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Section XXVIII Skin Diseases
| 466 URTICARIA, DRUG HYPERSENSITIVITY RASHES, NODULES AND TUMORS, AND ATROPHIC DISEASES Madeleine Duvic • |
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▪URTICARIA
Definition and Epidemiology
Urticaria, also known as hives, is one of the most common cutaneous reaction patterns (Fig. 466-1). It is triggered by a wide variety of antigens—internal or external—or by physical stimuli, including but not limited to cold, pressure, and sunlight (Chapter 273; Table 466-1).
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| FIGURE 466-1 Urticaria. (From dermnetnz.org/reactions/urticaria.html.) |
Urticaria is typically transient and self-limited, without leakage of blood cells into the skin or damage to the blood vessels. Chronic urticaria, defined as urticaria that recurs over a period of 6 weeks or more, is often of unknown cause. Chronic urticaria can be related to the ingestion of aspirin or agents that cross-react with salicylates, such as sodium benzoate (a common food preservative) or tartrazine (yellow dye #5). The number of mast cells has been found to be increased in the gastrointestinal tract of individuals with chronic urticaria, even in absence of gastrointestinal symptoms.
Pathobiology
Urticaria can be due to allergic IgE-mediated type I hypersensitivity reactions or to non–immunologically mediated physical factors. Local degranulation of mast cells with the release of histamine and other factors, such as slow-reacting substance of anaphylaxis, precipitates urticaria. Injections of corticotropin-releasing hormone (CRH) and acute stress cause degranulation of mast cells and increased vascular permeability, mediated through activation of CRH receptor 1 and mast cell histidine decarboxylase, both of which are elevated in the skin of patients with chronic urticaria. As a result of transient leakage of plasma into the dermis from capillaries and small postcapillary venules, a demarcated, pink, raised lesion (hive) develops. Larger raised plaques or annular forms (giant urticaria) and deep tissue swelling (angioedema) are less frequent manifestations.
Clinical Manifestations
Individual urticarial lesions are pink to light red, blanch with pressure, and are raised above the surface of the skin. The center of the lesions may be paler than the leading edge. A mosquito bite (Chapter 274) is an archetypal urticarial lesion. Individual hives can coalesce into giant plaques or annular rings called giant urticaria; such lesions are found especially in serum sickness (Chapter 44), where they are accompanied by arthralgias and fever. Confluent urticaria may also be accompanied by swelling of the underlying soft tissue or the mucous membranes (angioedema), as well as by anaphylaxis with laryngeal edema (Chapter 274), a life-threatening emergency. In otherwise normal individuals, pressure or writing on the skin will cause spontaneous local release of histamine, which induces a wheal and flare reaction known as dermatographism.
Other physical stimuli such as cold, heat, sun, or exercise may induce urticaria. Cold urticaria may be precipitated by putting an ice cube on the skin; the interval until hives develop and the duration of the hives correlate with the severity of the condition, which can be life-threatening if the patient is suddenly immersed in cold water. Heat, exercise, or exertion may be accompanied by small, 2- to 3-mm urticarial lesions or cholinergic urticaria. Exercise-induced anaphylaxis may be hereditary, but the defect is unknown. Cases of urticaria caused by exposure to the sun (solar urticaria) or to water (aquagenic urticaria) are less common forms of physically induced urticaria. By comparison, pruritus without detectible lesions represents the mildest expression of urticarial reactions.
Diagnosis
Urticaria typically results from exposure to antigen only minutes to a few hours before onset of the lesions. In many cases, pruritus may proceed onset of the rash or be the major feature. The most common triggers of IgE-mediated allergic urticarial reactions are drugs (especially penicillin, sulfa drugs, antibiotics, and contrast dye), foods (shellfish, salicylates in berries, tomatoes, yeast, and penicillin in blue cheese), food additives (sodium benzoate), nuts (especially peanuts), or insect bites (mosquitoes, bees, wasps, scabies, or animal mites). Nonimmunologic mediators of urticaria include aspirin and opiates, as well as physical agents that work through the prostaglandin pathway or degranulate mast cells.
Acute urticaria can also be triggered by skin contact with an antigen, such as latex, and can progress to anaphylaxis. In addition, urticaria can be a sign or prodrome of a latent infection, especially streptococcal pharyngitis in children or viral hepatitis in adults. The migratory urticarial rash accompanying rheumatic fever, erythema marginatum (Fig. 466-2), is characterized by evanescent, scalloped lesions that change location over the course of hours.
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| FIGURE 466-2 Erythema marginatum. (From http://www.medscape.com/content/1998/00/41/73/417394/art-m5649.fig2.jpg.) |
When urticarial lesions are present for more than 24 hours, underlying urticarial vasculitis should be suspected. Skin biopsy is required to distinguish urticarial vasculitis from urticaria in which no damage to the blood vessels is evident. Erythema multiforme (Chapter 465), most commonly precipitated by herpes simplex infections, other DNA viruses, or drugs, is characterized by lesions that are hybrids between urticaria and vasculitis. Erythema multiforme lesions are known as target or bull's-eye lesions and have deep red centers and pink urticarial rims (see Fig. 465-10). When vascular damage or purpura is present, the lesion is termed leukocytoclastic vasculitis, the most severe expression of hypersensitivity reactions involving cutaneous blood vessels (see Fig. 465-4).
