Elizabeth A. Abel MD1
Clinical Professor of Dermatology
1Stanford University School of Medicine
The author serves as an adviser for Amgen, Inc., Biogen Idec, Inc., Abbott Laboratories, Inc., Genentech, Inc., and Novartis Pharmaceuticals Corp.
Tumors of the cutaneous surface may arise from the epidermis, dermis, or subcutaneous tissue or from any of the specialized cell types in the skin or its appendages. Broad categories include tumors derived from epithelial, melanocytic, or connective tissue structures. Within each location or cell type, lesions are classified as benign, malignant, or, in certain cases, premalignant.1,2
Benign epithelial tumors include tumors of the surface epidermis that form keratin; tumors of the epidermal appendages; and cysts of the skin.
Melanocytic, or pigment-forming, lesions are very common. One of the most frequently encountered forms is the nevus cell nevus. The term nevus has two meanings: a malformation commonly involving the entire skin layer (tissue nevus) and a benign growth of melanocytic cells (nevus cells).
Nevus cells are closely related to melanocytes and may be defined as modified neuroectodermal melanin-producing elements. The word mole, often used as a synonym for nevus, is an imprecise term because it refers to birthmarks that may or may not contain nevus cells. Neural tumors, such as neurofibromas, are related to melanocytic tumors because both are of neuroectodermal origin.
Tumors that are derived from connective tissue include the following: fibromas, histiocytomas, lipomas, leiomyomas, and hemangiomas.
For cases in which it is not possible to distinguish clinically between benign and malignant cutaneous tumors, histopathologic examination is extremely important. The type of biopsy performed depends on the location, size, and nature of the lesion and on cosmetic considerations. In all cases, the clinical features must be correlated with the distinctive microscopic appearance of the tumor to confirm or exclude the diagnosis on the basis of physical examination.
Seborrheic keratosis (seborrheic wart) consists of a sharply circumscribed, rough or smooth papule or plaque that is 1 mm to several centimeters in size and dirty yellow or light to dark brown in color. The lesions often have the appearance of being stuck on and are characterized by prominent follicular plugging. They are most common in light-skinned races, first appearing in adults on the face and upper trunk and occurring more frequently with increasing age [see Figure 1].
Figure 1. Verrucous, hyperpigmented lesions of seborrheic keratosis with a stuck-on appearance are present on the trunk of this patient.
Transient eruptive seborrheic keratoses have been associated with inflammatory skin conditions, including erythroderma associated with psoriasis and drug eruptions. These keratoses tend to resolve when the skin inflammation clears.3 These transient keratoses should be distinguished from eruptive seborrheic keratoses—the sign of Leser-Trelat—which are associated with internal malignancy, particularly adenocarcinoma. The true value of the sign of Leser-Trelat as a marker of underlying malignancy is a subject of debate. Dermatosis papulosa nigra is similar to seborrheic keratosis, but it is seen in dark-skinned races; it usually appears on the face and presents at an earlier age than seborrheic keratosis [see Figure 2].
Figure 2. Dermatosis papulosa nigra, as seen on the face, appears in dark-skinned races at a younger age than seborrheic keratosis.
The differential diagnosis of seborrheic keratosis and dermatosis papulosa nigra includes lentigo, wart, and nevus cell nevus. A biopsy may be required to rule out a pigmented basal cell carcinoma or, in the case of an inflamed seborrheic keratosis, squamous cell carcinoma or malignant melanoma. A shave biopsy that includes the base of the lesion may be performed before treatment with curettage. Seborrheic keratosis with basal clear cells can microscopically mimic melanoma in situ; however, careful conventional microscopy combined with a panel of immunostains allows for an accurate diagnosis.4
Curettage is a satisfactory treatment. When multiple lesions are present, anesthesia may be achieved by freezing the affected area with an ethyl chloride spray before performing curettage. For larger lesions, electrodesiccation is unnecessary and may cause scarring. Smaller lesions may be successfully treated with electrodesiccation, cryotherapy, or topical application of 50% trichloroacetic acid.
Epidermal nevus consists of closely set, skin-colored or hyperpigmented papules that either may be localized to one side of the body and arranged in linear fashion or may be widespread. When localized, the condition is termed nevus unius lateris [see Figure 3]. When widespread, it is called systematized nevus. Lesions affect about one in 1,000 people; they are present at birth or appear in early childhood. The lesions have no malignant potential but may constitute a serious cosmetic problem.
Figure 3. Epidermal nevus with discrete and confluent brown papillomas is present in a somewhat linear arrangement.
Histologically, epidermal nevi exhibit hyperplasia of the epidermis; the structure or maturation of these lesions is not significantly different from that of normal epidermis. One variant, the inflammatory linear verrucous epidermal nevus, shows psoriasiform hyperplasia. Another variant, which is common in systematized nevi, shows granular degeneration of epidermolytic hyperkeratosis histologically. This type of epidermal nevus is a mosaic genetic disorder of suprabasal keratin. Mutations in the K10 gene are associated with lesions of the skin, whereas the normal gene is found in unaffected skin.5
The epidermal nevus syndrome involves a spectrum of different types of epidermal nevi associated with manifestations in the skeletal, urogenital, cardiovascular, and nervous systems that are caused by genomic mosaicism.6 This rare syndrome is apparent at birth; the presence of widespread epidermal nevi should trigger a search for associated anomalies.
Nevus comedonicus is a variant of an epidermal nevus affecting the pilosebaceous structures; it occurs as clusters of comedonelike papules, usually in a linear pattern on the face, neck, upper arms, and trunk.6
Nevus sebaceous is a benign tumor that shows sebaceous differentiation. The lesion has a yellow hue and a granular surface and occurs in a linear pattern on the face or scalp. At puberty, nevus sebaceous may become more elevated; in adulthood, there is an associated risk of basal cell carcinoma.
