesional methotrexate, psoriatic doses of oral methotrexate, and oral acitretin can also be useful.

Multiple Keratoacanthomas (Ferguson Smith Type)

This type of keratoacanthoma is frequently referred to as the Ferguson Smith type of multiple self-healing keratoacanthoma. These lesions are identical clinically and histologically to the solitary type. There is frequently a family history of similar lesions. The condition has been traced to two large Scottish kindreds. Affected families from other countries have also been reported. Beginning on average at about age 25, but possibly as early as the second decade, patients develop crops of keratoacanthomas that begin as small red macules and rapidly become papules that evolve to typical keratoacanthomas. Lesions may number from a few to hundreds, but generally only 3–10 lesions are noted at any one time. Sun-exposed sites are favored, especially the ears and nose, and in most cases scalp lesions occur. In addition, these patients typically develop keratoacanthomas at sites of trauma, often at the ends of surgical excisions. Lesions grow over 2–4 weeks, reaching a size of 2–3 cm, then remain stable for 1–2 months before slowly involuting. They leave a prominent crateriform scar. If the early lesions are aggressively treated with cryotherapy, shave removal, or curettage, the scar may be less marked than that induced by spontaneous involution. Treatment with an oral retinoid can be effective in stopping the appearance of new lesions and causing involution of existing ones.

Generalized Eruptive Keratoacanthomas (Grzybowski Variant)

The generalized eruptive keratoacanthoma is very rare and sporadic, with most patients having no affected family members. The usual age of onset is between 40 and 60. The patients are usually in good health and are not immunosuppressed. The cause of this condition is unknown. HPV has not been detected in most patients in whom it was sought. The clinical features are characteristic and unique. The Grzybowski type of multiple keratoacanthoma is characterized by a generalized eruption of numerous dome-shaped, skin-colored papules 2–7 mm in diameter. Multiple larger typical keratoacanthomas may also appear. Thousands of lesions may develop. The eruption is usually generalized, but spares the palms and soles. The oral mucous membranes and larynx can be involved. Severe pruritus may be a feature. Clinically, pityriasis rubra pilaris or widespread lichen planopilaris are often considered. Bilateral ectropion, narrowing of the oral aperture, and severe facial disfigurement can result. Linear arrangement of some lesions, especially over the shoulders and arms, has also been noted. Despite the multiplicity of lesions, no case of “metastasis” from a skin lesion or increased risk of internal malignancy has been reported in the Grzybowski variant of keratoacanthoma. Dr. Grzybowski’s original patient died of a myocardial infarction 16 years after diagnosis. Oral treatment with retinoids, methotrexate, and cyclophosphamide can prove effective.

Keratoacanthoma Centrifugum Marginatum

This uncommon variant of keratoacanthoma is usually solitary, although multiple lesions can occur. Keratoacanthoma centrifugum marginatum is characterized by progressive peripheral expansion and concomitant central healing, leaving atrophy. Spontaneous involution, as may be seen in other variants of keratoacanthoma, does not occur. Lesions range from 5–30 cm in diameter ( Fig. 29.14 ). The dorsum of the hands and pretibial regions are favored sites. Oral treatment with etretinate and methotrexate with prednisone has been effective in isolated cases.

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  Annest NM, et al: Intralesional methotrexate treatment for keratoacanthoma tumors. J Am Acad Dermatol 2007; 56: 989.

  
  
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  Anzalone CL, Cohen PR: Generalized eruptive keratoacanthomas of Grzybowski. Int J Dermatol 2014; 53: 131.

  
  
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  Baykal C, et al: Management of keratoacanthoma in patients with xeroderma pigmentosum. J Eur Acad Dermatol Venereol 2016; 30: e91.

  
  
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  Bieber AK, et al: Systemic methotrexate for prurigo nodularis and keratoacanthomas in actinically damaged skin. JAAD Case Rep 2016; 2: 269.

  
  
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  Hawilo A, et al: Keratoacanthoma centrifugum marginatum. Skinmed 2017; 15: 69.

  
  
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  John AM, et al: Muir-Torre syndrome (MTS). J Am Acad Dermatol 2016; 74: 558.

  
  
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  Kwiek B, et al: Keratoacanthoma (KA). J Am Acad Dermatol 2016; 74: 1220.

  
  
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  Ogita A, et al: Histopathological diagnosis of epithelial crateriform tumors. J Dermatol 2016; 43: 1321.

  
  
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  Rhee do Y, et al: Successful treatment of multiple vemurafenib-induced keratoacanthomas by topical application of imiquimod cream. J Dermatolog Treat 2016; 27: 448.

