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Skin Manifestations of Internal Disease

Skin Manifestations of Internal Disease

Jean L. Bolognia

Irwin M. Braverman

It is now a generally accepted concept in medicine that the skin can show signs of internal disease. Therefore, in textbooks of medicine one finds a chapter describing in detail the major systemic disorders that can be identified by cutaneous signs. The underlying assumption of such a chapter is that the clinician has been able to identify the disorder in the patient and needs only to read about it in the textbook. In reality, concise differential diagnoses and the identification of these disorders are actually difficult for the nondermatologist because he or she is not well versed in the recognition of cutaneous lesions or their spectrum of presentations.

Therefore, the authors of this chapter have decided to cover this particular topic of cutaneous medicine not by discussing individual disorders but by describing and discussing the various presenting clinical signs and symptoms that indicate the presence of these disorders. Concise differential diagnoses will be generated in which the significant diseases will be briefly discussed and distinguished from the more common disorders that have no significance for internal diseases. The latter disorders are reviewed in table form and always need to be excluded when considering the former. For a detailed description of individual diseases, the reader should consult a dermatologic text.

PAPULOSQUAMOUS SKIN LESIONS

When an eruption is characterized by elevated lesions, papules (<1 cm), or plaques (>1 cm), in association with scale, it is referred to as a papulosquamous lesion. The most common papulosquamous diseases—psoriasis, tinea, pityriasis rosea, and lichen planus—are primary cutaneous disorders. When psoriatic lesions are accompanied by arthritis, the possibility of psoriatic arthritis or Reiter's disease should be considered. A history of oral ulcers, conjunctivitis, uveitis, and/or urethritis points to the latter diagnosis. In guttate psoriasis there is an acute onset of small, widely scattered, uniform lesions, often in association with a streptococcal infection. Lithium, beta blockers, HIV infection, and a rapid taper of systemic glucocorticoids are also known to exacerbate psoriasis.

Whenever the diagnosis of pityriasis rosea or lichen planus is made, it is important to review the patient's medications because the eruption can be treated by simply discontinuing the offending agent. Pityriasis rosea–like drug eruptions are seen most commonly with beta blockers, angiotensin-converting enzyme (ACE) inhibitors, gold, and metronidazole, while the drugs that can produce a lichenoid eruption include gold, antimalarials, thiazides, quinidine, phenothiazines, sulfonylureas, and ACE inhibitors. Lichen planus–like lesions are also observed in chronic graft-versus-host disease.

In its early stages, cutaneous T cell lymphoma (CTCL) may be confused with ezcema or psoriasis, but it often fails to respond to the appropriate therapy for those inflammatory diseases. CTCL can develop within lesions of large-plaque parapsoriasis and is suggested by an increase in the thickness of the lesions. The diagnosis of CTCL is established by skin biopsy in which collections of atypical T lymphocytes are found in the epidermis and dermis. As the disease progresses, cutaneous tumors and lymph node involvement may appear.

In secondary syphilis there are scattered red-brown papules with thin scale. The eruption often involves the palms and soles and can resemble pityriasis rosea. Associated findings are helpful in making the diagnosis and include annular plaques on the face, nonscarring alopecia, condyloma lata (broad-based and moist), and mucous patches as well as lymphadenopathy, malaise, fever, headache, and myalgias. The interval between the primary chancre and the secondary stage is usually 4 to 8 weeks, and spontaneous resolution without appropriate therapy is seen.

ERYTHRODERMA

Erythroderma is the term used when the majority of the skin surface is erythematous (red in color). There may be associated scale, erosions, or pustules as well as shedding of the hair and nails. Potential systemic manifestations include fever, chills, hypothermia, reactive lymphadenopathy, peripheral edema, hypoalbuminemia, and high-output cardiac failure. The major etiologies of erythroderma are (1) cutaneous diseases such as psoriasis and dermatitis (Table 3); (2) drugs; (3) systemic diseases, most commonly CTCL; and (4) idiopathic. In the first three groups, the location and description of the initial lesions, prior to the development of the erythroderma, aid in the diagnosis. For example, a history of red scaly plaques on the elbows and knees would point to psoriasis. It is also important to examine the skin carefully for a migration of the erythema and associated secondary changes such as pustules or erosions. Migratory waves of erythema studded with superficial pustules are seen in pustular psoriasis.

Drug-induced erythroderma (exfoliative dermatitis) may begin as a morbilliform eruption or may arise as diffuse erythema. Fever and peripheral eosinophilia often accompany the eruption, and occasionally there is an associated allergic interstitial nephritis. A number of drugs can produce an erythroderma, including penicillins, sulfonamides, carbamazepine, phenytoin, gold, allopurinol, and captopril. While reactions to anticonvulsants can lead to a pseudolymphoma syndrome (with adenopathy, hepatitis, and circulating atypical lymphocytes), reactions to allopurinol may be accompanied by hepatitis, gastrointestinal bleeding, and nephropathy.

The most common malignancy that is associated with erythroderma is CTCL; in some series, up to 25% of the cases of erythroderma were due to CTCL. The patient may progress from isolated plaques and tumors, but more commonly the erythroderma is present throughout the course of the disease (Sézary syndrome). In the Sézary syndrome, there are circulating atypical T lymphocytes, pruritus, and lymphadenopathy. In cases of erythroderma where there is no apparent cause (idiopathic), longitudinal follow-up is mandatory to monitor for the possible development of CTCL. There have been isolated case reports of erythroderma secondary to some solid tumors—lung, liver, prostate, thyroid, and colon—but it is usually in a late stage of the disease.

ALOPECIA (Table 4)

The two major forms of alopecia are scarring and nonscarring. In scarring alopecia there are associated fibrosis, inflammation, and loss of hair follicles. A smooth scalp with a decreased number of follicular openings is usually observed clinically, but in some cases the changes are seen only in biopsy specimens from the affected areas. In nonscarring alopecia the hair shafts are gone, but the hair follicles are preserved, explaining the reversible nature of nonscarring alopecia.

The most common causes of nonscarring alopecia include telogen effluvium, androgenetic alopecia, alopecia areata, tinea capitis, and traumatic alopecia (Table 5). In women with androgenetic alopecia, an elevation in circulating levels of androgens may be seen as a result of ovarian or adrenal gland dysfunction. When there are signs of virilization, such as a deepened voice and enlarged clitoris, the possibility of an ovarian or adrenal gland tumor should be considered.

Exposure to various drugs can also cause diffuse hair loss, usually by inducing a telogen effluvium. An exception is the anagen effluvium observed with antimitotic agents such as daunorubicin. Alopecia is a side effect of the following drugs: warfarin, heparin, propylthiouracil, carbimazole, vitamin A, isotretinoin, acitretin, lithium, beta blockers, colchicine, and amphetamines. Fortunately, spontaneous regrowth usually follows discontinuation of the offending agent.

Less commonly, nonscarring alopecia is associated with lupus erythematosus and secondary syphilis. In systemic lupus there are two forms of alopecia—one is scarring secondary to discoid lesions (see below) and the other is nonscarring. The latter form may be diffuse and involve the entire scalp, or it may be localized to the frontal scalp and result in multiple short hairs (“lupus hairs”). Scattered, poorly circumscribed patches of alopecia with a “moth-eaten” appearance are a manifestation of the secondary stage of syphilis. Diffuse thinning of the hair is also associated with hypothyroidism and hyperthyroidism (Table 4).

Scarring alopecia is more frequently the result of a primary cutaneous disorder such as lichen planus, folliculitis decalvans, cutaneous lupus, or linear scleroderma (morphea) than it is a sign of systemic disease. Although the scarring lesions of discoid lupus can be seen in patients with systemic lupus, in the majority of cases the disease process is limited to the skin. Less common causes of scarring alopecia include sarcoidosis  and cutaneous metastases.

In the early phases of discoid lupus, lichen planus, and folliculitis decalvans, there are circumscribed areas of alopecia. Fibrosis and subsequent loss of follicles are observed primarily in the center of the individual lesions, while the inflammatory process is most prominent at the periphery. The areas of active inflammation in discoid lupus are erythematous with scale, whereas the areas of previous inflammation are often hypopigmented with a rim of hyperpigmentation. In lichen planus the peripheral perifollicular macules are usually violet-colored. Complete examination of the skin and oral mucosa combined with a biopsy and direct immunofluorescence microscopy will aid in distinguishing these two entities. The peripheral active lesions in folliculitis decalvans are follicular pustules; these patients can develop a reactive arthritis.

FIGURATE SKIN LESIONS (Table 6)

In figurate eruptions, the lesions form rings and arcs that are usually erythematous but can be skin-colored to brown. Most commonly, they are due to primary cutaneous diseases such as tinea, urticaria, erythema annulare centrifugum, and granuloma annulare. An underlying systemic illness is found in a second, less common group of migratory annular erythemas. It includes erythema gyratum repens, erythema migrans, erythema marginatum, and necrolytic migratory erythema.

In erythema gyratum repens, one sees hundreds of mobile concentric arcs and wavefronts that resemble the grain in wood. A search for an underlying malignancy is mandatory in a patient with this eruption. Erythema migrans is the cutaneous manifestation of Lyme disease, which is caused by the spirochete Borrelia burgdorferi. In the initial stage (3 to 30 days after tick bite), a single annular lesion is usually seen, which can expand to ≥10 cm in diameter. Within several days, approximately half the patients develop multiple smaller erythematous lesions at sites distant from the bite. Associated symptoms include fever, headache, photophobia, myalgias, arthralgias, and malar rash. Erythema marginatum is seen in patients with rheumatic fever, primarily on the trunk. Lesions are pink-red in color, flat to mildly elevated, and transient.