Treatment of epidermal nevi with electrodesiccation and curettage is often unsuccessful and may cause scarring. Surgical or laser removal may be indicated for localized lesions. Cryotherapy with curettage is useful for thinner lesions. Epidermal nevus syndromes involving other organ systems (e.g., Proteus syndrome, CHILD [congenital hemidysplasia with ichthyosiform erythroderma and limb defects] syndrome, Becker nevus syndrome) must be evaluated and managed appropriately through a multidisciplinary approach.
Tumors of the Epidermal Appendages
There are a large number of benign tumors of the hair follicles, the sebaceous glands, and the apocrine and eccrine glands. Solitary skin tumors of these epidermal appendages are typically nonhereditary, whereas multiple neoplasms may show an autosomal dominant inheritance pattern.7
Sebaceous hyperplasia is a common clinical condition that appears as multiple skin-colored or yellowish, often umbilicated papules or plaques, usually on the forehead, nose, or cheeks of persons after the fifth decade of life. These lesions consist of enlarged sebaceous gland lobules with a central dilated duct. Sebaceous hyperplasia may respond to electrodesiccation, cryotherapy with liquid nitrogen, or the application of a dilute solution of trichloroacetic or bichloroacetic acid. Individual lesions may be excised. Photodynamic therapy using topical 5-aminolevulinic acid and pulsed-dye laser irradiation has resulted in clinical improvement of sebaceous hyperplasia.8 Lesions may sometimes be confused clinically with basal cell carcinoma [see Figure 4]. In the familial form of this disorder, onset occurs in puberty; with the passage of time, the lesions increase in extent over the face, neck, and upper thorax. This condition must be distinguished from acne vulgaris, rosacea, and the angiofibromas of tuberous sclerosis.
Figure 4. Skin-colored or yellowish, often umbilicated papules of sebaceous hyperplasia, as seen on the forehead, may clinically resemble basal cell carcinomas.
Trichoepitheliomas usually present as multiple yellowish-pink, translucent papules distributed symmetrically on the cheeks, eyelids, and nasolabial areas [see Figure 5]. Often inherited as an autosomal dominant trait, the papules first appear at puberty and grow slowly for years. The gene for multiple familial trichoepitheliomas has been mapped to chromosome 9p21.9 Lesions may be confused both clinically and histologically with basal cell carcinoma, though trichoepithelioma usually shows differentiation toward the formation of hair. A single or localized trichoepithelioma may be removed by electrodesiccation and curettage. Multiple lesions are difficult to treat and may be a cosmetic problem. Treatment of multiple trichoepitheliomas with topical imiquimod and tretinoin has been reported to clear lesions without scarring; however, more evidence is required to assess the usefulness of this therapy.10
Figure 5. Symmetrical papules of trichoepithelioma appear on the eyelids and nasolabial areas and may be inherited as an autosomal dominant trait.
Syringomas usually present in groups of multiple small papules that are distributed symmetrically over the face, especially on the lower eyelids [see Figure 6]. Eruptive syringoma, a rare condition, is characterized by widespread lesions. Histologically, there is a benign proliferation of the eccrine ducts.
Figure 6. Syringomas—benign tumors of eccrine ducts—are commonly seen on the face, especially on the lower eyelids.
Commonly called wens, epidermoid cysts have a lining that resembles the epidermis. Several types of cyst exist, but they are usually clinically indistinguishable from one another. On histologic examination, most of these cysts appear to be derived from hair follicles.
The epidermoid cyst is commonly located on the back and consists of one or more slow-growing, elevated, firm nodules, often with a central pore [see Figure 7]. The diameters of the lesions vary from 0.2 to 5.0 cm.
Figure 7. This large epidermoid cyst has a central pore, contains thick keratinous material, and has a lining that resembles the epidermis.
Small, stable epidermoid cysts may be asymptomatic and not require treatment. The epidermoid cyst, when inflamed, may be incised with a pointed scalpel to express its wall and contents, which consist of a thick keratinous material. If the cyst wall is not completely removed, there may be a recurrence of the lesion. Occasionally, the entire cyst has to be excised. Preliminary treatment with a systemic antibiotic, such as erythromycin, and warm-water compresses applied three or four times daily may be instituted if the cyst is inflamed and infected. When the inflammation and infection resolve, the residual lesion can be removed. Repeated episodes of infection may cause fibrosis, after which the cyst may have to be surgically excised.
The pilar cyst, which is less common, has a wall that contains keratin similar to that found in hair. The contents of these cysts are semifluid and often have a rancid odor. A milium is similar to an epidermoid cyst but differs mainly in size. Milia are white, hard subepidermal keratin cysts, 1 to 2 mm in diameter, that commonly arise spontaneously on the face [see Figure 8]. They may also arise secondarily in scars or in association with certain bullous diseases. Incision and expression of contents with a comedo extractor may be performed.
Figure 8. Milia, which are multiple small subepidermal inclusion cysts, can be observed in the periorbital area of this patient.
Familial Tumor Syndromes
Multiple cutaneous neoplasms may be a feature of familial tumor syndromes that are thought to be mediated by inactivation of tumor suppressor genes. It is important to recognize these syndromes because they may be associated with underlying malignancies.