Chronic urticaria can be caused by occult infections (sinusitis, gallbladder disease, Helicobacter pylori, yeast infections, tooth abscesses, or silent hepatitis), as well as by collagen vascular diseases and tumors, especially Hodgkin's lymphoma. Deficiency of the C1 esterase inhibitor can be manifested as chronic urticaria with angioedema (Chapter 273). Although a thorough medical evaluation may aid in diagnosis, the cause of chronic urticaria may remain uncertain. In the absence of a known antigen, stress is often invoked as the underlying cause of chronic recurrent idiopathic urticaria.
Systemic mastocytosis (Chapter 276) may be accompanied by urticarial lesions, as well as gastrointestinal symptoms. In the form of mastocytosis known as urticaria pigmentosa, stroking the lesions produces urticaria, known as Darier's sign.
Treatment
Management of urticaria depends on its severity and the duration of the problem (Chapter 273). For mild urticaria limited to the skin, traditional antihistamines (diphenhydramine [Benadryl], hydroxyzine) or the newer nonsedating agents (terfenadine [Seldane], cetirizine [Zyrtec], loratadine [Claritin]) can be administered by mouth intermittently as needed (Table 466-2). Acute urticaria is often treated with diphenhydramine, 25 to 50 mg orally; if the urticaria is severe, short-term corticosteroids, up to 1 mg/kg, can be used. For urticaria associated with wheezing or anaphylaxis, subcutaneous epinephrine and intravenous corticosteroids, as well as oxygen, should be administered immediately.
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Finding the cause plus removing the antigen of chronic recurrent urticaria is highly preferable to recurrent or chronic administration of corticosteroids or antihistamines. The patient should avoid aspirin compounds and other drugs that could be the cause. The cyclooxygenase inhibitor montelukast (10 mg/day) may also help patients with aspirin-induced urticaria. Allergy testing is recommended if the history is unrevealing (Chapter 270). If lesions remain present for more than 24 hours, skin biopsy is indicated to determine whether vasculitis or mastocytosis is present. If infection, collagen vascular disease, or a tumor is suspected, a full serologic evaluation should be undertaken.
▪DRUG RASHES
Definition
Drugs have been associated with every type of cutaneous reaction pattern ranging from mild and self-limited to severe and life-threatening (see Table 27-5).
Pathobiology
Delayed hypersensitivity reactions are due to T-lymphocyte infiltrates, with or without eosinophils. Helper T cells are more abundant, but CD8+ suppressor cells that express granzyme B and perforin are implicated in keratinocyte damage. Peripheral eosinophilia, which is induced by interleukin-5 and eotaxin, can also occur.
Clinical Manifestations and Diagnosis
A careful drug history is critical. Most drug rashes are either immediate (urticaria) or delayed hypersensitivity reactions (exanthems). Immediate reactions such as pruritus, hives, angioedema, and anaphylaxis occur within minutes to a few hours after the drug is taken (see earlier). The most common drug-related rash (Table 466-3) is a macular, bright pink to salmon-colored exanthem that appears as early as 7 to 10 days and as late as 14 days after a drug is first administered. Delayed hypersensitivity reactions can be macular or papular exanthems (or both), morbilliform eruptions, annular erythemas, or confluent erythema (Fig. 466-3). Once sensitization to a particular drug has occurred, readministration of the same drug may trigger an eruption within 24 to 72 hours. Drug hypersensitivity reactions are typically very symmetrical. They characteristically begin on the upper part of the trunk and face and progress to the lower extremities. The lesions may become purpuric on the lower extremities or dependent areas as a result of gravity. Exanthems secondary to drugs most often become confluent erythematous patches after several days.
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| FIGURE 466-3 Delayed hypersensitivity reaction. A, Drug reaction. B, acral erythema. |
Pruritus may or may not accompany drug rashes; when present, it is helpful for making the diagnosis. The differential diagnosis for drug rashes includes viral exanthems (Chapter 465), graft-versus-host disease or the leukocyte recovery rash after allogeneic bone marrow transplantation, erythematous exanthems that accompany streptococcal (scarlet fever; Chapter 311) or staphylococcal (toxic shock syndrome; Chapter 310) infections, and the acute manifestation of collagen vascular diseases. A similar exanthema occurs when ampicillin is administered to patients who have infectious mononucleosis (Chapter 400).
Treatment and Prognosis
If use of the drug is discontinued, delayed hypersensitivity reactions resolve in about a week. Corticosteroids, such as 0.01% triamcinolone cream applied several times per day to the affected area, and antihistamines given orally three to four times daily are helpful in reducing the itching and shortening the course if given for a few days.
▪Specific Syndromes
▪ Drug Rash with Eosinophilia and Systemic Symptoms
An especially severe hypersensitivity drug rash with eosinophilia and systemic symptoms (DRESS) is most frequently seen with phenytoin (Dilantin) or carbamazepine (Tegretol) or when allopurinol is coadministered with thiazide diuretics (Fig. 466-4). DRESS may be delayed in onset by 4 to 6 weeks, persists longer than classic drug-induced eruptions do, and becomes generalized and severe, even when use of the agent is discontinued. Continued administration of the drug can result in generalized exfoliative erythroderma, toxic necrolysis, and systemic hypersensitivity, including hepatitis (50%), nephritis (10%), or less commonly, pneumonitis, myocarditis, pericarditis, or atypical lymphocytosis and lymphadenopathy mimicking mononucleosis or T-cell lymphoma. With visceral involvement there is a 10% mortality rate, usually from liver failure.
