Chapter 670

Tumors of the Skin

Kari L. Martin

See also Chapters 506.2 and 596.

Epidermal Inclusion Cyst (Epidermoid Cyst)

Epidermoid cysts are the nodules most commonly seen in children. Such a cyst is a sharply circumscribed, dome-shaped, firm, freely movable, skin-colored nodule (Fig. 670-1) often with a central dimple or punctum that is a plugged, dilated pore of a pilosebaceous follicle. Epidermoid cysts form most frequently on the face, neck, chest, or upper back and may periodically become inflamed and infected secondarily, particularly in association with acne vulgaris. The cyst wall may also rupture and induce an inflammatory reaction in the dermis. The wall of the cyst is derived from the follicular infundibulum. A mass of layered keratinized material that may have a cheesy consistency fills the cavity. Epidermoid cysts may arise from occlusion of pilosebaceous follicles, from implantation of epidermal cells into the dermis as a result of an injury that penetrates the epidermis, and from rests of epidermal cells. Multiple epidermoid cysts may be present in Gardner syndrome and the nevoid basal cell carcinoma syndrome. Excision of the cysts with removal of the entire sac and its contents is indicated, particularly if the cyst becomes recurrently infected. A fluctuant, infected cyst should be treated with antibiotics or intralesional corticosteroids. After the inflammation subsides, the cyst should be removed.

Milium

Milium is a 1-2 mm, firm, pearly white or yellowish, subepidermal keratin cyst. Milia in newborns is discussed in Chapter 647. Secondary milia occur in association with subepidermal blistering diseases, after dermabrasion or other injury to the skin. They are retention cysts caused by hyperproliferation of injured epithelium and are indistinguishable histopathologically from primary milia. Those that develop after blistering usually arise from the eccrine sweat duct, but they may develop from the hair follicle, sebaceous duct, or epidermis. A milium body differs from an epidermoid cyst only in its small size and superficial location.

Fibrofolliculomas

These lesions usually appear in late adolescents or in young adults and are characterized by multiple dome-shaped clear-white papules appearing on the nose, cheeks, and neck, and at times the trunk or ears (Fig. 670-2). They are associated with the familial cancer syndrome of Birt-Hogg-Dubé, an autosomal dominant disorder that results from a mutation in the folliculin (FLCN) gene. Associated features include pulmonary cysts, pneumothorax, renal cell carcinoma, and other benign or malignant tumors.

Pilar Cyst (Trichilemmal Cyst)

Pilar cyst may be clinically indistinguishable from an epidermoid cyst. It manifests as a smooth, firm, mobile nodule, predominantly on the scalp (Fig. 670-3). Pilar cysts occasionally develop on the face, neck, or trunk. A cyst may become inflamed and may occasionally suppurate and ulcerate. The cyst wall is composed of epithelial cells with indistinct intercellular bridges. The peripheral cell layer of the wall shows a palisade arrangement, which is not seen in an epidermoid cyst. No granular layer is present. The cyst cavity contains homogeneous eosinophilic keratinous material, and foci of calcification are seen in 25% of cases. The propensity for development of pilar cysts may be inherited in an autosomal dominant manner. More than one cyst generally develops in a patient. Numerous pilar and epidermoid cysts, desmoid tumors, fibromas, lipomas, or osteomas may be associated with colonic polyposis or adenocarcinoma in Gardner syndrome. Pilar cysts shell out easily from the dermis.

Pilomatricoma

The second most common nodule seen in children, pilomatricoma is a benign tumor that manifests as a 3-30 mm, firm, solitary, deep dermal or subcutaneous tumor on the head, neck, or upper extremities. The overlying epidermis is usually normal. The tumor may occasionally be located more superficially, however, tinting the overlying skin blue-red (Fig. 670-4). Multiple pilomatricomas are seen in myotonic dystrophy, Gardner syndrome, Rubinstein-Taybi syndrome, and Turner syndrome. In general, however, pilomatricomas are not hereditary. Histopathologically, irregularly shaped islands of epithelial cells are embedded in a cellular stroma. Calcium deposits are found in 75% of tumors. Pilomatricomas are caused by mutations in β-catenin.