Muir-Torre syndrome (MTS), previously known as Torre syndrome, is an autosomal-dominant disorder characterized by the presence of sebaceous gland neoplasms that are associated with visceral carcinoma and that arise from colonic epithelium. Sebaceous gland tumors may include, in decreasing order of frequency, adenomas, epitheliomas, and carcinomas.11 Keratoacanthomas and sebaceous hyperplasia are also seen in patients with MTS. Colorectal cancer develops in 51% of patients with MTS a decade earlier than it develops in the general population. Genitourinary cancer develops in 24% of MTS patients. A germline mutation in the DNA mismatch repair gene hMSH2 has been identified in patients with MTS. Predictive diagnosis in family members should be preceded by careful genetic counseling.11
Gardner syndrome consists of the triad of intestinal polyposis, bony tumors, and soft tissue lesions; it has an autosomal dominant inheritance. The colonic polyps eventually become malignant if left untreated. Soft tissue lesions include epidermoid cysts, sebaceous cysts, desmoid tumors, and scattered lentigines on the head and extremities.12
Cowden syndrome is characterized by facial trichilemmomas and acral fibromas, and it is associated with an increased risk of cancer of the breast, thyroid, and gastrointestinal tract. This rare genodermatosis, which is also known as multiple hamartoma syndrome, is inherited as an autosomal dominant trait. It is important to make a prompt diagnosis of this syndrome because of the high risk of malignancy, particularly cancer of the breast in women.13
Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant multisystem disorder characterized by the cutaneous triad of fibrofolliculomas, trichodiscomas, and acrochordons; the development of spontaneous pneumothorax in association with lung cysts; and a predisposition to renal neoplasms.14 Fibrofolliculomas, which are the characteristic skin lesions of BHDS, are benign tumors of the hair follicle; they are firm, pink or skin-colored papules measuring 1 to 3 mm that appear on the face, particularly the nose, earlobes, and forehead. In the original kindred described by Birt (a dermatologist), Hogg (a pathologist), and Dubé (a pathologist), family members were afflicted with medullary carcinoma of the thyroid. Subsequently, there appeared reports of patients with BHDS who had intestinal polyps, adenocarcinoma of the colon, parathyroid adenomas, and renal cell carcinoma. The skin tumors begin in early adulthood; systemic tumors appear years later. In families with recognized renal cell carcinoma, BHDS may account for 6% of the cases.15
Melanocytic (Pigment-Forming) Tumors
Benign tumors of pigment-forming cells, including those containing nevus cells (melanocytic nevi) and those of epidermal or dermal melanocytes, are of neuroectodermal origin.
Melanocytic nevus, also called nevus cell nevus, has a characteristic life history of evolution and involution. Melanocytic nevi are the most common of all skin tumors; each young adult has an average of 20 to 40 of them. Their incidence increases with age up to the second or third decade of life, after which they occur less commonly.
Risk Factors for Melanoma
An increase in the total number of melanocytic nevi is a risk factor for melanoma.16 In a study of 716 patients with newly diagnosed melanoma, an increased number of small nevi (25 to 49) was associated with a twofold increase in risk of melanoma, greater numbers of nevi were associated with further increased risk.17 The presence of one clinically dysplastic nevus was associated with a twofold increase in risk of melanoma, and 10 or more, with a 12-fold increase in risk. Criteria for dysplastic nevi included large size (over 5 mm), flatness (entirely macular or having a macular component), and at least two of the following: irregular pigmentation, asymmetry, and indistinct borders [see 2:X Malignant Cutaneous Tumors]. The presence of freckling conferred additional risk of melanoma for all types of nevi.
The relation between sun exposure and melanocytic nevi has been investigated to determine what environmental factors influence melanoma and to facilitate preventive measures. Studies suggest that melanocytic nevi are more common on sun-exposed skin sites and reach a peak incidence earlier in age on these sites than on covered areas of the body.16,18 A study of Australian schoolchildren showed an increasing prevalence of nevi with decreasing latitude, particularly in children 6 and 9 years of age.19 Sun exposure during childhood was considered to be a factor in the development of melanocytic nevi and an associated risk factor for melanoma.19,20 In Australia, however, sun exposure may be sufficient to maximally induce nevi regardless of latitude. Further studies need to be performed on persons living at higher latitudes to see whether the relation between sun exposure and nevi continues into adulthood.
Because melanomas form on skin not exposed to the sun, investigators are exploring what other factors besides sun exposure increase the risk of melanocytic nevi. Maldonado and colleagues studied the distribution of BRAF gene mutations in 115 patients with invasive primary melanomas; their findings indicated that BRAF mutations were significantly more common in melanomas occurring on intermittently sun-exposed skin and rare on chronically sun-damaged skin.21 These findings strongly suggest that distinct genetic pathways lead to melanoma.
A melanocytic nevus that is present at birth or appears during the first year of life is considered to be congenital. Certain syndromes are associated with congenital nevi, including epidermal (linear sebaceous) nevus syndrome, neurocutaneous melanosis, premature-aging syndrome, and occult spinal dysraphism or tethered cord syndrome.22 Various neuroectodermal defects and multisystem abnormalities may also be present. Giant congenital melanocytic nevi are associated with an increased risk of melanoma (see below).
Acquired melanocytic nevi vary considerably in form, ranging from flat to pedunculate. They may be hairy or hairless and may be skin colored, dark brown, or even black. Nevi that are flat and darkly pigmented are called junctional nevi. Slightly raised nevi are often compound; that is, they contain both epidermal and dermal components. Nevi that are predominantly intradermal are usually more elevated and contain less pigment than compound or junctional nevi. Nevi that are papillomatous, dome shaped, or pedunculate are usually intradermal [see Figures 9,10,11].
Figure 9. A flat junctional nevus with dark pigmentation is seen in this patient.
Figure 10. This slightly raised compound nevus typically has less pigmentation than a junctional nevus.
Figure 11. A skin-colored intradermal nevus with a dome-shaped configuration is seen on the face.
The differential diagnosis of benign melanocytic nevi includes ephelis (freckle), lentigo, café au lait spot (see below), wart, seborrheic keratosis, and skin tag (a small pedunculate protrusion of skin that does not contain nevus cells). Ephelis is a tan macule, commonly seen in children after sun exposure; it often disappears in the winter. Lentigo, also called senile lentigo or liver spot, is a tan or brown macule commonly seen on exposed skin areas, such as the face, the backs of the hands, and the neck. The labial melanotic macule is a distinct entity that appears in adults as a well-defined brown or black-pigmented macule on the lip. In a study of 79 patients, the majority of melanocytic lesions (94%) were on the central third of the lower lip, suggesting that exposure to ultraviolet light has a causative role.23Patients followed for up to 13 years had no adverse developments, a finding indicative of the benign nature of this lesion.