There are additional cutaneous diseases that present as annular eruptions but lack an obvious migratory component. Examples include CTCL, annular cutaneous lupus (also referred to as subacute lupus), secondary syphilis, and sarcoidosis.

ACNE (Table 7)

In addition to acne vulgaris and acne rosacea, the two major forms of acne, there are drugs and systemic diseases that can lead to acneiform eruptions (Table 7).

Patients with the carcinoid syndrome have episodes of flushing of the head, neck, and sometimes the trunk. Resultant skin changes of the face, in particular telangiectasias, may mimic the clinical appearance of acne rosacea.

PUSTULAR LESIONS

Acneiform eruptions and folliculitis represent the most common pustular dermatoses. An important consideration in the evaluation of follicular pustules is a determination of the associated pathogen, e.g., normal flora, Staphylococcus aureus, Pityrosporum. Noninfectious forms of folliculitis include HIV-associated eosinophilic folliculitis and folliculitis secondary to drugs such as glucocorticoids and lithium. Administration of high-dose oral glucocorticoids can result in a widespread eruption of follicular pustules on the trunk, characterized by lesions in the same stage of development. With regard to underlying systemic diseases, nonfollicular-based pustules are a characteristic component of pustular psoriasis and can be seen in septic emboli of bacterial or fungal origin.

TELANGIECTASIAS (Table 8)

In order to distinguish the various types of telangiectasias, it is important to examine the shape and configuration of the dilated blood vessels. Linear telangiectasias are seen on the face of patients with actinically damaged skin and acne rosacea and they are found on the legs of patients with venous hypertension and essential telangiectasia. Patients with an unusual form of mastocytosis (telangiectasia macularis eruptiva perstans) and the carcinoid syndrome also have linear telangiectasias. Lastly, linear telangiectasias are found in areas of cutaneous inflammation. For example, lesions of discoid lupus frequently have telangiectasias within them.

Poikiloderma is a term used to describe a patch of skin with (1) reticulated hypo- and hyperpigmentation, (2) wrinkling secondary to epidermal atrophy, and (3) telangiectasias. Poikiloderma does not imply a single disease entity—although becoming less common, it is seen in skin damaged by ionizing radiation, as well as in patients with autoimmune connective tissue diseases, primarily dermatomyositis (DM).

In scleroderma, the dilated blood vessels have a unique configuration and are known as mat telangiectasias. The lesions are broad macules that usually measure 2 to 7 mm in diameter but occasionally are larger. Mats have a polygonal or oval shape, and their erythematous color may be uniform or the result of delicate telangiectasias. The most common locations for mat telangiectasias are the face, oral mucosa, and hands—peripheral sites that are prone to intermittent ischemia. The CREST (calcinosis cutis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) variant of scleroderma is associated with a chronic course and anticentromere antibodies. Mat telangiectasias are an important clue to the diagnosis of the CREST syndrome as well as systemic scleroderma, for they may be the only cutaneous finding.

Periungual telangiectasias are pathognomonic signs of the three major autoimmune connective tissue diseases—lupus erythematosus, scleroderma, and DM. They are easily visualized by the naked eye and occur in at least two-thirds of these patients. In both DM and lupus there is associated nailfold erythema, and in DM the erythema is often accompanied by “ragged” cuticles and fingertip tenderness. Under 10× magnification, the blood vessels in the nailfolds of lupus patients are tortuous and resemble “glomeruli,” whereas in scleroderma and DM there is a loss of capillary loops and those that remain are markedly dilated.

In hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease), the lesions usually appear during adulthood and are most commonly seen on the mucous membranes, face, and distal extremities, including under the nails. They represent arteriovenous (AV) malformations of the dermal microvasculature, are dark red in color, and are usually slightly elevated. When the skin is stretched over an individual lesion, an eccentric punctum with radiating legs is seen. Although the degree of systemic involvement varies in this autosomal dominant disease (due to mutations in either the endoglin or activin receptor–like kinase gene), the major symptoms are recurrent epistaxis and gastrointestinal bleeding. The fact that these mucosal telangiectasias are actually AV communications helps to explain their tendency to bleed.

HYPOPIGMENTATION

Disorders of hypopigmentation are classified as either diffuse or localized. The classic example of diffuse hypopigmentation is oculocutaneous albinism (OCA). The most common forms are due to mutations in the tyrosinase gene (type I) or the P gene (type II); patients with type IA OCA have a total lack of enzyme activity. At birth, different forms of OCA can appear similar white hair, gray-blue eyes, and pink-white skin. However, the patients with no tyrosinase activity maintain this phenotype, whereas those with decreased activity or P gene mutations will acquire some pigmentation of the eyes, hair, and skin as they age. The degree of pigment formation is also a function of racial background, and the pigmentary dilution is readily apparent when patients are compared to their first-degree relatives. The ocular findings in OCA correlate with the degree of hypopigmentation and include decreased visual acuity, nystagmus, photophobia, and monocular vision.

The differential diagnosis of localized hypomelanosis includes the following primary cutaneous disorders: idiopathic guttate hypomelanosis, postinflammatory hypopigmentation, tinea (pityriasis) versicolor, vitiligo, chemical leukoderma, nevus depigmentosus (see below), and piebaldism (Table 9). In this group of diseases, the areas of involvement are macules or patches with a decrease or absence of pigmentation. Patients with vitiligo also have an increased incidence of several autoimmune disorders, including hypothyroidism, Graves' disease, pernicious anemia, Addison's disease, uveitis, alopecia areata, chronic mucocutaneous candidiasis, and the polyglandular autoimmune syndromes (types I and II). Diseases of the thyroid gland are the most frequently associated disorders, occurring in up to 30% of patients with vitiligo. Circulating autoantibodies are often found, and the most common ones are antithyroglobulin, antimicrosomal, and antiparietal cell antibodies.

There are three systemic diseases that should be considered in a patient with skin findings suggestive of vitiligo—Vogt-Koyanagi-Harada syndrome, scleroderma, and melanoma-associated leukoderma. A history of aseptic meningitis, nontraumatic uveitis, tinnitus, hearing loss, and/or dysacousis points to the diagnosis of the Vogt-Koyanagi-Harada syndrome. In these patients, the face and scalp are the most common locations of pigment loss. The vitiligo-like leukoderma seen in patients with scleroderma has a clinical resemblance to idiopathic vitiligo that has begun to repigment as a result of treatment; that is, perifollicular macules of normal pigmentation are seen within areas of depigmentation. The basis of this leukoderma is unknown;

there is no evidence of inflammation in areas of involvement, but it can resolve if the underlying connective tissue disease becomes inactive. In contrast to idiopathic vitiligo, melanoma-associated leukoderma often begins on the trunk, and its appearance should prompt a search for metastatic disease. The possibility exists that the destruction of normal melanocytes is the result of an immune response against malignant melanocytes.

There are two systemic disorders that may have the cutaneous findings of piebaldism (Table 10). They are Hirschsprung's disease and Waardenburg's syndrome. A possible explanation for both disorders is an abnormal embryonic migration or survival of two neural crest–derived elements, one of them being melanocytes and the other myenteric ganglion cells (Hirschsprung's disease) or auditory nerve cells (Waardenburg's syndrome). The latter syndrome is characterized by congenital sensorineural hearing loss, dystopia canthorum (lateral displacement of the inner canthi but normal interpupillary distance), heterochromic irises, and a broad nasal root, in addition to the piebaldism. Patients with Waardenburg's syndrome have been shown to have mutations in two genes that encode DNA-binding proteins, PAX-3 and MITF, while patients with Hirschsprung's disease and white spotting have mutations in one of three genes—endothelin 3, endothelin B receptor, and SOX-10.

In tuberous sclerosis, the earliest cutaneous sign is an ash leaf spot. These lesions are often present at birth and are usually multiple; however, detection may require Wood's lamp examination, especially in fair-skinned individuals. The pigment within them is reduced but not absent. The average size is 1 to 3 cm, and the common shapes are polygonal and lance-ovate. Examination of the patient for additional cutaneous signs such as adenoma sebaceum (multiple angiofibromas of the face), ungual and gingival fibromas, fibrous plaques of the forehead, and connective tissue nevi (shagreen patches) is recommended. It is important to remember that an ash leaf spot on the scalp will result in poliosis, which is a circumscribed patch of gray-white hair. Internal manifestations include seizures, mental retardation, central nervous system (CNS) and retinal hamartomas, renal angiomyolipomas, and cardiac rhabdomyomas. The latter can be detected in up to 60% of children (<18 years) with tuberous sclerosis by echocardiography.

Nevus depigmentosus is a stable, well-circumscribed hypomelanosis that is present at birth. There is usually a single circular or rectangular lesion, but occasionally the nevus has a segmental or whorled pattern. It is important to distinguish this more common entity from ash leaf spots especially when there are multiple lesions. In hypomelanosis of Ito, swirls and streaks of hypopigmentation run parallel to one another in a pattern that resembles a marble cake. Lesions may progress or regress with time, and in up to a third of patients, associated abnormalities are found including in the musculoskeletal system (asymmetry), the CNS (seizures and mental retardation), and the eyes (strabismus and hypertelorism). Chromosomal mosaicism has been detected in these patients; this lends support to the hypothesis that the pattern is the result of the migration of two clones of primordial melanocytes, each with a different pigment potential.

Localized areas of decreased pigmentation are commonly seen as a result of cutaneous inflammation (Table 10) and have been observed in the skin overlying active lesions of sarcoidosis as well as in CTCL. Cutaneous infections also present as disorders of hypopigmentation, and in tuberculoid leprosy there are a few asymmetric patches of hypomelanosis that have associated anesthesia, anhidrosis, and alopecia. Biopsy specimens of the palpable border show dermal granulomas that contain rare, if any, Mycobacterium leprae organisms.