  
  
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  Takai T: Advances in histopathological diagnosis of keratoacanthoma. J Dermatol 2017; 44: 304.

  
  
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  Veerula VL, et al: Multiple keratoacanthomas occurring in surgical margins and de novo treated with intralesional methotrexate. Cutis 2016; 98: E12.

Keratoacanthoma centrifugum marginatum.

Nodular Basal Cell Carcinoma (Classic Basal Cell Carcinoma)

The classic or nodular BCC constitutes 50%–80% of all BCCs. Nodular BCC is composed of one or a few small, waxy, semitranslucent nodules forming around a central depression that may or may not be ulcerated, crusted, and bleeding. The edge of larger lesions has a characteristic rolled border. Telangiectases course through the lesion. Bleeding on slight injury is a common sign. As growth progresses, crusting appears over a central erosion or ulcer, and when the crust is knocked or picked off, bleeding occurs, and the ulcer becomes apparent. This ulcer is characterized by chronicity and gradual enlargement over time. The lesions are asymptomatic, and bleeding is the only difficulty encountered. The lesions are most frequently found on the face ( Fig. 29.15 ) (85%–90% on head and neck) and especially on the nose (25%–30%). The forehead, ears, periocular areas, and cheeks are also favored sites. However, any part of the body may be involved.

Basal cell carcinoma.

Cystic Basal Cell Carcinoma

These dome-shaped, blue-gray cystic nodules are clinically similar to eccrine and apocrine hidrocystomas.

Morpheaform, or Cicatricial Basal Cell Carcinoma

This type of BCC presents as a white sclerotic plaque, and 95% of these occur on the head and neck. Ulceration, a pearly rolled border, and crusting are usually absent. Telangiectasia is variably present. Therefore the lesion is often missed or misdiagnosed for some time. The differential diagnosis includes desmoplastic trichoepithelioma, a scar, microcystic adnexal carcinoma, and desmoplastic melanoma. The unique histologic feature is the strands of basal cells interspersed amid densely packed, hypocellular connective tissue. Morpheic BCCs constitute 2%–6% of all BCCs. Data suggest use of fluorouracil may be a risk factor for morpheaform versus nonmorpheaform BCC.

Infiltrative Basal Cell Carcinoma

Infiltrative BCC is an aggressive subtype characterized by deep infiltration of spiky islands of basaloid epithelium in a fibroblast-rich stroma. Clinically, it lacks the scarlike appearance of morpheiform BCC. Histologically, the stroma is hypercellular, the islands are jagged in outline, and squamous differentiation is common.

Micronodular Basal Cell Carcinoma

These tumors are not clinically distinctive, but the micronodular growth pattern makes them less amenable to curettage.

Superficial Basal Cell Carcinoma

Superficial BCC is also termed superficial multicentric BCC. This is a common form of BCC, comprising at least 15% of the total. It favors the trunk (45%) or distal extremities (14%). Only 40% occur on the head and neck. The multicentricity is merely a histologic illusion created by the passing of the plane of section through the branches of a single, multiply branching lesion.

This type of BCC most frequently presents as a dry, psoriasiform, scaly lesion. It is usually a superficial flat growth, which in many cases exhibits little tendency to invade or ulcerate. The lesions enlarge very slowly and may be misdiagnosed as patches of eczema or psoriasis. They may grow to be 10–15 cm in diameter. Close examination of the edges of the lesion will show a threadlike raised border ( Fig. 29.16 ). These erythematous plaques with telangiectasia may occasionally show atrophy or scarring. Some lesions may develop an infiltrative component in their deeper aspect and grow into the deeper dermis. When this occurs, they may induce dermal fibrosis and multifocal ulceration, forming a “field of fire” type of large BCC. Sometimes the lesion will heal at one place with a white atrophic scar and then spread actively to the neighboring skin. A patient can have several of these lesions simultaneously or over time. This form of BCC is the most common pattern seen in patients with human immunodeficiency virus (HIV) infection and BCC.

Superficial basal cell carcinoma.

Pigmented Basal Cell Carcinoma

This variety has all the features of nodular BCC, but in addition, brown or black pigmentation is present ( Fig. 29.17 ). When dark-complexioned persons, such as Latin Americans, Hispanics, or Asians, develop BCC, this is the type they tend to develop. Pigmented BCCs make up 6% of all BCCs. In the management of these lesions, it should be known that, if ionizing radiation therapy is chosen, the pigmentation remains at the site of the lesion.

Pigmented basal cell carcinoma.

(Courtesy Debabrata Bandyopadhyay, MD.)