No treatment is required for melanocytic nevi. However, shave biopsy or excisional biopsy may be performed for cosmetic reasons or when a nevus is subject to irritation because of pressure from clothing or because it is located in an intertriginous area. Patients should be followed with serial photographs. Biopsy should be performed for nevi that appear prone to malignant transformation; nevi that show severe dysplasia should be removed. Removal of mildly or moderately dysplastic nevi is advocated by some but not all experts [see 2:XI Malignant Cutaneous Tumors].
CAFÉ AU LAIT SPOTS
Café au lait spots are common benign congenital or acquired birthmarks. They are tan, round to oval macules ranging in size from several millimeters to 10 to 20 cm. They can occur on any area of the body but are more common on the trunk, buttocks, and lower extremities. The presence in a prepubertal child of five or more café au lait spots larger than 0.5 cm may be a marker for neurofibromatosis-1 (NF-1) (see below).24 Histologically, café au lait spots show an increased number of dihydroxyphenylalanine (DOPA)-positive melanocytes that produce an increased concentration of melanosomes. The café au lait spots that are seen in Albright hereditary osteodystrophy are usually unilateral and show jagged rather than smooth margins. Some reports suggest that an association of juvenile xanthogranulomas with café au lait macules carries an increased risk of underlying systemic disorders, including leukemia25; however, other studies have reported no evidence of hematologic malignancy in these patients.26
A halo nevus consists of an acquired zone of hypopigmentation surrounding a pigmented tumor, most commonly a compound nevus [seeFigure 12]; other tumors, even malignant melanoma, may also be surrounded by a depigmented halo. The halo lesion typically involutes during a period of months in the absence of clinical signs of inflammation. Histologically, a chronic lymphocytic infiltrate surrounds the nevus cells, which may represent an autoimmune phenomenon.
Figure 12. The halo nevus may represent an autoimmune phenomenon; a zone of hypopigmentation may appear around a nevus, with subsequent involution of the pigmented tumor.
SPINDLE CELL NEVUS
Formerly called benign juvenile melanoma, spindle cell nevus usually arises in childhood as a pink or reddish-brown, smooth or slightly scaly, firm papule with a predilection for the face, especially the cheeks [see Figure 13].27 Although benign, spindle cell nevus may closely resemble a malignant melanoma. Excisional biopsy is therefore advisable in many cases.
Figure 13. The spindle cell nevus is an active compound nevus that may be difficult to distinguish histologically from a melanoma.
The mongolian spot is a bluish macule that is seen in newborns of dark-skinned races. The discoloration is caused by persistence of dermal melanocytes, often in the lumbosacral region [see Figure 14]. The lesion usually disappears by 3 or 4 years of age.
Figure 14. The bluish pigmentation of a mongolian spot is seen in the lumbosacral area and is caused by the persistence of dermal melanocytes.
The common blue nevus occurs as a solitary, sharply circumscribed, blue-black papule [see Figure 15]. This malformation consists of a group of melanocytes with long, thin surface projections in the middle and lower thirds of the dermis and in subcutaneous fat. The common blue nevus does not show a tendency toward malignant transformation. The cellular blue nevus, which appears as a blue-black nodule or an indurated plaque, contains two types of cells: spindle shaped and rounded. The cellular blue nevus may in rare instances become malignant.
Figure 15. The presence of melanocytes in the middle and lower dermis is responsible for the color of the blue nevus.
NEVUS OF OTA
The nevus of Ota occurs in infancy or appears in adolescence as a blue-gray macule in the distribution of the trigeminal nerve. The lesion is unilateral in 90% of cases. Asian females are most commonly affected. Histologically, a benign dendritic melanocytosis is present in the papillary and upper reticular dermis. High-energy fluences of the Q-switched ruby laser results in lightening of the lesion, without scarring, after a few treatments.28 A combination of the Q-switched 532 nm neodymium:yttrium-aluminum-garnet (Nd:YAG) laser and a Q-switched 1,064 nm Nd:YAG laser has been reported to be more effective than the 1.064 nm laser alone for the treatment of nevus of Ota.29
A malformation of epidermal melanocytes, Becker nevus occurs as a large area of hyperpigmentation and increased hair growth and is usually located on one shoulder. It appears most commonly in males during adolescence [see Figure 16]; however, cases with associated lipoatrophy are more frequently reported in women. Reports of atypical Becker nevus indicate that the clinical spectrum of Becker nevus may be greater than commonly thought.30 Underlying bony and soft tissue abnormalities may be associated with this disorder.31
Figure 16. Becker's nevus, an acquired localized malformation of epidermal melanocytes that may be associated with hypertrichosis, is seen on the shoulder.
Light microscopy reveals hyperpigmentation of the basal layer of the epidermis, with melanin-containing phagocytes in the dermis but no nevus cells.
CONGENITAL PIGMENTED NEVUS
Giant pigmented nevus is an uncommon birthmark appearing sporadically in one in 20,000 live births. Its features are different from those of an ordinary, acquired nevus. Lesions are often darkly pigmented, hairy, and slightly infiltrated, eventually becoming verrucous or nodular. They tend to occur in the distribution of a dermatome and may be quite extensive, as in bathing trunk nevus [see Figure 17]. Satellite lesions may be present. The condition not only is of cosmetic concern but also has a high association with malignant melanoma, with a reported 10% to 15% of nevus patients developing melanoma.32 Histologic features of an ordinary compound nevus, an intradermal nevus, a neural nevus, or a blue nevus may be present.1 Treatment consists of multiple operations to excise as much of the lesion as possible.