HYPERPIGMENTATION (Table -11)

Disorders of hyperpigmentation are also divided into two groups—localized and diffuse. The localized forms are due to an epidermal alteration, a proliferation of melanocytes, or an increase in pigment production. Both seborrheic keratoses and acanthosis nigricans belong to the first group. Seborrheic keratoses are common lesions, but in one clinical setting they are a sign of systemic disease, and that setting is the sudden appearance of multiple lesions, often with an inflammatory base and in association with acrochordons (skin tags) and acanthosis nigricans. This is termed the sign of Leser-Trélat and signifies an internal malignancy. Acanthosis nigricans can also be a reflection of an internal malignancy, most commonly of the gastrointestinal tract, and it appears as velvety hyperpigmentation, primarily in flexural areas. In the majority of patients, acanthosis nigricans is associated with obesity and insulin resistance, but it may be a reflection of an endocrinopathy such as acromegaly, Cushing's syndrome, the Stein-Leventhal syndrome, or insulin-resistant diabetes mellitus (type A, type B, and lipoatrophic forms).

A proliferation of melanocytes results in the following pigmented lesions: lentigo, melanocytic nevus, and melanoma. In an adult, the majority of lentigines are related to sun exposure, which explains their distribution. However, in the Peutz-Jeghers and LEOPARD [lentigines; ECG abnormalities, primarily conduction defects; ocular hypertelorism; pulmonary stenosis and subaortic valvular stenosis; abnormal genitalia (cryptorchidism, hypospadias); retardation of growth; and deafness (sensorineural)] syndromes, lentigines do serve as a clue to systemic disease. In LEOPARD syndrome, hundreds of lentigines develop during childhood and are scattered over the entire surface of the body. The lentigines in patients with Peutz-Jeghers syndrome are located primarily around the nose and mouth, on the hands and feet, and within the oral cavity. While the pigmented macules on the face may fade with age, the oral lesions persist. However, similar intraoral lesions are also seen in Addison's disease and as a normal finding in darkly pigmented individuals. Patients with this autosomal dominant syndrome (due to mutations in a novel serine threonine kinase gene) have multiple benign polyps of the gastrointestinal tract, testicular tumors, and an increased risk of developing gastrointestinal (primarily colon), breast, and gynecologic cancers.

Lentigines are also seen in association with cardiac myxomas and have been described in two syndromes whose findings overlap: LAMB (lentigines, atrial myxomas, mucocutaneous myxomas, and blue nevi) syndrome and NAME [nevi, atrial myxoma, myxoid neurofibroma, and ephelides (freckles)] syndrome. These patients can also have evidence of endocrine overactivity in the form of Cushing's syndrome, acromegaly, or sexual precocity (Carney complex).

The third type of localized hyperpigmentation is due to a local increase in pigment production, and it includes ephelides and café au lait macules (CALM). The latter are most commonly associated with two disorders—neurofibromatosis (NF) and McCune-Albright syndrome. CALM are flat, uniformly light brown in color, and can vary in size from 0.5 to 12 cm. Approximately 80% of adult patients with type I NF will have six or more CALM measuring ≥1.5 cm in diameter. Additional findings are discussed in the section on neurofibromas. In comparison with NF, the CALM in patients with McCune-Albright syndrome [polyostotic fibrous dysplasia with precocious puberty in females due to mosaicism for an activating mutation in a G protein (G_sα) gene] are usually larger, more irregular in outline, and tend to respect the midline. CALM have also been associated with pulmonary stenosis (Watson syndrome), tuberous sclerosis, the LEOPARD syndrome, and multiple endocrine neoplasia (MEN), but a few such lesions can be found in normal individuals.

In incontinentia pigmenti, dyskeratosis congenita, and bleomycin pigmentation, the areas of localized hyperpigmentation form a pattern—swirled in the first, reticulated in the second, and flagellate in the third. In dyskeratosis congenita, atrophic reticulated hyperpigmentation is seen on the neck, thighs, and trunk and is accompanied by nail dystrophy, pancytopenia, and leukoplakia of the oral and anal mucosa. The latter often develops into squamous cell carcinoma. In addition to the flagellate pigmentation (linear streaks) on the trunk, patients receiving bleomycin often have hyperpigmentation on the elbows, knees, and small joints of the hand.

Localized hyperpigmentation is seen as a side effect of several other systemic medications, including those that produce fixed drug reactions [phenolphthalein, nonsteroidal anti-inflammatory drugs (NSAIDs), sulfonamides, and barbiturates] and those that can complex with melanin (antimalarials). Fixed drug eruptions recur in the same location as circular areas of erythema that can become bullous and then resolve as brown macules. The eruption usually appears within hours of administration of the offending agent, and common locations include the genitalia, extremities, and perioral region. Chloroquine and hydroxychloroquine produce gray-brown to blue-black discoloration of the shins, hard palate, and face, while blue macules can be seen on the lower extremities and in sites of inflammation with prolonged minocycline administration. Estrogen in oral contraceptives can induce melasma—symmetric brown patches on the face, especially the cheeks, upper lip, and forehead. Similar changes are seen in pregnancy, in patients receiving phenytoin, and in the adult form of Gaucher's disease. In the latter group there is also hyperpigmentation of the distal lower extremities.

In the diffuse forms of hyperpigmentation, the darkening of the skin may be of equal intensity over the entire body or may be accentuated in sun-exposed areas. The causes of diffuse hyperpigmentation can be divided into four groups—endocrine, metabolic, autoimmune, and drugs. The endocrinopathies that frequently have associated hyperpigmentation include Addison's disease, Nelson syndrome, and ectopic ACTH syndrome. In these diseases, the increased pigmentation is diffuse but is accentuated in the palmar creases, sites of friction, scars, and the oral mucosa. An overproduction of the pituitary hormones α-MSH (melanocyte-stimulating hormone) and ACTH can lead to an increase in melanocyte activity. These peptides are products of the proopiomelanocortin gene and exhibit homology; e.g., α-MSH and ACTH share 13 amino acids. A minority of the patients with Cushing's disease or hyperthyroidism have generalized hyperpigmentation.

The metabolic causes of hyperpigmentation include porphyria cutanea tarda (PCT), hemochromatosis, vitamin B₁₂ deficiency, folic acid deficiency, pellagra, malabsorption, and Whipple's disease. In patients with PCT, the skin darkening is seen in sun-exposed areas and is a reflection of the photoreactive properties of porphyrins. The increased level of iron in the skin of patients with hemochromatosis stimulates melanin pigment production and leads to the classic bronze color. Patients with pellagra have a brown discoloration of the skin, especially in sun-exposed areas, as a result of nicotinic acid (niacin) deficiency. In the areas of increased pigmentation, there is a thin varnish-like scale. These changes are also seen in patients who are vitamin B₆ deficient, have functioning carcinoid tumors (increased consumption of niacin), or take isoniazid. Approximately 50% of the patients with Whipple's disease have an associated generalized hyperpigmentation in association with diarrhea, weight loss, arthritis, and lymphadenopathy. A diffuse slate-blue color is seen in patients with melanosis secondary to metastatic melanoma. Although there is a debate as to whether the color is due to single-cell metastases in the dermis or to a widespread deposition of melanin resulting from the high concentration of circulating melanin precursors, there is more evidence to support the latter.

Of the autoimmune diseases associated with diffuse hyperpigmentation, biliary cirrhosis and scleroderma are the most common, and occasionally both disorders are seen in the same patient. The skin is dark brown in color, especially in sun-exposed areas. In biliary cirrhosis the hyperpigmentation is accompanied by pruritus, jaundice, and xanthomas, whereas in scleroderma it is accompanied by sclerosis of the extremities, face, and, less commonly, the trunk. Additional clues to the diagnosis of scleroderma are telangiectasias, calcinosis cutis, Raynaud's phenomenon, and distal ulcerations. The differential diagnosis of cutaneous sclerosis with hyperpigmentation includes the POEMS [polyneuropathy; organomegaly (liver, spleen, lymph nodes); endocrinopathies (impotence, gynecomastia); M-protein; and skin changes] syndrome. The skin changes include hyperpigmentation, skin thickening, hypertrichosis, and angiomas.

Diffuse hyperpigmentation that is due to drugs or metals can result from one of several mechanisms—induction of melanin pigment formation, complexing of the drug or its metabolites to melanin, and deposits of the drug in the dermis. Busulfan; cyclophosphamide; long-term, high-dose ACTH; and inorganic arsenic induce pigment production. Complexes containing melanin or hemosiderin plus the drug or its metabolites are seen in patients receiving chlorpromazine and minocycline. The sun-exposed skin as well as the conjunctivae of patients on long-term, high-dose chlorpromazine can become blue-gray in color. Patients taking minocycline may develop a diffuse blue-gray, muddy appearance in sun-exposed areas in addition to pigmentation of the mucous membranes, teeth, nails, bones, and thyroid. Administration of amiodarone can result in both a phototoxic eruption (exaggerated sunburn) and/or a brown or blue-gray discoloration of sun-exposed skin. Biopsy specimens of the latter show yellow-brown granules in dermal macrophages, which represent intralysosomal accumulations of lipids, amiodarone, and its metabolites. Actual deposits of a particular drug or metal in the skin are seen with silver (argyria), where the skin appears blue-gray in color; gold (chrysiasis), where the skin has a brown to blue-gray color; and clofazimine, where the skin appears reddish brown. The associated hyperpigmentation is accentuated in sun-exposed areas, and discoloration of the eye is seen with gold (sclerae) and clofazimine (conjunctivae).

VESICLES/BULLAE (Table 12)

Depending on their size, cutaneous blisters are referred to as vesicles (<0.5 cm) or bullae (>0.5 cm). The primary blistering disorders include pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, paraneoplastic pemphigus, bullous pemphigoid, gestational pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita, linear IgA disease, and dermatitis herpetiformis.