Rodent Ulcer

Also known as Jacobi ulcer, rodent ulcer is a neglected BCC that has formed an ulceration. The pearly border of the lesion may not be recognized. If it occurs on the lower extremity, it may be misdiagnosed as a vascular ulceration.

Fibroepithelioma of Pinkus

First described by Pinkus as premalignant fibroepithelial tumor, this is usually an elevated, skin-colored, sessile lesion on the lower trunk, lumbosacral area, groin, or thigh and may be as large as 7 cm. The lesion is superficial and resembles a fibroma or papilloma. Histologically, interlacing basocellular sheets extend downward from the surface to form an epithelial meshwork enclosing a hyperplastic mesodermal stroma. As with infundibulocystic BCC, fibroepithelioma is composed of pink epithelial strands with blue basaloid buds. Fibroepithelioma has a more prominent fibromucinous stroma and lacks the horn cysts characteristic of infundibulocystic BCC. Fibroepithelioma often demonstrates sweat ducts within the pink epithelial strands. A slight inflammatory infiltrate may also be present. Simple removal by excision or electrosurgery is the treatment of choice.

Polypoid Basal Cell Carcinoma

The polypoid BCCs present as exophytic nodules of the head and neck.

Porelike Basal Cell Carcinoma

Patients with thick sebaceous skin of the central face may develop a BCC that resembles an enlarged pore or stellate pit. The lesions virtually always occur on the nose, melolabial fold, or lower forehead. Affected patients are generally men, and the majority are smokers. Many years pass from the appearance of the lesion until a diagnostic biopsy is taken, because the lesion is considered inconsequential.

Aberrant Basal Cell Carcinoma

Even in the absence of any apparent carcinogenic factor, such as arsenic, radiation, or chronic ulceration, BCC may occur in odd sites, such as the scrotum, vulva, perineum, nipple, and axilla.

Solitary Basal Cell Carcinoma in Young Persons

These curious lesions are typically located in the region of embryonal clefts in the face and are often deeply invasive. Complete surgical excision is much safer than curettage for their removal. Cases in children and teenagers, unassociated with the basal cell nevus syndrome or nevus sebaceus, are well documented.

Natural History

Basal cell carcinomas run a chronic course as the lesion slowly enlarges and tends to become more ulcerative ( Fig. 29.18 ). As a rule, the lesions tend to bleed without pain or other symptoms. Some tend to heal spontaneously and form scar tissue as they extend. Peripheral spreading may produce configurate, somewhat serpiginous patches. The ulceration may burrow deep into the subcutaneous tissues or even into cartilage and bone, causing extensive destruction and mutilation. At least half the deaths that occur from BCC result from direct extension into a vital structure rather than metastases.

Large basal cell carcinoma.

Immunosuppression

Immunosuppression for organ transplantation increases the risk for the development of BCC by about 10-fold. Some increased risk for BCC is also thought to occur in HIV-infected patients and in those receiving immunosuppressive medications for other reasons. Patients with chronic lymphocytic leukemia are also at increased risk for BCC. In the immunosuppressed population, a history of blistering sunburns in childhood is a strong risk factor for the development of BCC after immunosuppression.

Etiology and Pathogenesis

It appears that BCCs arise from immature pluripotential cells associated with the hair follicle. Mutations that activate the hedgehog signaling pathway, which controls cell growth, are found in most BCCs. The affected genes are those for sonic hedgehog, patched 1, and smoothened (SMO). Inactivation of patched 1 is most common, and SMO mutations are associated with 10%–20% of sporadic BCCs.

Histopathology

The general belief is that a correlation exists between histologic subtype of BCC and biologic behavior. BCCs are considered as being of low risk or high risk, depending on their probability of causing problems in the future: subclinical extension, incomplete removal, aggressive local invasive behavior, and local recurrence. Therefore the dermatopathology report of a BCC should include a subtype descriptor when possible. Unfortunately, many shave biopsy specimens do not allow for accurate typing, and the presence of an indolent growth pattern superficially does not exclude the possibility of a deeper, more aggressive growth pattern. The common histologic patterns are nodular, superficial, infiltrative, morpheic, micronodular, and mixed. The nodular type is a low-risk type. High-risk types include the infiltrative, morpheic, and micronodular patterns, because of aggressive local invasive behavior and a tendency to recur. Superficial BCC is prone to increased recurrence due to inadequate removal. When evaluating the histologic margin of superficial BCC, tumor stroma involving the margin should be considered a positive margin.