Figure 17. This form of congenital giant pigmented hairy nevus is associated with an increased risk of malignant melanoma, which develops within the lesion.
Lesions on the scalp and neck may be associated with neurocutaneous melanosis of the leptomeninges that can be complicated by epilepsy, mental retardation, or central nervous system melanoma. Large congenital melanocytic nevi (LCMN) carry a poor prognosis in the presence of CNS signs or symptoms such as abnormal reflexes, hydrocephalus, and papilledema. Posterior axial LCMN, especially in association with satellite nevi, is a risk factor for CNS melanosis. Magnetic resonance imaging should be considered in the evaluation of newborns with these findings. In one study, CNS involvement occurred in 33 of 289 patients with LCMN. All the patients with CNS involvement had nevi in the posterior axial location. Satellite nevi were present in 31 of the 33 patients.33 These findings suggest that melanocytic malformation occurs during the migration of neural crest cells that give rise to cutaneous leptomeningeal melanocytes. Malformation resulting in LCMN on the extremities occurs after migration from the neural crest and is not associated with CNS melanosis.
Neural tumors, such as neurofibromas, are of neuroectodermal origin, as are melanocytic tumors. Neurilemmomas (also called schwannomas) are benign nerve sheath tumors that extend subcutaneously adjacent to a peripheral nerve. They usually occur in solitary form but may occur as multiple lesions in the syndrome of neurilemmomatosis.34 These tumors are usually painful and may be associated with nerve compression. Other benign tumors that must be considered in the differential diagnosis of painful skin nodules are neuromas, angiolipomas and angiomyolipomas, leiomyomas, eccrine spiradenomas, glomus tumors, and the blue rubber bleb nevus.
Neurofibromatosis represents a spectrum of disorders involving the skin, central and peripheral nervous systems, bones, and blood vessels. This neurocutaneous syndrome is transmitted via an autosomal dominant gene at an estimated frequency of one in 3,000 persons with almost complete penetrance.35
Two distinct forms of neurofibromatosis are recognized, but variant forms also exist.
The most common form (occurring in 85% to 90% of all cases) is NF-1, or von Recklinghausen disease [see Figure 18]. This is a common autosomal disorder, with an incidence of one in 2,600 to one in 3,000 persons.36 Mutations in the NF1 gene result in loss of functional protein, causing the wide spectrum of clinical findings, including NF1-associated tumors. NF-1 is characterized by the presence of café au lait spots, intertriginous freckling, multiple spinal and peripheral neurofibromas, plexiform neuromas, bilateral iris hamartomas (also known as Lisch nodules), neurologic impairment, and bone abnormalities. The disease is progressive and is associated with a predisposition to a malignant state.
Figure 18. Multiple neurofibromas, as seen in von Recklinghausen's disease, usually appear in late childhood and increase in size and number with age.
Sarcomatous degeneration of skin lesions is rare but may occur in extracutaneous tumors. Café au lait spots of NF-1 may be present at birth and may be best visualized under a Wood light. Neurofibromas begin to appear at puberty as soft, globoid, and pedunculated tumors that are skin colored or violaceous. Lesions may be large and numerous, causing complications resulting from impingement on surrounding structures.
A diagnosis of NF-1 can be established in most patients by the age of 6 years on the basis of routine physical examination, with special attention given to the disease-associated cutaneous features.36 Patients with NF-1 develop both benign and malignant tumors at increased frequency throughout life.37 Optic pathway gliomas are the predominant type of intracranial neoplasms; however, other central CNS and non-CNS tumors can occur.
A second form of the disease, neurofibromatosis-2 (NF-2), is characterized by bilateral acoustic neuromas, which are Schwann cell tumors that arise from vestibular nerves.38 Associated features may include meningiomas, gliomas, paraspinal neurofibromas, and subcapsular cataracts. Skin tumors and café au lait spots are less commonly seen in NF-2 than in NF-1. NF-2 has been attributed to inactivating mutations in the NF2 tumor suppressor gene, whose product, merlin, plays a number of roles in tumorigenesis.39
Other forms of neurofibromatosis include segmental cases in which café au lait spots or neurofibromas are localized to a single dermatome.
Patients with either NF-1 or NF-2 should seek genetic counseling because there is a 50% risk that their offspring will also be affected with neurofibromatosis. In NF-1, optic glioma can appear in early childhood; patients with NF-1 may also have scoliosis. In NF-2, bilateral acoustic neuromas can cause deafness. The genes for the two distinct forms of neurofibromatosis have been located on two separate chromosomes. This finding may lead to improved diagnosis, which would facilitate genetic counseling and enable prenatal testing.38
For treatment of selected neurofibromas, surgery, radiation, and, in rare instances, chemotherapy are the major treatment modalities employed. Surgical excision is more successful than scalpel removal or electrodesiccation and curettage.40 For patients who are not candidates for surgical resection or in whom only a partial resection is possible, fractionated radiation therapy or stereotactic radiosurgery may be used to treat tumors.
The bilateral acoustic neuromas of NF-2 may be visualized by computed tomography or MRI. Hearing loss is an early symptom that may begin in the second or third decade of life; it can be detected by an audiologic study with brain stem auditory-evoked response. Unilateral acoustic neuromas that are not associated with neurofibromatosis and that are not inherited are more common in older persons and pose fewer management problems.38 Surgical removal of small acoustic neuromas may improve neurologic or audiologic status.
Connective Tissue Tumors
Fibroma of the skin comprises multiple conditions that may represent reactions to hemorrhage, infection, or chronic irritation.
Skin tag, also called acrochordon, commonly occurs as multiple skin-colored or tan, filiform or smooth-surfaced papules that are 2 to 3 mm in diameter. Lesions are often located on the neck or axillae but may also appear in the groin or on the extremities, often as isolated larger polypoid growths [see Figure 19]. The fibrous stalk consists of loose connective tissue with dilated capillaries. Lesions may become inflamed if they are irritated or are traumatized from twisting of the stalk. Biopsy is performed if the clinical diagnosis is uncertain. Skin tags may be removed for cosmetic reasons by using scissors to clip the pedunculate lesions at the base.