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| FIGURE 466-4 Hypersensitivity drug rash caused by phenytoin. |
▪ Erythema Multiforme
Drugs are almost always implicated when blistering conditions known as erythema multiforme (see Fig. 465-10), Stevens-Johnson syndrome, or toxic epidermal necrolysis develop in adults (Fig. 466-5). Commonly implicated medications include allopurinol, phenytoin, and sulfa drugs (see Table 27-5).
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| FIGURE 466-5 Toxic epidermal necrolysis. A, Clinical appearance. B, Close-up appearance of epidermal sheets. |
▪ Leukocytoclastic Vasculitis
Severe drug reactions can also be manifested as vasculitis, neutrophilic eruptions, and ulcerations. Vasculitis is further categorized by the size of the involved vessel and the nature of the cellular reaction and immune complexes. Leukocytoclastic vasculitis (Chapter 465), which is the most common form of vasculitis induced by drugs, is manifested as palpable purpura, usually on the extremities (see Fig. 465-4).
▪ Neutrophilic Drug Reactions
Neutrophilic drug reactions include iododermas and bromodermas, as well as drug-induced Sweet's syndrome (see Inflammatory and Hematopoietic Papular and Tumors) and acute generalized exanthemic pustulosis (see Fig. 465-19), which is characterized by numerous (>100), small (<5 mm), nonfollicular subcorneal pustules that arise on erythematous skin, often beginning in skin creases or on the face. High fever and peripheral neutrophilia may proceed or accompany the eruption. The pustules are sterile, present for 5 to 10 days, and followed by desquamation. Ninety percent of cases are due to drugs and usually appear within 2 to 3 days after the administration of antibiotics or 1 to 2 weeks after other drugs; the pustules resolve within 15 days. This syndrome has also been called pustular drug rash, pustular psoriasis after corticosteroid withdrawal, and toxic pustuloderma. When severe, it may be confused with toxic epidermal necrolysis, but the mortality rate is only 1 to 2%. Skin patch testing is frequently positive.
▪ Fixed Drug Eruptions
A fixed drug reaction is an eruption that occurs at the same location every time that the drug is ingested. The mucous membranes of the mouth or genital region are most commonly involved. The lesion may begin as erythema and then become gray or brown. Phenolphthalein-containing laxatives, barbiturates, and acetaminophen are common causes. If skin that is involved in a fixed drug reaction is grafted to another area, the eruption will be transferred to the new location, thereby suggesting that local antigens are important.
▪ Photosensitivity and Withdrawal Reactions
Light may combine with drugs (Table 466-4) to produce photosensitivity reactions (Chapter 464) that can be quite severe. Thiazides, tetracyclines, sulfa drugs, antipsychotic agents, and hydralazine are often implicated in photosensitivity reactions.
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Drugs can exacerbate existing cutaneous diseases. Examples are steroid withdrawal, β-blockers, and lithium, which worsen psoriasis. Photosensitizing drugs may exacerbate lupus erythematosus or porphyria cutanea tarda.
▪ Contact Dermatitis
Allergic contact dermatitis, which is a T-cell–mediated delayed hypersensitivity reaction, can result from topical drug application. In clinical practice, contact dermatitis manifested by erythema and microvesiculation occurs in the area where the drug has been applied but may spread beyond the area (termed an ID reaction). Common contact sensitizers include Neosporin (polymyxin B/neomycin/bacitracin), bacitracin, diphenhydramine, doxepin, lidocaine, lanolin, mercury, and p-aminobenzoic acid.
▪BENIGN NODULES AND TUMORS
The skin is a heterogeneous organ composed of epidermis, dermis, subcutaneous compartments, and blood vessels. The skin hosts a number of migrating cells (Chapter 461), all of which can give rise to benign or malignant tumors. Lesions that arise from epidermal keratinocytes are usually papules (warts, sebaceous hyperplasia) or plaques (psoriasis, Bowen's disease; Chapter 465). Nodules are deep lesions that are best felt rather than seen because they arise in the dermis or in subcutaneous tissue. Nodules may arise from collections of cells around vessels or in fat, from foreign bodies, or from metabolic deposits. Nodules may induce no surface change or be accompanied by an overlying epidermal reaction such as hyperpigmentation, erythema, or scaling. Dermal invasion by a malignant basal or squamous cell carcinoma or invasive melanoma may also produce nodules (Chapter 214).
Nodules may be tender or asymptomatic and single or multiple. They can have a purple vascular component and may break down to form ulcers. Nodules are classified as inflammatory (granulomas, vasculitis, or panniculitis), infectious, or metabolic or as benign or malignant tumors arising from skin or invading cells (Table 466-5). Nodules that are smaller and symmetrical are more likely to be benign than lesions that grow rapidly, are larger, or invade surrounding tissue. Any rapidly changing skin nodule should be investigated with an excisional biopsy to the level of fat for correct histopathologic diagnosis. Culture of the lesion is also highly recommended because deep fungal infections and tuberculosis may be manifested as nodules.