The early lesion shows small, dark-staining, polyhedral cells resembling those of the basal cell layer of the epidermis, with large nuclei and small nucleoli. These occur within the epidermis as thickenings or immediately beneath the epidermis as downgrowths connected with it. After the growth has progressed, regular compact columns of these cells fill the tissue spaces of the dermis, and a connection with the epidermis may be difficult to demonstrate. At the periphery of the masses of cells, the columnar cells may be characteristically arranged like fence posts (palisading). This may be absent when the tumor cells are in cord arrangement or in small nests. Cysts may form. The interlacing strands of tumor cells may present a lattice-like pattern. The dermal stroma is an integral and important part of the BCC. The stroma is loose and fibromyxoid, with a sparse lymphoid infiltrate often present. The stroma can be highlighted by metachromatic toluidine blue staining, which can be useful during Mohs surgery.

Differential Diagnosis

Distinguishing between small BCCs and small SCCs is largely an intellectual exercise. Both are caused chiefly by sunlight, neither is likely to metastasize, and both will require removal, usually by simple surgical excision or curettage. A biopsy is always indicated but may be performed at the definitive procedure, when the likelihood of the diagnosis of NMSC is high and the patient is fully informed and gives consent.

A waxy, nodular, rolled edge is fairly characteristic of BCC ( Fig. 29.19 ). The SCC is a dome-shaped, elevated, hard, and infiltrated lesion. The early BCC may easily be confused with sebaceous hyperplasia, which has a depressed center with yellowish small nodules surrounding the lesion. However, these lesions never bleed and do not become crusted.

Basal cell carcinoma, accentuation of pearly border when skin is stretched.

Bowen disease, Paget disease, amelanotic melanoma, and actinic and seborrheic keratoses may also simulate BCC. Ulcerated BCC on the shins is frequently misdiagnosed as a stasis ulcer, and a biopsy may be the only way to differentiate the two. Pigmented BBC is frequently misdiagnosed as melanoma or as a pigmented nevus. The superficial BCC is easily mistaken for psoriasis or eczema. The careful search for the rolled edge of the peripheral nodules is important in differentiating BCC from all other lesions.

Treatment

Each lesion of BCC must be thoroughly evaluated individually. Age and gender of the patient as well as the size, site, and type of lesion are important factors to be considered when choosing the proper method of treatment. No single treatment method is ideal for all lesions or all patients. The choice of treatment will also be influenced by the experience and ability of the treating physician in the various treatment modalities. A biopsy should be performed in all patients with suspected BCC to determine the histologic subtype and confirm the diagnosis.

The aim of treatment is for a permanent cure with the best cosmetic results. This is important because the most common location of BCC is the face. Recurrences result from inadequate treatment and are usually seen during the first 4–12 months after treatment. A minimum 5-year follow-up is indicated, however, to continue a search for new lesions, because the development of a second BCC is common.

Treatment of BCC is usually surgical (see Chapter 37 ), but some forms of BCC are amenable to medical treatment, PDT or radiation therapy. Vismodegiband related inhibitors of smoothened that targets the hedgehog pathway, has antitumor activity and clinically meaningful response in locally advanced or metastatic BCC. Electrochemotherapy, combining bleomycin with short electric pulses, has been used as palliative skin-directed therapy for patients with multiple or large BCC for whom conventional treatments are not viable options.

Clinical Features

The nevoid BCC syndrome (NBCCS) or basal cell nevus syndrome is an autosomal dominant inherited disorder. The major diagnostic criteria for NBCCS include the following:

• 1.
  

  Development of multiple BCCs (>5) or a BCC before age 30 ( Fig. 29.20 )

  
  

  
  

  
  

  

  
  

  
  

  Multiple basal cell carcinomas in nevoid basal cell carcinoma syndrome.

  
  
  
  
• 2.
  

  Odontogenic keratocysts of the jaws

  
  
• 3.
  

  Pitted depressions on the hands and feet (palmar plantar pits) (two or more)

  
  
• 4.
  

  Lamellar calcification of the falx under age 20

  
  
• 5.
  

  First-degree relative with NBCCS

Minor criteria are as follows:

• 1.
  

  Childhood medulloblastoma

  
  
• 2.
  

  Lympho-mesenteric or pleural cysts

  
  
• 3.
  

  Macrocephaly (97th percentile)

  
  
• 4.
  

  Cleft lip/palate

  
  
• 5.
  

  Vertebral/rib abnormalities

  
  
• 6.
  

  Preaxial or postaxial polydactyly

  
  
• 7.
  

  Ovarian/cardiac fibromas

  
  
• 8.
  

  Ocular abnormalities

The diagnosis of NBBCS is made if the affected individual has two major criteria and one minor criterion, or one major criterion and three minor criteria. Genetic testing has revealed that some persons carrying the genetic mutation do not meet the diagnostic criteria.