Vesicles and bullae are also seen in contact dermatitis, both allergic and irritant forms. When there is a linear arrangement of vesicular lesions, an exogenous cause should be suspected. Bullous disease secondary to the ingestion of drugs can take one of several forms, including phototoxic eruptions, isolated bullae, toxic epidermal necrolysis (TEN), and erythema multiforme major. Clinically, phototoxic eruptions resemble an exaggerated sunburn with diffuse erythema and bullae in sun-exposed areas. The most commonly associated drugs are thiazides, doxycycline, sulfonamides, NSAIDs, and psoralens. The development of a phototoxic eruption is dependent on the doses of both the drug and ultraviolet (UV)-A irradiation.

Toxic epidermal necrolysis is characterized by bullae that arise on widespread areas of erythema and then slough. This results in large areas of denuded skin. The associated morbidity, such as sepsis, and mortality are relatively high and are a function of the extent of epidermal necrosis. In addition, these patients may also have involvement of the mucous membranes and intestinal tract. Drugs are the primary cause of TEN, and the most common offenders are phenytoin, barbiturates, sulfonamides, penicillins, and NSAIDs. Severe acute graft-versus-host disease (grade 4) can also resemble TEN.

In erythema multiforme (EM), the primary lesions are pink-red macules and edematous papules, the centers of which may become vesicular. The clue to the diagnosis of EM, as opposed to a drug-induced morbilliform exanthem, is the development of a “dusky” violet color or petechiae in the center of the lesions. Target or iris lesions are also characteristic of EM and arise as a result of active centers and borders in combination with centrifugal spread. However, iris lesions need not be present to make the diagnosis of EM.

EM has been subdivided into two major groups: (1) herpes simplex virus (HSV)-associated and (2) EM major due to drugs or Mycoplasma pneumoniae. Involvement of the mucous membranes (oral, nasal, ocular,

and genital) is seen more commonly in the latter form. Hemorrhagic crusts of the lips are characteristic of EM major as well as herpes simplex, pemphigus vulgaris, and paraneoplastic pemphigus. Fever, malaise, myalgias, sore throat, and cough may precede or accompany the eruption. The lesions of EM usually resolve over 3 to 6 weeks but may be recurrent, especially when due to HSV.

Induction of EM major is most often due to drugs, especially sulfonamides, phenytoin, barbiturates, penicillins, and carbamazepine. In addition to HSV (in which lesions appear 7 to 12 days after the viral eruption), EM can also follow vaccinations, radiation therapy, and exposure to environmental toxins.

In addition to primary blistering disorders and hypersensitivity reactions, bacterial and viral infections can lead to vesicles and bullae. The most common infectious agents are herpes simplex, herpes varicella-zoster, and staphylococci.

Staphylococcal scalded-skin syndrome (SSSS) and bullous impetigo are two blistering disorders associated with staphylococcal (phage group II) infection. In SSSS, the initial findings are redness and tenderness of the central face, neck, trunk, and intertriginous zones. This is followed by short-lived flaccid bullae and a slough or exfoliation of the superficial epidermis. Crusted areas then develop, characteristically around the mouth. SSSS is distinguished from TEN by the following features: younger age group, more superficial site of blister formation, no oral lesions, shorter course, less morbidity and mortality, and an association with staphylococcal exfoliative toxin (“exfoliatin”), not drugs. A rapid diagnosis of SSSS versus TEN can be made by a frozen section of the blister roof or exfoliative cytology of the blister contents. In SSSS the site of staphylococcal infection is usually extracutaneous (conjunctivitis, rhinorrhea, otitis media, pharyngitis, tonsillitis), and the cutaneous lesions are sterile, whereas in bullous impetigo the skin lesions are the site of infection. Impetigo is more localized than SSSS and usually presents with honey-colored crusts. Occasionally, superficial purulent blisters also form. Cutaneous emboli from gram-negative infections may present as isolated bullae, but the base of the lesion is purpuric or necrotic, and it may develop into an ulcer.

Several metabolic disorders are associated with blister formation, including diabetes mellitus, renal failure, and porphyria. Local hypoxia secondary to decreased cutaneous blood flow can also produce blisters, which explains the presence of bullae over pressure points in comatose patients (coma bullae). In diabetes mellitus, tense bullae with clear viscous fluid arise on normal skin. The lesions can be as large as 6 cm in diameter and are located on the distal extremities. There are several types of porphyria, but the most common form with cutaneous findings is PCT. In sun-exposed areas (primarily the face and hands), the skin is very fragile, and trauma leads to erosions and tense vesicles. These lesions then heal with scarring and formation of milia; the latter are firm, 1- to 2-mm white or yellow papules that represent epidermoid inclusion cysts. Associated findings can include hypertrichosis of the lateral malar region (men) or face (women) and, in sun-exposed areas, hyperpigmentation and firm sclerotic plaques. An elevated level of urinary uroporphyrins confirms the diagnosis and is due to a decrease in uroporphyrinogen decarboxylase activity. Precipitating agents include alcohol, iron, chlorinated hydrocarbons, hepatitis C infection, and hepatomas.

The differential diagnosis of PCT includes (1) porphyria variegata—the skin signs of PCT plus the systemic findings of acute intermittent porphyria; it has a diagnostic plasma porphyrin fluorescence emission at 626 nm; (2) drug-induced bullous photosensitivity (pseudoporphyria)—the clinical and histologic findings are similar to PCT, but porphyrins are normal; etiologic agents include naproxen, furosemide, tetracycline, and nalidixic acid; (3) bullous dermatosis of hemodialysis—the same appearance as PCT, but porphyrins are usually normal or occasionally borderline elevated; patients have chronic renal failure and are on hemodialysis; (4) PCT associated with hepatomas, hepatic carcinomas, and hemodialysis; and (5) epidermolysis bullosa acquisita

EXANTHEMS

Exanthems are characterized by an acute generalized eruption. The two most common presentations are erythematous macules and papules (morbilliform) and confluent blanching erythema (scarlatiniform). Morbilliform eruptions are usually due to either drugs or viral infections. For example, up to 5% of the patients receiving penicillins, sulfonamides, phenytoin, or gold will develop a maculopapular eruption. Accompanying signs may include pruritus, fever, eosinophilia, and transient lymphadenopathy. Similar maculopapular eruptions are seen in the classic childhood viral exanthems, including (1) rubeola (measles)—a prodrome of coryza, cough, and conjunctivitis followed by Koplik's spots on the buccal mucosa; the eruption begins behind the ears, at the hairline, and on the forehead and then spreads down the body, often becoming confluent; (2) rubella—it begins on the forehead and face and then spreads down the body; it resolves in the same order and is associated with retroauricular and suboccipital lymphadenopathy; and (3) erythema infectiosum (fifth disease)—erythema of the cheeks is followed by a reticulated pattern on extremities; it is secondary to a parvovirus B19 infection, and an associated arthritis is seen in adults.

Both measles and rubella are seen in unvaccinated young adults, and an atypical form of measles is seen in adults immunized with either killed measles vaccine or killed vaccine followed in time by live vaccine. In contrast to classic measles, the eruption of atypical measles begins on the palms, soles, wrists, and knuckles, and the lesions may become purpuric. The patient with atypical measles can have pulmonary involvement and be quite ill. Rubelliform and roseoliform eruptions are also associated with Epstein-Barr virus (5 to 15% of patients), echovirus, coxsackievirus, and adenovirus infections. Detection of specific IgM antibodies or fourfold elevations in IgG antibodies allows the proper diagnosis. Occasionally, a maculopapular drug eruption is a reflection of an underlying viral infection. For example, about 95% of the patients with infectious mononucleosis who are given ampicillin will develop a rash.

Of note, early in the course of infections with Rickettsia and meningococcus, prior to the development of purpura, the lesions may be erythematous macules and papules. This is also the case in chickenpox prior to the development of vesicles. Maculopapular eruptions are associated with early HIV infection, early secondary syphilis, typhoid fever, and acute graft-versus-host disease. In the last, lesions frequently begin on the palms and soles; the macular rose spots of typhoid fever involve primarily the anterior trunk.

The prototypic scarlatiniform eruption is seen in scarlet fever and is due to an erythrotoxin produced by group A β-hemolytic streptococcal infections, most commonly pharyngitis. This eruption is characterized by diffuse erythema, which begins on the neck and upper trunk, and red follicular puncta. Additional findings include a white strawberry tongue (white coating with red papillae) followed by a red strawberry tongue (red tongue with red papillae); petechiae of the palate; a facial flush with circumoral pallor; linear petechiae in the antecubital fossae; and desquamation of the involved skin, palms, and soles 5 to 20 days after onset of the eruption. A similar desquamation of the palms and soles is seen in toxic shock syndrome (TSS), Kawasaki's disease, and after severe febrile illnesses. Certain strains of staphylococci also produce an erythrotoxin that leads to the same clinical findings as in streptococcal scarlet fever, except that the antistreptolysin O titers are not elevated.

In toxic shock syndrome, staphylococcal (phage group I) infections produce an exotoxin (TSST-1) that causes the fever and rash, as well as enterotoxins. Initially, the majority of cases were reported in menstruating women who were using tampons. However, other sites of infection, including wounds and vaginitis, can lead to TSS. The diagnosis of TSS is based on clinical criteria, and three of these involve mucocutaneous sites (diffuse erythema of the skin, desquamation of the palms and soles 1 to 2 weeks after onset of illness, and involvement of the mucous membranes). The latter is characterized as hyperemia of the vagina, oropharynx, or conjunctivae. Similar systemic findings have been described in streptococcal toxic shock–like syndrome, and although an exanthem is seen less often than in TSS due to a staphylococcal infection, the underlying infection is often in the soft tissue.