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▪Benign Epidermal Tumors
The top layer of skin is the avascular epidermis, which is composed of resident keratinocytes, as well as migratory melanocytes, Langerhans cells, and in disease states, inflammatory cells (Chapter 461). Epidermal stem cells arising near the hair follicle differentiate to form adnexal organs, including hair follicles and glands (sebaceous, eccrine, and apocrine), each of which can give rise to benign or malignant tumors.
▪ Seborrheic Keratoses
The most common benign epidermal tumors are seborrheic keratoses, which are pleomorphic verrucous, oval lesions that have regular borders, are often raised, and appear to be stuck onto the skin (Fig. 466-6). Seborrheic keratoses arise from a keratinocyte clone and are often inherited in an autosomal dominant pattern. Their color can be white, flesh colored, pink, yellow, tan, brown, or black, and several different colors can be present in the same patient and in the same lesion. Seborrheic keratoses may be friable and peel off with scraping. The appearance of large numbers of eruptive seborrheic keratoses may also signal an internal carcinoma that is producing a growth factor such as epidermal growth factor. Seborrheic keratoses can be distinguished from melanocytic nevi, melanomas, and pigmented basal cell carcinoma by the presence of white to yellow horn cysts on their surface, which are best appreciated under magnification. Although seborrheic keratoses are benign, they must be differentiated from other pigmented lesions, especially superficial spreading melanoma (see Fig. 214-3).
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| FIGURE 466-6 Seborrheic keratoses. |
▪ Papules
Papules (Chapter 465) include warts (see Fig. 465-2), which are caused by the human papillomavirus (HPV). HPV can also be detected in squamous carcinomas arising on the digits and in keratoacanthoma, a low-grade, well-demarcated, dome-shaped squamous cell carcinoma that grows rapidly and spontaneously involutes in 6 to 8 weeks. In acrodermatitis verruciformis, multiple warts that have the appearance of seborrheic keratoses (see later) are found on the extremities and give rise to squamous carcinomas. Tricholemmomas are wartlike epidermal lesions found in association with Cowden's syndrome, which is associated with mutations in the PTEN gene; Cowden's syndrome is defined by warty papules on the gums, tricholemmomas (Fig. 466-7), fibrous papules, and multiple hamartomas involving the breast, thyroid, intestines, ovary, and cerebellum (Chapter 203). Molluscum contagiosum (Chapter 465) (Fig. 466-8), caused by a DNA virus, are small, shiny, domed-shaped, 1- to 5-mm papules with a central dell; they are common in children and immunocompromised patients. Epidermoid tumors on the scalp in a patient with a family history of colon cancer are helpful in making the diagnosis of Gardner's syndrome (Chapter 203).
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| FIGURE 466-7 Cowden's syndrome: cobblestone gums (left) and tricholemmoma (right). |
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| FIGURE 466-8 Molluscum contagiosum in an immunocompromised patient. |
▪ Adnexal Tumors
Adnexal tumors arise from the hair follicles or from sebaceous or other glands and are commonly found on the face. Trichoepitheliomas have features similar to basal cell carcinoma, whereas sebaceous hyperplasia describes small yellow papules with a central depression. Sebaceous carcinomas occur around the upper part of the face or eyelids as solitary lesions or as markers for the Muir-Torre syndrome of familial breast and colon cancer. Epidermal or sebaceous cysts, which are found in acne or as single firm nodules with a central pore, are filled with sebum or keratin.
▪ Actinic Keratoses
Actinic keratoses arise from sun-induced DNA damage to keratinocytes in exposed areas. They are precursor lesions of in situ squamous cell carcinoma (Bowen's disease) and invasive squamous carcinoma (Chapter 214). Actinic keratoses are scaly, 0.1- to 1.0-cm, white or pink lesions that appear on the forearms, hands, face, and scalp (Fig. 466-9). They are rough in texture and may have little induration. Individual lesions can be destroyed locally by cryotherapy or topical agents such as fluorouracil, retinoid, or imiquimod. Pink or red scaly lesions with induration, thick crusts, ulceration, or pain must be sampled to exclude invasive squamous cell carcinoma. Because the skin on which actinic keratoses arise is photodamaged and may carry mutations in p53, a more effective approach is to treat the entire area with 5-fluorouracil cream (5%) applied daily for 2 weeks or twice weekly for 8 weeks, with use of a topical antibiotic for a shorter period.