Essentially, all cases of NBCCS are caused by mutations in the PTCH (or PTCH1 ) gene. One family with a mutation in the SUFU gene has been reported. SUFU mutations have been reported with meduloblastoma susceptibility. Mutations occur throughout the PTCH gene, and no correlation appears to exist between the site of the mutation and the clinical phenotype. Most mutations result in premature termination and production of shortened gene product. Loss of the PTCH gene can also occur by deletions of part of the long arm of chromosome 9, where the PTCH gene is located (region q22). This represents about 6% of NBCCS patients.

The clinical findings seen with NBCCS depend on two characteristics: the race of the patient and the form of mutation (nucleotide point mutation or chromosome deletion). Of 105 patients reported in one series, 80% were white. The first tumor developed by the mean age of 23 years for white patients. Palmar pits were seen in 87%. Jaw cysts were found in 74%, with 80% manifested by age 20. The total number of cysts ranged from 1 to 28. Medulloblastomas developed in four patients, and three had cleft lip or palate. Physical findings in this series included “coarse face” (54%), macrocephaly (50%), hypertelorism (42%), frontal bossing (27%), pectus deformity (13%), and Sprengel deformity (11%). In Japanese and African American patients with NBCCS, palmar and plantar pits, odontogenic keratocysts, and skeletal abnormalities are most common, with BCCs not appearing until much later in life. Those patients with NBCCS caused by deletions of chromosome 9q22 have all the stigmata of typical NBCCS patients, and in addition often have severe mental retardation, hyperactivity, overfriendliness with strangers, short stature, and less often, neonatal hypotonia, epicanthic folds, short neck, pectus, scoliosis, and epilepsy.

Histopathology

The histology of BCCs arising in syndromic patients is identical to that arising in nonsyndromic patients, with the solid and superficial types being most common.

Differential Diagnosis

Several other unique types of BCC presentation should not be confused with NBCCS. One type is the linear unilateral BCC syndrome, in which a linear arrangement of close-set papules, sometimes interspersed with comedones, is present at birth. Biopsy reveals BBCs, but they do not increase in size with the age of the patient. A second type, referred to as Bazex syndrome, is an X-linked dominant inherited disease comprising follicular atrophoderma of the extremities, localized or generalized hypohidrosis, hypotrichosis, and multiple BCCs of the face, which often arise at an early age. A third type consists of multiple hereditary infundibulocystic BCCs and is an autosomal dominant syndrome. It is distinguished from NBCCS by the absence of palmar pits and jaw cysts in most cases. Clinically, patients appear to have multiple trichoepitheliomas. Numerous skin-colored pearly papules affect the central face, accentuated in the nasolabial folds. The generalized basaloid follicular hamartoma (BFH) syndrome differs from NBCCS by having basaloid follicular hamartomas instead of BCCs. It is reported from a large kindred in the southeastern United States (see later). Tiny palmar pits are present. Histologically, infundibulocystic BCC and BFH may be indistinguishable, so the two familial syndromes may be difficult to separate. Rombo syndrome, reported in one large Swedish family, has multiple BCCs, vermiculate atrophoderma, and hypotrichosis. A patient with multiple BCCs and myotonic dystrophy has been reported, suggesting yet another genodermatosis associated with multiple BCCs.

Treatment

Genetic counseling is essential. Strict sun avoidance and maximum sun protection, as recommended for xeroderma pigmentosum patients, is advised. Avoidance of ionizing radiation is also paramount, because NBCCS patients are particularly sensitive to radiation; multiple BCCs may appear in the distribution of radiation therapy used to treat medulloblastoma or BCC or other cancers. Treatment involves very regular monitoring and biopsy of suspicious lesions. Topical therapy with tazarotene and imiquimod may be of some use in preventing and treating the superficial tumors. Oral retinoid therapy may reduce the frequency of new BCCs appearing and may slow the growth of existing small BCCs. However, once the oral retinoids are stopped, the lesions again begin to grow. Vismodegib, the hedgehog pathway inhibitor, reduces BCC tumor burden and prevents growth of new BCCs in those with NBCCS; however, poor tolerability of the medication leads to a high rate of discontinuation (≈50%). A topical formulation of a smoothened inhibitor appears to be effective and better tolerated, leading to BCC regression. Surgical treatments are used for most lesions, either curettage and desiccation or excision. At times, megasessions, with removal of multiple tumors under general anesthesia in the operating room, are needed to keep up with the large number of BCCs these patients develop. PDT appears to be particularly beneficial when used to treat areas that have had multiple BCCs in the past.

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