The cutaneous eruption in Kawasaki's disease (mucocutaneous lymph node syndrome) is polymorphous, but the two most common forms are morbilliform and scarlatiniform. Additional mucocutaneous findings include bilateral conjunctival injection; erythema and edema of the hands and feet followed by desquamation; and diffuse erythema of the oropharynx, red strawberry tongue, and erosions with crusting on the lips. This clinical picture can resemble TSS and scarlet fever, but clues to the diagnosis of Kawasaki's disease are cervical lymphadenopathy, lip erosions, and thrombocytosis. The most serious associated systemic finding in this disease is coronary aneurysm secondary to arteritis. Aneurysms may lead to sudden death, primarily within the first 30 days of the illness. Scarlatiniform eruptions are also seen in the early phase of SSSS and as reactions to drugs.

URTICARIA

Urticaria (hives) are transient lesions that are composed of a central wheal surrounded by an erythematous halo. Individual lesions are round, oval, or figurate and are often pruritic. Acute and chronic urticaria have a wide variety of allergic etiologies and reflect edema in the dermis. Urticarial lesions can also be seen in patients with mastocytosis (urticaria pigmentosa), hyperthyroidism, and juvenile rheumatoid arthritis (JRA). In JRA, the lesions coincide with the fever spike, are transient, and are due to dermal infiltrates of neutrophils.

The common physical urticarias include dermographism, solar urticaria, cold urticaria, and cholinergic urticaria. Patients with dermographism exhibit linear wheals following minor pressure or scratching of the skin. It is a common disorder, affecting ~5% of the population. Solar urticaria characteristically occurs within minutes of sun exposure and is a skin sign of one systemic disease—erythropoietic protoporphyria. In addition to the urticaria, these patients have subtle pitted scarring of the nose and hands. Cold urticaria is precipitated by exposure to the cold, and therefore exposed areas are usually affected. In some cases, the disease is associated with abnormal circulating proteins—more commonly cryoglobulins and less commonly cryofibrinogens and cold agglutinins. Additional systemic symptoms include wheezing and syncope, thus explaining the need for these patients to avoid swimming in cold water. Cholinergic urticaria is precipitated by heat, exercise, or emotion and are characterized by small wheals with relatively large flares. They are occasionally associated with wheezing.

Whereas urticaria are the result of dermal edema, subcutaneous edema leads to the clinical picture of angioedema. Sites of involvement include the eyelids, lips, tongue, larynx, and gastrointestinal tract as well as the subcutaneous tissue. Angioedema occurs alone or in combination with urticaria, including urticarial vasculitis and the physical urticarias. Both acquired and hereditary (autosomal dominant) forms of angioedema occur, and in the latter, urticaria is rarely, if ever, seen.

Urticarial vasculitis is an immune complex disease that may be confused with simple urticaria. In contrast to simple urticaria, individual lesions tend to last longer than 24 h and usually develop central petechiae that can be observed even after the urticarial phase has resolved. The patient may also complain of burning rather than pruritus. On biopsy, there is a leukocytoclastic vasculitis of the small blood vessels. Although many cases of urticarial vasculitis are idiopathic in origin, it can be a reflection of an underlying systemic illness such as lupus erythematosus, Sjögren's syndrome, or hereditary complement deficiency. There is a spectrum of urticarial vasculitis that ranges from purely cutaneous to multisystem involvement. The most common systemic signs and symptoms are arthralgias and/or arthritis, nephritis, and crampy abdominal pain, with asthma and chronic obstructive lung disease seen less often. Hypocomplementemia occurs in one- to two-thirds of patients, even in the idiopathic cases. Urticarial vasculitis can also be seen in patients with hepatitis B and hepatitis C infections, serum sickness, and serum sickness–like illnesses.

PAPULONODULAR SKIN LESIONS

In the papulonodular diseases, the lesions are elevated above the surface of the skin and may coalesce to form plaques. The location, consistency, and color of the lesions are the keys to their diagnosis; this section is organized on the basis of color.

White Lesions

In calcinosis cutis there are firm white to white-yellow papules with an irregular surface. When the contents are expressed, a chalky white material is seen. Dystrophic calcification is seen at sites of previous inflammation or damage to the skin. It develops in acne scars as well as on the distal extremities of patients with scleroderma and in the subcutaneous tissue and intermuscular fascial planes in DM. The latter is more extensive and is more commonly seen in children. An elevated calcium phosphate product, most commonly due to secondary hyperparathyroidism in the setting of renal failure, can lead to nodules of metastatic calcinosis cutis, which tend to be subcutaneous and periarticular. These patients can also develop calcification of muscular arteries and subsequent ischemic necrosis (calciphylaxis).

Skin-Colored Lesions

There are several types of skin-colored lesions, including epidermoid inclusion cysts, lipomas, rheumatoid nodules, neurofibromas, angiofibromas, neuromas, and adnexal tumors such as tricholemmomas. Both epidermoid inclusion cysts and lipomas are very common mobile subcutaneous nodules—the former are rubbery and compressible and drain cheeselike material (sebum and keratin) if incised. Lipomas are firm and somewhat lobulated on palpation. When extensive facial epidermoid inclusion cysts develop in childhood or there is a family history of such lesions, the patient should be examined for other signs of Gardner syndrome, including osteomas and desmoid tumors. Rheumatoid nodules are firm, 0.5- to 4-cm nodules that tend to localize around pressure points, especially the elbows. They are seen in approximately 20% of patients with rheumatoid arthritis and 6% of patients with Still's disease. Biopsies of the nodules show palisading granulomas. Similar lesions that are smaller and shorter-lived are seen in rheumatic fever.

Neurofibromas (benign Schwann cell tumors) are soft papules or nodules that exhibit the “button-hole” sign, that is, they invaginate into the skin with pressure in a manner similar to a hernia. Single lesions are seen in normal individuals, but multiple neurofibromas, usually in combination with six or more CALM measuring >1.5 cm, axillary freckling, and multiple Lisch nodules, are seen in von Recklinghausen's disease (NF type I). In some patients the neurofibromas are localized and unilateral due to somatic mosaicism.

Angiofibromas are firm, pink to skin-colored papules that measure from 3 mm to several centimeters in diameter. When they are located on the central cheeks (adenoma sebaceum), the patient has tuberous sclerosis or MEN syndrome, type 1. The former is an autosomal disorder due to mutations in two different genes, and the associated findings are discussed in the section on ash leaf spots as well as in.

Neuromas (benign proliferations of nerve fibers) are also firm, skin-colored papules. They are more commonly found at sites of amputation and as rudimentary supernumerary digits. However, when there are multiple neuromas on the eyelids, lips, distal tongue, and/or oral mucosa, the patient should be investigated for other signs of the MEN syndrome, type 2b. Associated findings include marfanoid habitus, protuberant lips, intestinal ganglioneuromas, and medullary thyroid carcinoma (>75% of patients).

Adnexal tumors are derived from pluripotential cells of the epidermis that can differentiate toward hair, sebaceous, apocrine, or eccrine glands or remain undifferentiated. Basal cell carcinomas (BCCs) are examples of adnexal tumors that have little or no evidence of differentiation. Clinically, they are translucent papules with rolled borders, telangiectasias, and central erosion. BCCs commonly arise in sun-damaged skin of the head and neck. When a patient has multiple BCCs, especially prior to age 30, the possibility of the nevoid basal cell carcinoma syndrome should be raised. It is inherited as an autosomal dominant trait and is associated with jaw cysts, palmar and plantar pits, frontal bossing, medulloblastomas, and calcification of the falx cerebri and diaphragma sellae. Tricholemmomas are also skin-colored adnexal tumors but differentiate toward hair follicles and can have a wartlike appearance. The presence of multiple tricholemmomas on the face and cobblestoning of the oral mucosa points to the diagnosis of Cowden's disease (multiple hamartoma syndrome) due to mutations in the PTEN gene. Internal organ involvement (in decreasing order of frequency) includes fibrocystic disease and carcinoma of the breast, adenomas and carcinomas of the thyroid, and gastrointestinal polyposis. Keratoses of the palms, soles, and dorsa of the hands are also seen.

Pink Lesions

The cutaneous lesions associated with primary systemic amyloidosis are pink in color and translucent. Common locations are the face, especially the periorbital and perioral regions, and flexural areas. On biopsy, homogeneous deposits of amyloid are seen in the dermis and in the walls of blood vessels; the latter lead to an increase in vessel wall fragility. As a result, petechiae and purpura develop in clinically normal skin as well as in lesional skin following minor trauma, hence the term pinch purpura. Amyloid deposits are also seen in the striated muscle of the tongue and result in macroglossia.

Even though specific mucocutaneous lesions are rarely seen in secondary amyloidosis and are present in only about 30% of the patients with primary amyloidosis, a rapid diagnosis of systemic amyloidosis can be made by an examination of abdominal subcutaneous fat. By special staining, deposits are seen around blood vessels or individual fat cells in 40 to 50% of patients. There are also three forms of amyloidosis that are limited to the skin and that should not be construed as cutaneous lesions of systemic amyloidosis. They are macular amyloidosis (upper back), lichenoid amyloidosis (usually lower extremities), and nodular amyloidosis. In macular and lichenoid amyloidosis, the deposits are composed of altered epidermal keratin. Recently, macular and lichenoid amyloidosis have been associated with MEN syndrome, type 2a.