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| FIGURE 466-9 Actinic keratoses. |
▪Benign Tumors of Cells That Migrate into Skin
▪ Melanocytes
Benign melanocytic moles or nevi (new) are discrete nests of melanocytes acquired during childhood and young adulthood and stimulated by sun exposure. Nevi are benign lesions, in contrast to malignant melanomas, which also arise from melanocytes (Chapter 214). Nevi tend to regress with age and may change in color during pregnancy. Benign melanocytic nevi are formed by nests of melanocytes at the epidermal junction (junctional nevi), in the dermis (intradermal nevi), or in both compartments (compound nevi). The appearance of moles depends on the type and age of the lesion. Junctional nevi (Fig. 466-10) are small, flat, and light to dark brown. Intradermal nevi are soft, flesh-colored to pink papules with smooth regular borders and surface. Compound nevi are also papules but have brown pigmentation. Blue nevi (Fig. 466-11) are flat, grayish blue, and regular. Small congenital nevi are dark brown, whereas large (>20 cm) congenital nevi have variegated colors and are more likely to transform with melanoma (Fig. 466-12). Patients who have more than 10 large, atypical moles with irregular borders and colors that resemble melanoma have a very high risk for the development of melanoma, especially if there is a family history; such patients require regular surveillance examinations. Other recognized risk factors for melanoma include having more than 50 small nevi, red or blonde hair, or fair skin that burns and a history of blistering sunburns as a child.
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| FIGURE 466-10 Junctional nevus. |
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| FIGURE 466-11 Benign blue nevus. |
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| FIGURE 466-12 Dysplastic nevus syndrome. |
▪ Langerhans Cell Histiocytosis
The skin immune system includes surveillance mediated by antigen-presenting cells such as Langerhans cells and dermal dendritic cells, as well as skin-homing T lymphocytes. Langerhans cells migrate from lymph nodes, process antigen, and present peptides to T cells. Proliferation of Langerhans cells characterizes one form of histiocytosis. Childhood histiocytosis X is manifested as severe seborrheic dermatitis of the scalp and gluteal areas with underlying purpura and may result in the hemophagocytic syndrome. In adults, lesions appear in the intertriginous areas (Fig. 466-13). Patients with the non–Langerhans cell histiocytosis have lytic bone involvement (eosinophilic granulomas) or diabetes insipidus (Hand-Schüller-Christian syndrome).
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| FIGURE 466-13 Histiocytosis X. |
▪Dermal Tumors
▪ Dermatofibromas
Fibroblasts are the resident cells of the dermis and are responsible for producing collagen, elastin, and mucopolysaccharides. Accumulation of these products results in sclerosis, papules, or nodules. Fibroblasts in small dense clusters form firm papules or nodules known as dermatofibromas, which are brown papules most commonly found on the extremities and form after insect bites or trauma. They are firm and well-demarcated papules with puckering around them when lateral pressure is applied. Dermatofibromas can be treated, but increased scarring may occur. The malignant counterpart is dermatofibroma sarcoma protuberans, which is a poorly defined, rapidly expanding, dermal malignant tumor. Overlying erythema or hyperpigmentation is often present.
▪ Collagenomas
Collagenomas and elastic tumors with the appearance of small white to yellow papules are found in the skin and bone of patients with Buschke-Ollendorff syndrome. Pseudoxanthoma elasticum (Chapter 281), an autosomal recessive disorder, is typically manifested as cutaneous yellow plaques about the neck or antecubital fossa from damaged elastin tissue. Mucin cysts are gray, shiny, well-demarcated round nodules that generally arise on the mucosa or on the digits, where they may have an underlying connection to the joint space.
Benign tumors in the dermis can also arise from neural crest cells: neurofibromas (soft, flesh-colored papules; Fig. 466-14) and schwannomas (larger subcutaneous soft tumors or plaques; Fig. 466-15). Although solitary neurofibromas may occur, the presence of multiple lesions plus cafe au lait spots (tan macules) or axillary freckling (Crowe's sign) is diagnostic of neurofibromatosis type I, an autosomal dominant disorder caused by mutations in neurofibromin (Chapter 444). Schwannomas can become malignant and be manifested as dermal nodules.
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| FIGURE 466-14 Neurofibromatosis with cafe au lait spots and neurofibromas. |
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| FIGURE 466-15 Schwannoma. |
▪ Merkel Cell Carcinoma
Merkel cell carcinoma is a particularly aggressive small cell tumor arising from the cutaneous nerve endings or Meissner's corpuscles. Merkel cell tumors are accompanied by translucent or purple papules or plaques on sun-exposed areas (Fig. 466-16), but their appearance is not distinctive. Treatment requires full excision, radiation therapy, and often chemotherapy because the cancer tends to recur and metastasize. Glomus tumors are benign and blue or purple, with small, painful tumors arising from nerve endings. Soft, well-demarcated nodules of fatty tissue, called lipomas, are benign and may be multiple; they may have a vascular component or be painful.
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| FIGURE 466-16 Merkel cell tumor. |
▪Vascular Lesions
▪ Hemangiomas
Benign capillary hemangiomas are bright cherry-red to purple raised papules less than 5 mm in diameter that appear on the trunk with aging and may be numerous (Fig. 466-17). Pyogenic granulomas, which are sterile collections of polymorphonuclear leukocytes, can resemble capillary hemangiomas, but they have a friable epidermal surface and bleed easily; they may be similar in appearance to amelanotic melanoma. In the presence of multiple pyogenic granuloma-like lesions, infectious bacillary angiomatosis should be considered (Chapter 336). Flat red macules found on the posterior of the neck are due to a benign capillary network and are referred to as nevus flammeus or stork bite. Cavernous or strawberry hemangiomas can also appear in the neonatal period as rapidly growing vascular tumors; they may obstruct the eye or the pharynx before regressing. Corticosteroids, interferon, or antiangiogenic factors can be used to treat these lesions successfully. Cavernous hemangiomas are deeper and less likely to resolve than smaller lesions. When associated with platelet consumption, the Kasabach-Merritt syndrome is present (Chapter 179).