Figure 19. Skin tags, also called acrochordons or soft fibromas, are skin-colored or tan papules. They are commonly seen in such intertriginous areas as the groin or axillae.
Dermatofibroma, also called histiocytoma, is a firm, skin-colored or reddish-brown sessile papule or nodule that arises spontaneously or after minor trauma, usually in adults [see Figure 20]. A dermatofibromatous lesion may occur, for example, after an insect bite on an extremity. A solitary lesion is most common, though multiple or eruptive histiocytomas have been reported. It may be necessary to perform a biopsy when the diagnosis is uncertain. Treatment is necessary only for cosmetic reasons.
Figure 20. Dermatofibroma appears as a firm skin-colored or reddish-brown papule and may arise spontaneously or follow minor trauma to the skin.
KELOID AND HYPERTROPHIC SCAR
Normal wound healing in response to tissue injury involves several integrated processes: inflammation, production of granulation tissue, formation of the extracellular matrix, wound contraction, and, finally, scar formation. In the final phases of wound healing, fibroblasts degrade and produce bundles of collagen fibers. These bundles become thicker and are aligned along the lines of tension to which the tissues are exposed. As a result of these changes, wound tensile strength gradually increases. The resulting scar is relatively acellular and has fewer macrophages, blood vessels, and fibroblasts than the unwounded tissue.
Scars may be normotrophic, atrophic, hypertrophic, or keloidal. Both hypertrophic and keloidal scars are abnormal responses to tissue injury. Hypertrophic scars mature and flatten over time, usually after 6 months. The keloid appears as a shiny, smooth, raised proliferation of scar tissue with typical crablike extensions beyond the site of the original injury [see Figure 21]. Keloids differ from hypertrophic scars in that their development is delayed, sometimes occurring months after tissue injury. Keloids do not regress, and they frequently cause pain, itching, and burning. Keloids are more common in African Americans, Hispanics, and persons with a personal or family history of keloids. Other factors associated with the development of keloids include wound tension, especially in skin sites such as the chest, shoulders, and back; ear piercing; healing by second intention; pregnancy; young age; and deep laceration.41
Figure 21. The proliferation of scar tissue in a keloid may extend beyond the original site of injury.
In atrophic scars, there is thinning of the skin and loss of normal architecture. Striae distensae, a so-called stretch mark, is a common dermal atrophic scar that tends to appear during periods of rapid weight gain and in the presence of excess glucocorticoid, as well as late in gestation.
Treatment with intralesional corticosteroids, 10 to 40 mg/ml once a month for up to 6 months, can effectively flatten keloid and hypertrophic scars. A systematic review found that injection of intralesional corticosteroid resulted in flattening of keloids in up to 70% of patients, although the recurrence rate was high in some studies.42 Potential side effects of intralesional corticosteroid treatment include atrophy, depigmentation, telangiectasia, ulceration, and dose-related systemic effects.
Cryotherapy (a 30-second application once a month for 3 months) has been found to be safe and effective43; it may prove particularly useful in combination with intralesional corticosteroid injection.44 Topical silicone gel sheeting, which was first used for burn scars, has been used in the treatment of keloids and hypertrophic scars; however, a meta-analysis of 13 trials found that there was weak evidence that silicon gel sheeting provides benefit as treatment for hypertrophic and keloid scarring.45 Medical treatment for keloid and hypertrophic scarring includes corticosteroids, 5-fluorouracil, and imiquimod.46
Vascular proliferations are broadly classified as hyperplasias that show a tendency to regress or as benign vascular tumors that persist.47,48Vascular hyperplasias include pyogenic granuloma and pseudo-Kaposi sarcoma. Vascular hemangiomas are proliferating vascular tumors that are not necessarily present at birth [see Hemangiomas, below]. Hemangiomas can be subdivided according to their histologic cell of origin (endothelial cell, pericyte, glomus cell), depth of tissue involvement (superficial or deep), and size of involved vessels (capillaries, venules, arterioles, veins, or arteries). Vascular birthmarks such as nevus flammeus and salmon patch may resemble angiomas but are nonproliferative malformations that usually do not involute [see Vascular Malformations, below].
Hemangiomas occur in a female-to-male ratio of 5:1, whereas vascular malformations occur with equal frequency in males and females. A rare familial occurrence of hemangiomas, vascular malformations, or both has been reported in six kindreds, suggesting autosomal dominant inheritance in these cases.49 Vascular malformations are congenital developmental defects that are generally of unknown etiology. Port-wine stains are the most common vascular malformations, occurring in one in 1,000 people. Most port-wine stains are isolated anomalies, but they may be associated with developmental defects, such as the Klippel-Trenaunay and Sturge-Weber syndromes.
The etiopathogenesis of hemangiomas and vascular malformations is not well understood. Hemangiomas arise in response to an angiogenic stimulus that may begin in utero. Through use of immunohistochemical techniques, infantile hemangiomas and placental microvessels were found to coexpress the vascular antigens GLUT-1 and Lewis Y antigen (LeY).50 These antigens are not present in other vascular tumors, such as pyogenic granulomas, or in vascular malformations. A pathogenic link involving aberrant differentiation of vascular precursor cells or embolization of placental cells to fetal tissue has been hypothesized.50 These antigens are also absent in congenital nonprogressive hemangioma, a distinctive hemangioma consisting of lesions that are fully formed at birth and that either remain static or rapidly involute.51
OVERVIEW OF MANAGEMENT
Evaluation and management of hemangiomas and malformations require a multidisciplinary approach. Specific diagnosis may be aided by imaging techniques such as CT and MRI to assess depth of involvement and extension to adjacent structures and to evaluate associated abnormalities. Laboratory evaluation for associated systemic disease may be required in addition to ophthalmologic, neurologic, and cardiologic assessment for complications of vascular tumors and dysmorphic syndromes.