Patients with multicentric reticulohistiocytosis also have pink-colored papules and nodules on the face and mucous membranes as well as on the extensor surface of the hands and forearms. They have a polyarthritis that can mimic rheumatoid arthritis clinically. On histologic examination, the papules have characteristic giant cells that are not seen in biopsies of rheumatoid nodules. Pink to skin-colored papules that are firm, 2 to 5 mm in diameter, and often in a linear arrangement are seen in patients with papular mucinosis. This disease is also referred to as lichen myxedematosus or scleromyxedema. The latter name comes from the brawny induration of the face and extremities that may accompany the papular eruption. Biopsy specimens of the papules show localized mucin deposition, and serum protein electrophoresis demonstrates a monoclonal spike of IgG, usually with a λ light chain.

Yellow Lesions

Several systemic disorders are characterized by yellow-colored cutaneous papules or plaques—hyperlipidemia (xanthomas), gout (tophi), diabetes (necrobiosis lipoidica), pseudoxanthoma elasticum, and Torre syndrome (sebaceous tumors). Eruptive xanthomas are the most common form of xanthomas, and are associated with hypertriglyceridemia (types I, III, IV, and V). Crops of yellow papules with erythematous halos occur primarily on the extensor surfaces of the extremities and the buttocks, and they spontaneously involute with a fall in serum triglycerides. Increased β-lipoproteins (primarily types II and III) result in one or more of the following types of xanthoma: xanthelasma, tendon xanthomas, and plane xanthomas. Xanthelasma are found on the eyelids, whereas tendon xanthomas are frequently associated with the Achilles and extensor finger tendons; plane xanthomas are flat and favor the palmar creases, face, upper trunk, and scars. Tuberous xanthomas are frequently associated with hypertriglyceridemia, but they are also seen in patients with hypercholesterolemia (type II) and are found most frequently over the large joints or hand. Biopsy specimens of xanthomas show collections of lipid-containing macrophages (foam cells).

Patients with several disorders, including biliary cirrhosis, can have a secondary form of hyperlipidemia with associated tuberous and planar xanthomas. However, patients with myeloma have normolipemic flat xanthomas. This latter form of xanthoma may be ≥12 cm in diameter and is most frequently seen on the upper trunk or side of the neck. It is important to note that the most common setting for eruptive xanthomas is uncontrolled diabetes mellitus. The least specific sign for hyperlipidemia is xanthelasma, because at least 50% of the patients with this finding have normal lipid profiles.

In tophaceous gout there are deposits of monosodium urate in the skin around the joints, particularly those of the hands and feet. Additional sites of tophi formation include the helix of the ear and the olecranon and prepatellar bursae. The lesions are firm, yellow in color, and occasionally discharge a chalky material. Their size varies from 1 mm to 7 cm, and the diagnosis can be established by polarization of the aspirated contents of a lesion. Lesions of necrobiosis lipoidica are found primarily on the shins (90%), and patients can have diabetes mellitus or develop it subsequently. Characteristic findings include a central yellow color, atrophy (transparency), telangiectasias, and an erythematous border. Ulcerations can also develop within the plaques. Biopsy specimens show necrobiosis of collagen, granulomatous inflammation, and obliterative endarteritis.

In pseudoxanthoma elasticum (PXE) there is an abnormal deposition of calcium on the elastic fibers of the skin, eye, and blood vessels. In the skin, the flexural areas such as the neck, axillae, antecubital fossae, and inguinal area are the primary sites of involvement. Yellow papules coalesce to form reticulated plaques that have an appearance similar to that of plucked chicken skin. In severely affected skin, hanging, redundant folds develop. Biopsy specimens of involved skin show swollen and irregularly clumped elastic fibers with deposits of calcium. In the eye, the calcium deposits in Bruch's membrane lead to angioid streaks and choroiditis; in the arteries of the heart, kidney, gastrointestinal tract, and extremities, the deposits lead to angina, hypertension, gastrointestinal bleeding, and claudication, respectively. Long-term administration of D-penicillamine can lead to PXE-like skin changes as well as elastic fiber alterations in internal organs.

Adnexal tumors that have differentiated toward sebaceous glands include sebaceous adenoma, sebaceous carcinoma, and sebaceous hyperplasia. Except for sebaceous hyperplasia, which is commonly seen on the face, these tumors are fairly rare. Patients with Torre syndrome have one or more sebaceous adenoma(s), and they can also have sebaceous carcinomas and sebaceous hyperplasia as well as keratoacanthomas. The internal manifestations of Torre syndrome include multiple carcinomas of the gastrointestinal tract (primarily colon) as well as cancers of the larynx, genitourinary tract, and endometrium.

Red Lesions

Cutaneous lesions that are red in color have a wide variety of etiologies; in an attempt to simplify their identification, they will be subdivided into papules, papules/plaques, and subcutaneous nodules. Common red papules include arthropod bites and cherry hemangiomas; the latter are small, bright-red, dome-shaped papules that represent benign proliferation of capillaries. In patients with AIDS, the development of multiple red hemangioma-like lesions points to bacillary angiomatosis, and biopsy specimens show clusters of bacilli that stain positive with the Warthin-Starry stain; the pathogens have been identified as Bartonella henselae and B. quintana. Disseminated visceral disease is seen primarily in immunocompromised hosts but can occur in immunocompetent individuals.

Multiple angiokeratomas are seen in Fabry's disease, an X-linked recessive lysosomal storage disease that is due to a deficiency of α-galactosidase A. The lesions are red to red-blue in color and can be quite small in size (1 to 3 mm), with the most common location being the lower trunk. Associated findings include chronic renal failure, peripheral neuropathy, and corneal opacities (cornea verticillata). Electron photomicrographs of angiokeratomas and clinically normal skin demonstrate lamellar lipid deposits in fibroblasts, pericytes, and endothelial cells that are diagnostic of this disease. Widespread acute eruptions of erythematous papules are discussed in the section on exanthems.

There are several infectious diseases that present as erythematous papules or nodules in a sporotrichoid pattern, that is, in a linear arrangement along the lymphatic channels. The two most common etiologies are Sporothrix schenckii (sporotrichosis) and M. marinum (atypical mycobacteria). The organisms are introduced as a result of trauma, and a primary inoculation site is often seen in addition to the lymphatic nodules. Additional causes include Nocardia, Leishmania, and other dimorphic fungi; culture of lesional tissue will aid in the diagnosis.

The diseases that are characterized by erythematous plaques with scale are reviewed in the papulosquamous section, and the various forms of dermatitis are discussed in the section on erythroderma. Additional disorders in the differential diagnosis of red papules/plaques include erysipelas, polymorphous light eruption (PMLE), lymphocytoma cutis, cutaneous lupus, lymphoma cutis, and leukemia cutis. The first three diseases represent primary cutaneous disorders. PMLE is characterized by erythematous papules and plaques in a primarily sun-exposed distribution—dorsum of the hand, extensor forearm, and face. Lesions follow exposure to UV-B and/or UV-A, and in northern latitudes PMLE is most severe in the late spring and early summer. A process referred to as “hardening” occurs with continued UV exposure, and the eruption fades, but in temperate climates it will recur in the spring. PMLE must be differentiated from cutaneous lupus, and this is accomplished by histologic examination and direct immunofluorescence of the lesions. Lymphocytoma cutis (pseudolymphoma) is a benign polyclonal proliferation of lymphocytes in the skin that presents as infiltrated pink-red to red-purple papules and plaques; it must be distinguished from lymphoma cutis.

Several types of red plaques are seen in patients with systemic lupus, including (1) erythematous urticarial plaques across the cheeks and nose in the classic butterfly rash; (2) erythematous discoid lesions with fine or “carpet-tack” scale, telangiectasias, central hypopigmentation, peripheral hyperpigmentation, follicular plugging, and atrophy located on the face, scalp, external ears, arms, and upper trunk; and (3) psoriasiform or annular lesions of subacute lupus with hypopigmented centers located on the face, extensor arms, and upper trunk. Additional cutaneous findings include (1) a violaceous flush on the face and V of the neck; (2) urticarial vasculitis (; (3) lupus panniculitis (see below); (4) diffuse alopecia; (5) alopecia secondary to discoid lesions; (6) periungual telangiectasias and erythema; (7) EM-like lesions that may become bullous; and (8) distal ulcerations secondary to Raynaud's phenomenon, vasculitis, or livedoid vasculopathy. Patients with only discoid lesions usually have the form of lupus that is limited to the skin. However, 2 to 10% of these patients eventually develop systemic lupus. Direct immunofluorescence of involved skin shows deposits of IgG or IgM and C3 in a granular distribution along the dermal-epidermal junction.

In lymphoma cutis there is a proliferation of malignant lymphocytes or histiocytes in the skin, and the clinical appearance resembles that of lymphocytoma cutis—infiltrated pink-red to red-purple papules and plaques. Lymphoma cutis can occur anywhere on the surface of the skin, whereas the sites of predilection for lymphocytomas include the malar ridge, tip of the nose, and earlobes. Patients with non-Hodgkin's lymphomas have specific cutaneous lesions more often than those with Hodgkin's disease, and occasionally, the skin nodules precede the development of extracutaneous non-Hodgkin's lymphoma or represent the only site of involvement. Arcuate lesions are sometimes seen in lymphoma and lymphocytoma cutis as well as in CTCL. Leukemia cutis has the same appearance as lymphoma cutis, and specific lesions are seen more commonly in monocytic leukemias than in lymphocytic or granulocytic leukemias. Cutaneous chloromas (granulocytic sarcomas) may precede the appearance of circulating blasts in acute nonlymphocytic leukemia and, as such, represent a form of aleukemic leukemia cutis.