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| FIGURE 466-17 Benign capillary hemangioma. |
▪ Kaposi's Sarcoma
Kaposi's sarcoma (Chapter 415) is a disseminated angiomatosis that arises from viral interleukin-8 production by herpesvirus 8. The lesions are often symmetrical and can appear as purple patches; as raised purple, brown, or gray plaques; or as small papules, firm nodules, or ulcers (Fig. 466-18). Mucosal involvement is more common in advanced disease. Kaposi's sarcoma in young African adults and Kaposi's sarcoma associated with human immunodeficiency virus (HIV) infection often have a more aggressive course than Kaposi's sarcoma in elderly men of Mediterranean background, in whom the disease tends to be indolent and confined to the lower extremities. Treatment of HIV disease with highly active retroviral therapy has been associated with a decreased incidence and severity of HIV-associated Kaposi's sarcoma. Angiosarcomas are malignant purple to red vascular tumor nodules that are more common in elderly individuals or on the extremities of patients with chronic lymphedema.
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| FIGURE 466-18 Kaposi's sarcoma. A, Involvement of the lower extremity (Mediterranean Kaposi's sarcoma). B, Histology. |
▪Inflammatory and Hematopoietic Papules and Tumors
Inflammatory diseases of the skin often involve the vessels of the dermis or deeper subcutaneous tissue. The inflammatory infiltrates can be mixed or restricted in nature. Lymphocytes, polymorphonuclear leukocytes, histocytes, eosinophils, and plasma cells are the most common components of inflammatory reactions. Hematologic malignancies can be manifested in the skin as patches, nodules, papules, or vasculitic lesions. T cells that home to skin give rise to cutaneous T-cell lymphoma, a heterogeneous group of extranodal non-Hodgkin's lymphomas (Chapter 196). In mycosis fungoides, the lesions are usually pleomorphic pink, white, or brown patches or plaques; patches of alopecia can occur, and diffuse erythroderma is found with blood involvement (Sézary's syndrome) or with staphylococcal colonization. Tumors occur late in the disease or if the cells have transformed to a large phenotype, which may express CD30 (see Fig. 465-15). The early phase of mycosis fungoides is indistinguishable from chronic eczematous or psoriasiform dermatitis. Peripheral cutaneous T-cell lymphomas may also be found in subcutaneous tissue as panniculitic lesions. Lymphomatoid papulosis is characterized by crops of red to pink regressing papules with a histologic picture of anaplastic large cell lymphoma, including expression of the Ki-1 or CD30 antigen. The lesions are self-regressing and should be distinguished from CD30+ lymphoma and transformed mycosis fungoides for the purpose of treatment. Natural killer T-cell lymphomas and immunoblastic lymphomas may be manifested in skin as brown dermal nodules.
B-cell lymphomas in skin are pink, infiltrated, dome-shaped shiny papules or tumors that are most commonly located on the face, scalp, or upper part of the back. With the exception of large cell lymphoma, many B-cell lymphomas of the skin are indolent and some are stimulated by Borrelia infection or chronic inflammation. Plasmacytomas can arise in the skin, as well as in bone, with multiple myeloma or independent of it. Extramedullary hematopoiesis or endometriosis can be associated with red or brown nodules in the dermis.
▪ Sarcoidosis
Sarcoidosis (Chapter 95) is an inflammatory granulomatous process manifested as ichthyosis, papules, plaques, or tumors with an apple jelly color (Fig. 466-19). Patients with lepromatous leprosy have histiocytic plaques or tumors (Fig. 466-20); treatment of leprosy may induce an inflammatory reaction called erythema nodosum leprosum. Granulomatous inflammation within the dermis can result in damage to collagen, as seen in granuloma annulare (ringlike pink to red infiltrated lesions often on the hands or elbows), rheumatoid nodules that occur on the extensor surface of the arms, and necrobiosis lipoidica on the shins of diabetics. All three lesions typically include fibrin deposits within dermal blood vessels. Multicentric reticulohistiocytosis is a rare paraneoplastic syndrome in which histiocytic nodules form over joints with associated arthritis.
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| FIGURE 466-19 Cutaneous sarcoidosis. |
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| FIGURE 466-20 Leonine facies associated with lepromatous leprosy. |
▪ Inflammatory Skin Nodules
Inflammatory skin nodules arise from inflamed deeper structures, especially blood vessels (vasculitis) or adipose tissue (panniculitis); both can arise in response to underlying infection or antigen stimulation with influx of inflammatory cells. Vasculitis is further categorized by the size of the vessels and the type of circulating immune complexes. Damage to blood vessels results in leakage of red blood cells with the development of purpura (nonblanching red to purple lesions; Chapter 291). Erythema elevatum diutinum is manifested as multiple, infiltrated pink or yellow to red and violaceous nodules or papules that may be painful or asymptomatic. The lesions can coalesce to form gyrate lesions on the dorsum of the hands or extensor surfaces similar to granuloma annulare. Erythema elevatum diutinum is associated with upper respiratory infections (especially Streptococcus), HIV infection, and inflammatory bowel disease. The underlying histopathology is a necrotizing vasculitis with neutrophils and hyalinization of the vessels. Erythema elevatum diutinum must be distinguished from Sweet's syndrome (recurrent febrile, neutrophilic dermatosis of Sweet), which is characterized by similar lesions clinically (Fig. 466-21). Sweet's syndrome is accompanied by fever, and biopsy specimens show sheets of leukocytes filling the upper dermis in the absence of infection. It occurs in patients with leukemia, inflammatory bowel disease, or rheumatoid arthritis. Sweet's syndrome, but not erythema elevatum diutinum, is highly responsive to corticosteroids, whereas dapsone can improve both conditions.