Eruptive Vellus Hair Cysts

Eruptive vellus hair cysts are 1-3 mm, asymptomatic, soft, skin-colored follicular papules on the central chest (Fig. 670-5). They may become crusted or umbilicated. Abnormal vellus hair follicles become occluded at the level of the infundibulum, resulting in retention of hairs within an epithelium-lined cystic dilation of the proximal part of the follicle. Most cases are chronic, but spontaneous regression has been reported.

Syringoma

The benign tumors known as syringomas are soft, small, skin-colored or yellowish brown papules that develop on the face, particularly in the periorbital regions (Fig. 670-6). Other sites of predilection include the axillae and umbilical and pubic areas. They often develop during puberty and are more frequent in females. Eruptive syringomas develop in crops over the anterior trunk during childhood or adolescence. A syringoma is derived from an intraepidermal sweat gland duct. Syringomas are of cosmetic significance only. Sparse lesions may be excised, but they are often too numerous to remove.

Dermatofibroma (Histiocytoma)

A benign dermal tumor, dermatofibroma may be pedunculated, nodular (Fig. 670-7), or flat and is usually well circumscribed and firm but occasionally feels soft on palpation. The overlying skin is usually hyperpigmented, may be shiny or keratotic, and dimples when the tumor is pinched. Dermatofibromas range in size from 0.5-10.0 mm, arise most frequently on the limbs, and are usually asymptomatic but may occasionally be pruritic. They are composed of fibroblasts, young and mature collagen, capillaries, and histiocytes in varying proportions, forming a nodule in the dermis that has poorly defined edges. The cause of these tumors is unknown, but trauma such as an insect bite or folliculitis appears to induce reactive fibroplasia. The differential diagnosis includes epidermal inclusion cyst, juvenile xanthogranuloma, hypertrophic scar, and neurofibroma. Dermatofibromas may be excised or left intact, according to the patient's preference. They usually persist indefinitely.

Juvenile Xanthogranuloma

A firm, dome-shaped, yellow, pink, or orange papule or nodule (Fig. 670-8), juvenile xanthogranuloma varies from 5 mm to approximately 4 cm in diameter. The average age at onset is 2 yr. These nodules are 10 times more common in white than in African-American individuals. Sites of predilection are the scalp, face, and upper trunk, where they may erupt in profusion or remain as solitary lesions. Nodular lesions may appear on the oral mucosa. Mature lesions are characterized histopathologically by a dermal infiltrate of lipid-laden histiocytes, admixed inflammatory cells, and Touton giant cells. The lesions may clinically resemble papulonodular urticaria pigmentosa, dermatofibromas, or xanthomas of hyperlipoproteinemia, but can be distinguished from these entities histopathologically.

Affected infants are nearly always otherwise normal, and blood lipid values are not elevated. Café-au-lait macules are found on 20% of patients with juvenile xanthogranuloma. Xanthogranulomatous infiltrates occur occasionally in ocular tissues. This process may result in glaucoma, hyphema, uveitis, heterochromia iridis, iritis, or sudden proptosis. Age less than 2 yr, multiple lesions, and periocular location may heighten concerns for intraocular involvement. There appears to be an association among juvenile xanthogranuloma, neurofibromatosis, and childhood leukemia, most frequently juvenile chronic myelogenous leukemia. There is no need to remove the benign lesions of juvenile xanthogranuloma because most of them regress spontaneously in the 1st few yr. Residual pigmentation and atrophy may result.

Lipoma

A benign collection of fatty tissue, lipoma appears on the trunk, neck, or proximal portions of the limbs. Lipomas are soft, compressible, lobulated, subcutaneous masses. Multiple lesions may occur occasionally, as in Gardner syndrome. Atrophy, calcification, liquefaction, or xanthomatous change may sometimes complicate their course. A lipoma is composed of normal fat cells surrounded by a thin connective tissue capsule. Lipomas represent a cosmetic defect and may be surgically excised. Multiple lipomas, identical to those that occur singly, are inherited in an autosomal dominant fashion and often appear by the 3rd decade in patients with familial multiple lipomatosis. Lipomas may appear intraabdominally, intramuscularly, and subcutaneously. Congenital lipomatosis manifests in the 1st few mo of life as large subcutaneous fatty masses on the chest, with extension into skeletal muscle. Congenital lipomatosis can also be a manifestation of Proteus syndrome (overgrowth/hyperplasia skin, connective tissue, mutation in AKT1). Angiolipomas usually manifest as numerous painful subcutaneous nodules on the arms and trunk.