Common causes of erythematous subcutaneous nodules include inflamed epidermoid inclusion cysts, acne cysts, and furuncles. Panniculitis, an inflammation of the fat, also presents as subcutaneous nodules and is frequently a sign of systemic disease. There are several forms of panniculitis, including erythema nodosum, erythema induratum/nodular vasculitis, lupus profundus, lipomembranous lipodermatosclerosis, α₁-antitrypsin deficiency, facticial, and fat necrosis secondary to pancreatic disease. Except for erythema nodosum, these lesions may break down and ulcerate or heal with a scar. The shin is the most common location for the nodules of erythema nodosum, whereas the calf is the most common location for lesions of erythema induratum. In erythema nodosum the nodules are initially red but then develop a blue color as they resolve. Patients with erythema nodosum but no underlying systemic illness can still have fever, malaise, leukocytosis, arthralgias, and/or arthritis. However, the possibility of an underlying illness should be excluded, and the most common associations are streptococcal infections, upper respiratory infections, sarcoidosis, and inflammatory bowel disease. The less common associations include tuberculosis, histoplasmosis, coccidioidomycosis, psittacosis, drugs (oral contraceptives, sulfonamides, aspartame, bromides, iodides), cat-scratch fever, and infections with Yersinia, Salmonella, and Chlamydia.

Erythema induratum and nodular vasculitis share a similar histology and were thought to represent the clinical spectrum of a single entity; subsequently they have been separated, with the latter idiopathic and the former associated with the presence of M. tuberculosis DNA by polymerase chain reaction (PCR) in 25 to 70% of patients. The lesions of lupus profundus are found primarily on the upper arms and buttocks (sites of abundant fat) and are seen in both the cutaneous and systemic forms of lupus. The overlying skin may be normal, erythematous, or have the changes of discoid lupus. The subcutaneous fat necrosis that is associated with pancreatic disease is presumably secondary to circulating lipases and is seen in patients with pancreatic carcinoma as well as in patients with acute and chronic pancreatitis. In this disorder there may be an associated arthritis, fever, and inflammation of visceral fat. Histologic examination of deep incisional biopsy specimens will aid in the diagnosis of the particular type of panniculitis.

Subcutaneous erythematous nodules are also seen in cutaneous polyarteritis nodosa (PAN) and as a manifestation of systemic vasculitis, e.g., systemic PAN, allergic granulomatosis, or Wegener's granulomatosis. Cutaneous PAN presents with painful subcutaneous nodules and ulcers within a red-purple, netlike pattern of livedo reticularis. The latter is due to slowed blood flow through the superficial horizontal venous plexus. The majority of lesions are found on the lower extremity, and while arthralgias and myalgias may accompany cutaneous PAN, there is no evidence of systemic involvement. In both the cutaneous and systemic forms of vasculitis, skin biopsy specimens of the associated nodules will show the changes characteristic of a vasculitis; the size of the vessel involved will depend on the particular disease.

Red-Brown Lesions

The cutaneous lesions in sarcoidosis are classically red to red-brown in color, and with diascopy (pressure with a glass slide) a yellow-brown residual color is observed that is secondary to the granulomatous infiltrate. The waxy papules and plaques may be found anywhere on the skin, but the face is the most common location. Usually there are no surface changes, but occasionally the lesions will have scale. Biopsy specimens of the papules show “naked” granulomas in the dermis, i.e., granulomas surrounded by a minimal number of lymphocytes. Other cutaneous findings in sarcoidosis include annular lesions with an atrophic or scaly center, papules within scars, hypopigmented macules and papules, alopecia, acquired ichthyosis, erythema nodosum, and lupus pernio (see below).

The differential diagnosis of sarcoidosis includes foreign-body granulomas produced by chemicals such as beryllium and zirconium, late secondary syphilis, and lupus vulgaris. Lupus vulgaris is a form of cutaneous tuberculosis that is seen in previously infected and sensitized individuals. There is often underlying active tuberculosis elsewhere, usually in the lungs or lymph nodes. At least 90% of the lesions occur in the head and neck area and are red-brown plaques with a yellow-brown color on diascopy. Secondary scarring and squamous cell carcinomas can develop within the plaques. Cultures or PCR analysis of the lesions should be done because it is rare for the acid-fast stain to show bacilli within the dermal granulomas.

Sweet's syndrome is characterized by red to red-brown plaques and nodules that are frequently painful and occur primarily on the head, neck, and upper extremities. The patients also have fever, neutrophilia, and a dense dermal infiltrate of neutrophils in the lesions. In approximately 10% of the patients there is an associated malignancy, most commonly acute nonlymphocytic leukemia. Sweet's syndrome has also been reported with lymphoma, chronic leukemia, myeloma, myelodysplastic syndromes, and solid tumors (primarily of the genitourinary tract). The differential diagnosis includes neutrophilic eccrine hidradenitis and atypical forms of pyoderma gangrenosum. Extracutaneous sites of involvement include joints, muscles, eye, kidney (proteinuria, occasionally glomerulonephritis), and lung (neutrophilic infiltrates). The idiopathic form of Sweet's syndrome is seen more often in women, following a respiratory tract infection.

A generalized distribution of red-brown macules and papules is seen in the form of mastocytosis known as urticaria pigmentosa. Each lesion represents a collection of mast cells in the dermis, with hyperpigmentation of the overlying epidermis. Stimuli such as rubbing cause these mast cells to degranulate, and this leads to the formation of localized urticaria (Darier's sign). Additional symptoms can result from mast cell degranulation and include headache, flushing, diarrhea, and pruritus. Mast cells also infiltrate various organs such as the liver, spleen, and gastrointestinal tract in up to 30 to 50% of patients with urticaria pigmentosa, and accumulations of mast cells in the bones may produce either osteosclerotic or osteolytic shadows on radiographs. In the majority of these patients, however, the internal involvement remains fairly static. A subtype of chronic leukocytoclastic vasculitis, erythema elevatum diutinum (EED), also presents with papules that are red-brown in color. The papules coalesce into plaques on the extensor surfaces of knees, elbows, and the small joints of the hand. Flares of EED have been associated with streptococcal infections.

Blue Lesions

Lesions that are blue in color are the result of either vascular ectasias and tumors or melanin pigment in the dermis. Venous lakes (ectasias) are compressible dark-blue lesions that are found commonly in the head and neck region. Venous malformations are also compressible blue papules and nodules that can occur anywhere on the body, including the oral mucosa. When there are multiple rather than single congenital lesions, the patient may have the blue rubber bleb syndrome or Mafucci's syndrome. Patients with the blue rubber bleb syndrome also have vascular anomalies of the gastrointestinal tract that may bleed, whereas patients with Mafucci's syndrome have associated dyschondroplasia and osteochondromas. Blue nevi (moles) are seen when there are collections of pigment-producing nevus cells in the dermis. These benign papular lesions are dome-shaped and occur most commonly on the dorsum of the hand or foot.

Violaceous Lesions

Violaceous papules and plaques are seen in lupus pernio, lymphoma cutis, and cutaneous lupus. Lupus pernio is a particular type of sarcoidosis that involves the tip of the nose and the earlobes, with lesions that are violaceous in color rather than red-brown. This form of sarcoidosis is associated with involvement of the upper respiratory tract. The plaques of lymphoma cutis and cutaneous lupus may be red or violaceous in color and were discussed above.

Purple Lesions

Purple-colored papules and plaques are seen in vascular tumors, such as Kaposi's sarcoma and angiosarcoma, and when there is extravasation of red blood cells into the skin in association with inflammation, as in palpable purpura. Patients with congenital or acquired AV fistulas and venous hypertension can develop purple papules on the lower extremities that can resemble Kaposi's sarcoma clinically and histologically; this condition is referred to as pseudo-Kaposi sarcoma (acral angiodermatitis). Angiosarcoma is found most commonly on the scalp and face of elderly patients or within areas of chronic lymphedema and presents as purple papules and plaques. In the head and neck region the tumor often extends beyond the clinically defined borders and may be accompanied by facial edema.

Brown and Black Lesions

Brown- and black-colored papules are reviewed in “Hyperpigmentation,” above.

Cutaneous Metastases

These are discussed last because they can have a wide range of colors. Most commonly they present as either firm, skin-colored subcutaneous nodules or firm, red to red-brown papulonodules. The lesions of lymphoma cutis range from pink-red to plum in color, whereas metastatic melanoma can be pink, blue, or black in color. Cutaneous metastases develop from hematogenous or lymphatic spread and are most often due to the following primary carcinomas: in men, lung, colon, melanoma, and oral cavity; and in women, breast, colon, and lung. These metastatic lesions may be the initial presentation of the carcinoma, especially when the primary site is the lung, kidney, or ovary.

PURPURA

Purpura are seen when there is an extravasation of red blood cells into the dermis and, as a result, the lesions do not blanch with pressure. This is in contrast to those erythematous or violet-colored lesions that are due to localized vasodilatation—they do blanch with pressure. Purpura (≥3 mm) and petechiae (≤2 mm) are divided into two major groups, palpable and nonpalpable. The most frequent causes of nonpalpable petechiae and purpura are primary cutaneous disorders such as trauma, solar purpura, and capillaritis. Less common causes are steroid purpura and livedoid vasculitis. Solar purpura are seen primarily on the extensor forearms, while glucocorticoid purpura secondary to potent topical steroids or endogenous or exogenous Cushing's syndrome can be more widespread. In both cases there is alteration of the supporting connective tissue that surrounds the dermal blood vessels. In contrast, the petechiae that result from capillaritis are found primarily on the lower extremities. In capillaritis there is an extravasation of erythrocytes as a result of perivascular lymphocytic inflammation. The petechiae are bright red, 1 to 2 mm in size, and scattered within annular or coin-shaped yellow-brown macules. The yellow-brown color is caused by hemosiderin deposits within the dermis.