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| FIGURE 466-21 Sweet's syndrome in patients with leukemia. |
▪ Polyarteritis Nodosa
Polyarteritis nodosa (Chapter 291) arises in larger arterioles and may be associated with hepatitis C infection, mesenteric aneurysms, cryoglobulinemia, cutaneous ulceration, and livedo reticularis. Polyarteritis nodosa is distinct from small vessel leukocytoclastic vasculitis, which is characterized by smaller areas (a few millimeters) of purpura.
In the clinical setting, panniculitis occurs more frequently than nodular vasculitis. The differential diagnosis of vasculitis versus septal or lobular panniculitis requires an excisional biopsy, including fat, with appropriate cultures and stains. Lobular panniculitis with necrosis and purpura is actually called nodular vasculitis or erythema induratum. Nodular vasculitis is characterized by painful, chronic recurrent nodules that develop on the shin or thighs and that become bluish, ulcerate, and heal with scarring. Erythema induratum (Fig. 466-22), which is exacerbated by cold exposure, is sometimes associated with infection with Mycobacterium tuberculosis (Chapter 345). True lobular panniculitis, with or without fat necrosis, occurs more often in males with underlying pancreatitis (Chapter 147) and may precede the detection of pancreatic cancer (Chapter 204). The lesions have a predilection for the anterior aspect of the shins and may be fluctuant as a result of fat necrosis. Lupus panniculitis or lupus profundus involves the fat and is diagnosed by overlying granular immune complex deposition of IgM along the dermal-epidermal junction. Lupus panniculitis of the breast can be mistaken for adenocarcinoma; it is treated with antimalarials or corticosteroids. Lobular panniculitis with calcification of the small arterioles, which occurs in the setting of renal failure with hyperparathyroidism, is called calciphylaxis (Chapter 131).
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| FIGURE 466-22 Erythema induratum. |
▪ Fungal Infections
Especially in immunocompromised patients, necrotic or granulomatous lobular panniculitis can be caused by disseminated fungal infections with Candida, Sporothrix schenckii, Cryptococcus, Histoplasma, Nocardia, Rhizopus, Aspergillus, Fusarium, or chromomycosis. Fungal mycelia invade vessel walls, where they produce purpuric and painful lesions that may ulcerate. Osler's nodes, which are tender nodular vasculitic lesions on the extremities, occur in the setting of bacterial endocarditis (Chapter 76). Staphylococcal or streptococcal sepsis may be manifested as pustules, papules, or panniculitic lesions. Klebsiella and Pseudomonas are associated with hemorrhagic necrosis of vessels or ecthyma gangrenosa. Granulomatous lobular panniculitis may also arise in the setting of syphilis, atypical mycobacterial infection, tuberculosis, or leprosy.
▪ Erythema Nodosum
Erythema nodosum (Fig. 466-23) is characterized by tender nodules, 1 to 2 cm in diameter, that have warm, pink, overlying epidermis and appear in crops on the extremities. A perivascular inflammatory infiltrate is present around small intralobular vessels without vasculitis. Erythema nodosum frequently arises in response to various infections, inflammatory bowel disease, or drug use, but often the underlying cause remains unknown (Table 466-6).
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| FIGURE 466-23 Erythema nodosum. A and B, Erythema nodosum and septal panniculitis of the lower extremities. |
▪ATROPHIC AND SCLEROTIC LESIONS
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▪ Atrophic Lesions
Atrophic lesions can result from thinning or loss of the normal epidermal layers, as occurs in photoaging, in lupus erythematosus, and in genetic disorders of collagen production (e.g., Ehlers-Danlos syndrome; Fig. 466-24). Use of high-potency topical corticosteroids also produces loss of collagen and atrophy. In Cushing's syndrome, the epidermis and underlying connective tissue become atrophic and promote the formation of striae. Striae appear as red or purple streaks because the underlying dermis can be seen through the epidermis. Epidermal wrinkling can result in a cigarette paper appearance with prominence of the underlying blood vessels.
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| FIGURE 466-24 Atrophic skin in Ehlers-Danlos syndrome type 2. |
Aging skin is most pronounced in sun-exposed areas, but intrinsic aging beginning as early as 30 years of age is characterized by abnormalities in the formation of elastin fibers. Aging of the skin is also accompanied by decreasing numbers of epidermal-dermal involutions (rete ridges) and poor circulation as a result of changes in dermal blood vessels. Aging of the skin secondary to sunlight involves the induction or production of proteolytic enzymes that digest the underlying collagen and elastin (wrinkles). These changes can be partially prevented or restored with the use of topical vitamin A creams on a regular basis and with use of sun protection, including sunscreen. In addition, sun exposure induces pigment incontinence (freckling), increased junctional nevi, and proliferation of benign keratinocyte growths (seborrheic keratoses).