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and scoliosis/skeletal-spinal anomalies) is usually a sporadic disorder with an asymmetric truncal lipomatous mass present at birth. Additional features include macrodactyly, vascular malformations (low flow), linear epidermal nevus and renal anomalies. The differential diagnosis includes Proteus, Klippel-Trenaunay, and Bannayan-Riley-Ruvalcaba syndrome.

Nevoid Basal Cell Carcinoma Syndrome (Basal Cell Nevus Syndrome, Gorlin Syndrome)

The autosomal dominant entity known as nevoid basal cell carcinoma syndrome is caused by mutations in the PTCH1 and PTCH2 (“patched”) genes. These tumor-suppressor genes, part of the hedgehog signaling pathway, are important in determining embryonic patterning and cell fate in a number of structures in the developing embryo. Mutations in human patched genes produce dysregulation of several genes involved in organogenesis and carcinogenesis. Consequently, the syndrome includes a wide spectrum of defects involving the skin, eyes, central nervous and endocrine systems, and bones. The predominant features are early-onset basal cell carcinomas and mandibular cysts. Approximately 20% of those in whom a basal cell carcinoma develops before age 19 yr have this syndrome. Basal cell carcinomas appear between puberty and age 35 yr, erupting in crops of tumors that vary in size, color, and number, and may be difficult to distinguish from other types of skin lesions. Sites of predilection are the periorbital skin, nose, malar areas, and upper lip, but the lesions can develop on the trunk and limbs and are not restricted to sun-exposed areas. Ulceration, bleeding, crusting, and local invasion can occur. Small milia, epidermal cysts, pigmented lesions, hirsutism, and palmar and plantar pits are additional cutaneous findings.

The facies of patients with this syndrome are characterized by temporoparietal bossing, prominent supraorbital ridges, a broad nasal root, ocular hypertelorism or dystopia canthorum, and prognathism. Keratinized cysts (odontogenic keratocysts) in the maxilla and mandible occur in most patients. They range in size from a few millimeters to several centimeters, may result in maldevelopment of the teeth, and cause pain, swelling of the jaw, facial deformity, bone erosion, pathologic fractures, and suppurating sinus tracts. Osseous defects such as anomalous rib development, spina bifida, kyphoscoliosis, and brachymetacarpalism occur in 60% of patients, and ocular abnormalities including cataracts, glaucoma, coloboma, strabismus, and blindness occur in approximately 25%. Some males have hypogonadism, and the testes are absent or undescended. Kidney malformations have also been reported. Neurologic manifestations include calcification of the falx, seizures, mental retardation, partial agenesis of the corpus callosum, hydrocephalus, and nerve deafness. The incidence of medulloblastoma, ameloblastoma of the oral cavity, fibrosarcoma of the jaw, teratoma, cystadenoma, cardiac fibroma, ovarian fibroma, and fetal onset rhabdomyoma is higher in patients with nevoid basal cell carcinoma syndrome.

Treatment of these patients requires the participation of various specialists according to individual clinical problems. Basal cell carcinomas should not be treated with irradiation. Most of the basal cell carcinomas have a clinically benign course, and it is often impossible to remove them all. Those with an aggressive growth pattern and those on the central areas of the face, however, should be removed promptly. Treatment options include surgery, Mohs micrographic surgery, laser ablation, cryotherapy, photodynamic therapy, topical 5% imiquimod and oral retinoids (0.5-1.0 mg/kg/day). Vismodegib, which inhibits smoothened protein in the hedgehog pathway, is a targeted therapy available for unresectable basal cell carcinomas. Genetic counseling is also indicated.