The biologic classification of hemangiomas is very different from that of vascular malformations. Vascular tumors can be classified according to their cell of origin, the size of the involved vessels, and the depth of involvement. Such classifications have led to refinement in terminology.52 The terms strawberry hemangioma and cavernous hemangioma are descriptive clinical terms that do not specify the type of vessels that are involved.
The vascular lesion may appear in neonates as a faint pink patch that subsequently undergoes rapid proliferation over a period of months to years before the lesion stabilizes and regresses.
Capillary hemangioma, also known as strawberry hemangioma, appears as a single vascular lesion or multiple lesions during the second to the fifth week of life. Infantile hemangiomas are bright-red, soft, lobulated tumors that increase in size for a period of months [see Figure 22]. Lesions spontaneously involute, sometimes with fibrosis, over a period of several years.47 Histologically, the capillary hemangioma shows a proliferation of endothelial cells that form many new small vessels.
Figure 22. The strawberry, or capillary, hemangioma appears between the second and fifth weeks of life and undergoes spontaneous involution over a period of several years.
It is important to realize that most hemangiomas are uncomplicated and regress without treatment early in life with minimal residual scarring. Parents may require considerable reassurance that the best course is to refrain from treatment.53 Care must be taken to prevent trauma and infection, which may lead to scarring.
There is considerable controversy as to when to intervene in the treatment of complicated hemangiomas because of potential side effects, such as scarring. The ideal time to treat would be at the beginning of the period of rapid growth, but this is difficult to predict. Indications for treatment include involvement of a vital orifice, infection, ulceration, ocular involvement, and severe cosmetic deformity.
Medical options for the treatment of hemangiomas include intralesional or systemic corticosteroids, the latter at a dose of 1 to 3 mg/kg/day. Antimetabolites have been used for their antiproliferative effect. Interferon alfa has been used to treat severe hemangiomatosis, but its use is associated with systemic side effects and the potential risk of spastic diplegia. Laser surgery with 585 nm pulsed dye laser may be used to treat the superficial proliferative component of the hemangioma; however, early therapeutic intervention with laser therapy may not prevent proliferative growth of the deeper or subcutaneous component.54
Radiation therapy may lead to scarring. In addition, radiation therapy is discouraged in children because of long-term radiation effects, including risk of malignancy. Interventional techniques involving embolization of vessels may be required in cases involving airway obstruction or other life-threatening complications. A multidisciplinary team approach involving the dermatologist, a pediatrician, a radiologist, a surgeon, and other specialists is needed for optimal management of complicated cases.55
Vascular malformations are usually present at birth. They are permanent or progress in the form of ectasias but do not proliferate. Vascular malformations may be subdivided into the following groups: venous, lymphatic, combined arteriovenous, and capillary (such as port-wine stain).56 Dysmorphic syndromes such as Sturge-Weber and Klippel-Trénaunay syndromes are more commonly associated with vascular malformations than with hemangiomas.
The salmon patch, one of the most common vascular birthmarks, is a dull-pink macule that appears on the nape of the neck, central forehead, or eyelids. Although the salmon patch is sometimes classified as a nevus flammeus, it is distinguished from the latter by its tendency to fade in early life. The salmon patch is caused by the persistence of fetal capillary ectasia in the dermis.47
Port-wine stain, also called nevus flammeus, appears at birth as a reddish or violaceous macular discoloration, usually in a unilateral, segmental distribution [see Figure 23]. Mature dilated capillaries are present in the dermis. After puberty, nevus flammeus lesions may become thickened and nodular or papular. There is little tendency toward involution. Nevus flammeus lesions may be associated with abnormalities of the larger vessels and with neurologic manifestations.
Figure 23. A nevus flammeus is present at birth as a reddish or violaceous macular discoloration, often in a unilateral and segmental distribution; it shows little tendency to involute later in life.
A facial port-wine stain that involves the skin innervated by the first branch of the trigeminal nerve is a feature of the Sturge-Weber syndrome, a rare congenital vascular disorder (also known as encephalotrigeminal angiomatosis). Other features of the Sturge-Weber syndrome include ipsilateral congenital glaucoma and contralateral seizures caused by leptomeningeal angiomatosis. Ophthalmologic and neurologic evaluation may be warranted in patients with the Sturge-Weber syndrome.
The triad of findings seen in Klippel-Trénaunay syndrome includes a port-wine stain, usually in a patchy distribution on the involved extremity; varicose veins; and soft tissue or bony hypertrophy. The most common site of involvement is the lower leg; the next most common sites of involvement are the arms and trunk.51 One study indicated that the morphologic characteristics of port-wine stains may have importance in identifying lymphatic disease and risk of complications in patients with Klippel-Trénaunay syndrome.57 Patients with sharply demarcated geographic stains had greater evidence of lymphatic disease and increased risk of complications than patients with blotchy, poorly demarcated stains.
Formerly referred to as cavernous hemangiomas, vascular malformation consists of a collection of abnormal veins and venous pouches that commonly occur around the head and neck but can occur anywhere on the body. They are frequently multiple or have satellite lesions. Superficially, they appear as a subcutaneous swelling with a bluish hue on the skin surface or mucous membrane. Deeper components may be invisible on clinical examination. Lesions enlarge for several months, become stationary for an indefinite period, and spontaneously resolve.
Because vascular malformations do not proliferate, treatment may be cosmetic and can be postponed to later in life. However, a multidisciplinary approach is needed to treat potential complications of vascular malformations associated with dysmorphic syndromes. Salmon patch tends to fade in early life and usually requires no treatment.