Atrophy can also result from ongoing inflammatory processes that lead to scarring, such as collagen vascular disease or mycosis fungoides. Anetodermas, which are localized sclerotic lesions (Fig. 466-25) with distinctive clinical features, have likewise been attributed to underlying inflammatory processes. Connective tissue diseases often produce sclerosis and atrophy after active inflammation. The cutaneous and discoid forms of lupus erythematosus (Chapter 287) are manifested as scaly plaques with atrophy or alopecia on sun-exposed areas; the systemic form is characterized by malar rash, urticaria, or vasculitic lesions. Dermatomyositis (Chapter 290) can be associated with collagen vascular disease or malignancy; periorbital suffusion, telangiectasia of the nail beds, and Gottron's papules or scaly lesions over the joints are the skin manifestations.
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| FIGURE 466-25 Anetoderma. |
Eosinophilic fasciitis is accompanied by nodules or sclerosis of the lower extremities, myopathy, pulmonary disease, and eosinophilia. This syndrome, which follows the ingestion of l-tryptophan or its contaminants (Fig. 466-26), resembles the panniculitis seen in systemic sclerosis, in which fat lobules are replaced by new collagen formation. Eosinophilic cellulitis, or Wells' syndrome, is manifested as nodules, papules, or ulcerative lesions, as well as red plaques; in this disorder, eosinophils infiltrate the area between collagen fibers.
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| FIGURE 466-26 Eosinophilic fasciitis secondary to tryptophan. |
▪ Sclerotic Lesions
Sclerotic lesions are accompanied by more collagen production; the skin has a thicker or glossy appearance. Sclerosis may also result from the accumulation of mucopolysaccharides in scleromyxedema or lichen myxedematosus or from amyloid deposits. A new entity associated with renal failure—nephrogenic fibrosing dermopathy—is also characterized by acral fibrosis and deposition of hyaluronate in the skin. In scleroderma (Chapter 288), collagen deposition is associated with Raynaud's syndrome, calcinosis, and telangiectasia. A localized form of scleroderma, termed morphea, may occur down the center of the face (coup de sabre), in plaques on the extremities (Fig. 466-27), after radiation exposure, or with Borrelia infections. Lichen sclerosis et atrophicus is a superficial inflammatory morphea characterized by white atrophic patches, especially in the genital regions. Widespread systemic sclerosis may also follow bone marrow transplantation in the setting of chronic graft-versus-host disease.
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| FIGURE 466-27 Linear morphea. |
▪ Telangiectasia
Telangiectasia, or prominence of skin blood vessels, frequently accompanies atrophic as well as sclerotic processes and is common in photoaged skin. Telangiectasia of the mucous membranes is found in Osler-Weber-Rendu syndrome, and vascular spiders are found both in α1-antitrypsinase deficiency and alcoholism. The presence of telangiectasia and hyperpigmentation and hypopigmentation (poikiloderma) in sun-shielded areas of the body should alert the clinician to the diagnosis of early mycosis fungoides.
▪ Ulcers
Ulcers are secondary skin lesions that may arise from trauma, loss of proper blood supply, aging, vasculitis, blister formation, infection, or underlying neoplasia. Ulcers may be shallow erosions (loss of the epidermis) or be deeper and involve the dermis and underlying subcutaneous structures. Ulcers most commonly appear on the lower extremities, where they result from status dermatitis and venous insufficiency, arteriolar insufficiency, diabetic neuropathy, or vasculitis. For example, pyoderma gangrenosum is a trauma-induced ulcer that is part of the spectrum of Sweet's syndrome, accompanies other conditions, and may require immunosuppressive therapy. In contrast, decubitus ulcers require débridement, elimination of local pressure, and attention to nutrition (Chapter 232). In some cases, diagnosis may require skin biopsy, cultures, and serologic testing for other associated diseases.
After an inflammatory or ulcerated skin wound heals, scarring is common. Epidermal stem cells that reside in the bulge region of the hair follicle are capable of regenerating a normal epidermis. When a wound is deeper than the bulge region, scarring and loss of hair are likely to occur. Scarring alopecia (lichen planopilaris, discoid lupus, scarring folliculitis) results in permanent baldness and must be distinguished from the less severe, nonscarring conditions such as telogen effluvium or alopecia areata. Scarring also accompanies the most severe epidermolysis bullosa disorders caused by sub-basement membrane defects in proteins. Scarring accompanies third-degree burns, deep cryotherapy, or other trauma to the dermis. Scarring may also follow severe inflammation (discoid lupus) or infection (syphilis, leprosy).
▪ Keloids
Some individuals have more pronounced and hypertrophic scar formation known as keloids, with an autosomal dominant inheritance pattern. Keloids are tumor-like in appearance and result from an overproduction of collagen. They are especially common on the anterior of the chest, neck, and earlobes and may require antineoplastic treatment after surgical removal.
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