Systemic causes of nonpalpable purpura fall into several categories, and those secondary to clotting disturbances and vascular fragility will be discussed first. The former group includes thrombocytopenia, abnormal platelet function as is seen in uremia, and clotting factor defects. The initial site of presentation for thrombocytopenia-induced petechiae is the distal lower extremity. Capillary fragility leads to nonpalpable purpura in patients with systemic amyloidosis, disorders of collagen production such as Ehlers-Danlos syndrome, and scurvy. In scurvy there are flattened corkscrew hairs with surrounding hemorrhage on the lower extremities, in addition to gingivitis. Vitamin C is a cofactor for lysyl hydroxylase, an enzyme involved in the posttranslational modification of procollagen that is necessary for cross-link formation.

In contrast to the previous group of disorders, the purpura seen in the following group of diseases are associated with thrombi formation within vessels. It is important to note that these thrombi are demonstrable in skin biopsy specimens. This group of disorders includes disseminated intravascular coagulation (DIC), monoclonal cryoglobulinemia, thrombotic thrombocytopenic purpura, and reactions to warfarin. DIC is triggered by several types of infection (gram-negative, gram-positive, viral, and rickettsial) as well as by tissue injury and neoplasms. Widespread purpura and hemorrhagic infarcts of the distal extremities are seen. Similar lesions are found in purpura fulminans, which is a form of DIC associated with fever and hypotension that occurs more commonly in children following an infectious illness such as varicella, scarlet fever, or an upper respiratory tract infection. In both disorders, hemorrhagic bullae can develop in involved skin.

Monoclonal cryoglobulinemia is associated with multiple myeloma, Waldenström's macroglobulinemia, lymphocytic leukemia, and lymphoma. Purpura, primarily of the lower extremities, and hemorrhagic infarcts of the fingers and toes are seen in these patients. Exacerbations of disease activity can follow cold exposure or an increase in serum viscosity. Biopsy specimens show precipitates of the cryoglobulin within dermal vessels. Similar deposits have been found in the lung, brain, and renal glomeruli. Patients with thrombotic thrombocytopenic purpura can also have hemorrhagic infarcts as a result of intravascular thromboses. Additional signs include thrombocytopenic purpura, fever, and microangiopathic hemolytic anemia.

Administration of warfarin can result in painful areas of erythema that become purpuric and then necrotic with an adherent black eschar. This reaction is seen more often in women and in areas with abundant subcutaneous fat—breasts, abdomen, buttocks, thighs, and calves. The erythema and purpura develop between the third and tenth day of therapy, most likely as a result of a transient imbalance in the levels of anticoagulant and procoagulant vitamin K–dependent factors. Continued therapy does not exacerbate preexisting lesions, and patients with an inherited or acquired deficiency of protein C are at increased risk for this particular reaction as well as for purpura fulminans.

Purpura secondary to cholesterol emboli are usually seen on the lower extremities of patients with atherosclerotic vascular disease. They often follow anticoagulant therapy or an invasive vascular procedure such as an arteriogram but also occur spontaneously from disintegration of atheromatous plaques. Associated findings include livedo reticularis, gangrene, cyanosis, subcutaneous nodules, and ischemic ulcerations. Multiple step sections of the biopsy specimen may be necessary to demonstrate the cholesterol clefts with the vessels. Petechiae are also an important sign of fat embolism and occur primarily on the upper body 2 to 3 days after a major injury. By using special fixatives, the emboli can be demonstrated in biopsy specimens of the petechiae. Emboli of tumor or thrombus are seen in patients with atrial myxomas and marantic endocarditis.

In the Gardner-Diamond syndrome (autoerythrocyte sensitivity), female patients develop large ecchymoses within areas of painful, warm erythema. Intradermal injections of autologous erythrocytes or phosphatidyl serine derived from the red cell membrane can reproduce the lesions in some patients; however, there are instances where a reaction is seen at an injection site of the forearm but not in the midback region. The latter has led some observers to view Gardner-Diamond syndrome as a cutaneous manifestation of severe emotional stress. Waldenström's hypergammaglobulinemic purpura is a chronic disorder characterized by petechiae on the lower extremities. There are circulating complexes of IgG–anti-IgG molecules, and exacerbations are associated with prolonged standing or walking.

Palpable purpura are further subdivided into vasculitic and embolic. In the group of vasculitic disorders, leukocytoclastic vasculitis (LCV), also known as allergic or small-vessel vasculitis, is the one most commonly associated with palpable purpura. Underlying etiologies include drugs (e.g., antibiotics), infections (e.g., hepatitis C), and connective tissue diseases. Henoch-Schönlein purpura is a subtype of acute LCV that is seen primarily in children and adolescents following an upper respiratory infection. The majority of lesions are found on the lower extremities and buttocks. Systemic manifestations include fever, arthralgias (primarily of the knees and ankles), abdominal pain, gastrointestinal bleeding, and nephritis. Direct immunofluorescence examination shows deposits of IgA within dermal blood vessel walls. In polyarteritis nodosa, specific cutaneous lesions result from a vasculitis of arterial vessels rather than postcapillary venules as in LCV. The arteritis leads to ischemia of the skin, and this explains the irregular outline of the purpura (see below).

Several types of infectious emboli can give rise to palpable purpura. These embolic lesions are usually irregular in outline as opposed to the lesions of LCV, which are circular in outline. The irregular outline is indicative of a cutaneous infarct, and the size corresponds to the area of skin that received its blood supply from that particular arteriole or artery. The palpable purpura in LCV are circular because the erythrocytes simply diffuse out evenly from the postcapillary venules as a result of inflammation. Infectious emboli are most commonly due to gram-negative cocci (meningococcus, gonococcus), gram-negative rods (Enterobacteriaceae), and gram-positive cocci (Staphylococcus). Additional causes include Rickettsia and, in immunocompromised patients, Candida and opportunistic fungi.

The embolic lesions in acute meningococcemia are found primarily on the trunk, lower extremities, and sites of pressure, and a gunmetal-gray color often develops within them. Their size varies from 1 mm to several centimeters, and the organisms can be cultured from the lesions. Associated findings include a preceding upper respiratory tract infection, fever, meningitis, DIC, and, in some patients, a deficiency of the terminal components of complement. In disseminated gonococcal infection (arthritis-dermatitis syndrome), a small number of papules and vesicopustules with central purpura or hemorrhagic necrosis are found on the distal extremities. Additional symptoms include arthralgias, tenosynovitis, and fever. To establish the diagnosis, a Gram stain of these lesions should be performed. Rocky Mountain spotted fever is a tick-borne disease that is caused by R. rickettsii. A several-day history of fever, chills, severe headache, and photophobia precedes the onset of the cutaneous eruption. The initial lesions are erythematous macules and papules on the wrists, ankles, palms, and soles. With time, the lesions spread centripetally and become purpuric.

Lesions of ecthyma gangrenosum begin as edematous, erythematous papules or plaques and then develop central purpura and necrosis. Bullae formation also occurs in these lesions, and they are frequently found in the girdle region. The organism that is classically associated with ecthyma gangrenosum is Pseudomonas aeruginosa, but other gram-negative rods such as Klebsiella, Escherichia coli, and Serratia can produce similar lesions. In immunocompromised hosts, the list of potential pathogens is expanded to include Candida and opportunistic fungi.

ULCERS

The approach to the patient with a cutaneous ulcer is outlined in Table 17.

Livedoid vasculitis (atrophie blanche) represents a combination of a vasculopathy with intravascular thrombosis. Purpuric lesions and livedo reticularis are found in association with painful ulcerations of the lower extremities. These ulcers are often slow to heal, but when they do, irregularly shaped white scars are formed. The majority of cases are secondary to venous hypertension, but possible underlying illnesses include cryofibrinogenemia and disorders of hypercoagulability, e.g., the antiphospholipid syndrome.

In pyoderma gangrenosum, the border of the ulcers has a characteristic appearance of an undermined necrotic violaceous edge and a peripheral erythematous halo. The ulcers often begin as pustules that then expand rather rapidly to a size as large as 20 cm. Although these lesions are most commonly found on the lower extremities, they can arise anywhere on the surface of the body, including sites of trauma (pathergy). An estimated 30 to 50% of cases are idiopathic, and the most common associated disorders are ulcerative colitis and Crohn's disease. Less commonly, it is associated with chronic active hepatitis, seropositive rheumatoid arthritis, acute and chronic granulocytic leukemia, polycythemia vera, and myeloma. Additional findings in these patients, even those with idiopathic disease, are cutaneous anergy and a benign monoclonal gammopathy. Because the histology of pyoderma gangrenosum is nonspecific, the diagnosis is made clinically by excluding less common causes of similar-appearing ulcers such as necrotizing vasculitis, Meleney's ulcer (synergistic infection at a site of trauma or surgery), dimorphic fungi, cutaneous amebiasis, spider bites, and facticial. In the myeloproliferative disorders, the ulcers may be more superficial with a pustulobullous border, and these lesions provide a connection between classic pyoderma gangrenosum and acute febrile neutrophilic dermatosis (Sweet's syndrome).

FEVER AND RASH

The major considerations in a patient with a fever and a rash are inflammatory diseases versus infectious diseases. In the hospital setting, the most common scenario is a patient who has a drug rash plus a fever secondary to an underlying infection. However, it should be emphasized that a drug reaction can lead to both a cutaneous eruption and a fever (“drug fever”). Additional inflammatory diseases that are often associated with a fever include pustular psoriasis, erythroderma, and Sweet's syndrome. Lyme disease, secondary syphilis, and viral and bacterial exanthems are examples of infectious diseases that produce a rash and a fever. Lastly, it is important to determine whether or not the cutaneous lesions represent septic emboli. Such lesions usually have evidence of ischemia in the form of purpura, necrosis, or impending necrosis (gunmetal-gray color). In the patient with thrombocytopenia, however, purpura can be seen in inflammatory reactions such as morbilliform drug eruptions and infectious lesions.

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