Treatment of port-wine stains by excision, tattooing, ionizing radiation, cryosurgery, or dermabrasion is largely unsatisfactory. Use of the argon laser has resulted in lightening of vascular lesions; however, there is wide variability in the response to argon laser therapy. The effectiveness of this treatment results from the selective absorption of the monochromatic 585 nm laser light by red hemoglobin pigment, which produces thermal energy with resultant photocoagulation of tissue.58 Thinner lesions are more responsive than thicker lesions that have undergone progressive vascular ectasia. In a study of 100 patients of different age groups who had port-wine stains of the head and neck and who were treated with a flashlamp pulsed dye laser, treatment was no more effective when given in early childhood than when given at a later date.59
Acquired Vascular Disorders
Spider angioma, also called spider nevus or arterial spider, appears as a central red punctum from which fine vessels radiate; the appearance of the lesion is suggestive of a red spider [see Figure 24]. The central arteriole may be pulsatile. These telangiectasias (dilated capillaries) are commonly seen on the face, neck, trunk, and upper extremities and occur most commonly in middle-aged or elderly persons. They may arise spontaneously or in association with pregnancy or hepatic dysfunction.56 Spider angiomas may be treated with laser therapy for cosmetic purposes.
Figure 24. A spider angioma, which has a central arteriole from which fine vessels radiate, blanches with pressure.
Acquired unilateral telangiectatic nevi are uncommon; those that have been reported resulted from mechanical or physical trauma, including sun damage.60
Cherry angioma, also called senile angioma, appears as multiple bright-red, soft, dome-shaped papules on the trunk of middle-aged or older persons. Trauma produces slight bleeding. Electrodesiccation may be performed for cosmetic purposes.
Pyogenic Granuloma and Other Vascular Tumors
The pyogenic granuloma is a soft red lesion that is solitary, raised, and nonpulsatile; it often appears after minor skin trauma, such as a puncture wound. Other predisposing factors include hormonal effects, infection, viral oncogenes, microscopic arteriovenous anastomoses, and growth factors.61 Epulis gravidarum is a variant of a pyogenic granuloma. The lesion was formerly believed to be caused by a pyogenic infection of a small wound; histologically, however, an early lesion resembles a capillary hemangioma. The thin, sometimes verrucous epidermis is friable and apt to become eroded or ulcerated. Lesions rapidly reach a size of 1 to 2 cm and then remain static. Common sites of involvement are the fingers, feet, and face [see Figure 25]. Biopsy is performed to rule out malignant tumors, such as Kaposi sarcoma and amelanotic melanoma.
Figure 25. The pyogenic granuloma, which may show a smooth, verrucous, eroded, or friable surface, may be confused with a malignant tumor.
Other benign tumors with a vascular component include angiofibroma, angioleiomyoma, and angiolipoma. Some of these can be painful. The differential diagnosis of painful skin tumors includes glomus tumor, angiolipoma, angioleiomyoma, neuromas, and eccrine spiradenoma.48Lesions are usually easily removed by electrodesiccation and curettage. If they recur or if satellite lesions appear after such treatment, excisional biopsy is recommended.
Kimura disease and angiolymphoid hyperplasia with eosinophilia are rare tumors of unknown cause that occur mainly on the head and neck in young adults and may resemble pyogenic granuloma.62 Kimura disease, which was first reported in Korea, is most common in Asians. It appears as a granulomatous proliferation of lymphoid tissue that may be accompanied by peripheral eosinophilia and contiguous lymphadenopathy. Lesions may occasionally be seen on the trunk, extremities, and genitalia in addition to the head and neck. Angiolymphoid hyperplasia with eosinophilia, which may or may not represent a different disease, appears as localized single or multiple nodules. Infectious, allergic, hormonal, and traumatic mechanisms have been postulated. Immunodermatopathologic studies suggest an unusual distribution of adhesion molecules, IgE, and CD23 in these angioproliferating tumors.63
The lipoma, which is a soft, rounded to lobulated subcutaneous tumor of mature fat cells, is commonly seen on the trunk, neck, or forearms. Lesions are rubbery in consistency and are freely movable under the overlying skin, which appears normal. There may be a single lesion or multiple lesions, and they are usually asymptomatic unless they impinge on a nerve. Lipomas are of variable size and grow slowly. Histologically, the tumors are usually encapsulated and show fat cells that are indistinguishable from normal adipose tissue. Admixture of other tissue components may result in fibrolipomas (fibrous tissue), angiolipomas (blood vessels), and myolipomas (smooth muscle). Excision may be performed for cosmetic reasons. If a lesion grows rapidly, biopsy should be performed, though lipomas rarely become malignant.
The leiomyoma is an uncommon tumor of smooth muscle that appears as a single brownish-red papule or as multiple papules or small nodules, which are sometimes painful [see Figure 26]. Leiomyomas may arise from the arrector pili (the smooth muscle attached to the hair follicle sheath) or from the smooth muscle surrounding cutaneous blood vessels (angioleiomyoma). Painful lesions can be excised.
Figure 26. Leiomyomas are sometimes painful papules that arise from smooth muscle of blood vessels or the arrector pili.
Lymphangioma circumscriptum is characterized by groups of persistent localized or diffuse translucent vesicles. Indications for treatment include severe cosmetic problems, persistent leakage of lymphatic fluid or blood, and recurrent infection. The vesicles frequently recur after surgery, radiotherapy, electrocautery, or cryosurgery because of the persistence of deep lymphatic cisterns. Carbon dioxide laser in a vaporization mode has been used to ablate superficial cutaneous lesions in patients with lymphangioma circumscriptum.64 The major advantage of this technique is that it may reduce the frequency of recurrences because it seals the communicating channels to the deeper cisterns by vaporizing the superficial lymphatics. Sclerotherapy has been reported as useful in the treatment of cutaneous lesions in patients with lymphangioma circumscriptum.65
Editors: Dale, David C.; Federman, Daniel D.