Photo Quiz

Blue-Gray Centrofacial Hyperpigmentation

Question Which one of the following is the correct diagnosis, given the patient's history, the physical and skin biopsy findings? A. Actinic lichen planus. B. Hemochromatosis. C. Amiodarone-induced hyperpigmentation. D. Ashy dermatosis (erythema dyschromicum perstans). E. Argyria.

A 68-year-old man presented to a university dermatology department with an asymptomatic blue-gray discoloration of the centrofacial region. Physical examination revealed a blue-gray hyperpigmentation of the forehead, cheeks, nose, malar regions and chin (see the accompanying figure). The medical history revealed that the patient was diagnosed with ischemic dilated cardiomyopathy two years previously and was resuscitated from a syncopal episode associated with sustained ventricular tachycardia that was refractory to quinidine, disopyramide phosphate and procainamide. Results of routine laboratory tests were normal. A 3-mm punch biopsy specimen showed normal epidermis and a perivascular deposition of yellow-brown pigment within microphages in the dermis.

Discussion

The correct answer is C: amiodarone-induced hyperpigmentation. Amiodarone is an iodinated compound used in the treatment of ventricular arrhythmias that are refractory to other medications. Actinic lichen planus is a rare clinical form of lichen planus that occurs in exposed skin areas. The pigmented variant of the disease typically involves only the face, with clinical features resembling melasma. Histopathologic features seen on skin biopsy of actinic lichen planus include a band-like lymphocytic infiltrate with numerous melanophages observed in the dermis.
1

Hemochromatosis is one of the most common genetic errors of metabolism and is characterized by a diffuse cutaneous slate-gray pigmentation in light-exposed areas. The onset of the disease generally occurs during the fourth or fifth decade of life. Men are more commonly affected than women. Other findings may include diabetes and a high serum iron level.
2

Ashy dermatosis, also known as erythema dyschromicum perstans, is a rare idiopathic dermatosis characterized by ash-gray skin lesions. The ash-colored macules vary in size and shape and are localized to the arms, neck and trunk. The face is usually involved. The characteristic blue-gray skin color reflects the presence of melanin in the macrophages of the dermis.
3

Argyria occurs in persons exposed to silver salts and clinically appears as a slate-gray pigmentation on sun-exposed areas of the skin, especially the forehead and nose. The diagnosis of argyria is well established by skin biopsy. Conventional histology shows silver granules in the dermis particularly evident near the basal layer of sweat glands.
4

Several systemic and dermatologic side effects are attributed to amiodarone, such as pulmonary fibrosis (which has a 10 percent mortality rate), thyroid abnormalities, fulminant hepatitis, keratitis, chronic anxiety reaction, photosensitivity reaction and cutaneous hyperpigmentation (in 2 to 5 percent of patients). The pigmentation is clinically
5,6

characterized by progressive blue-gray discoloration of predominantly sun-exposed areas. Lipofuscin is a yellow-brown pigment that accumulates in lysosomes with aging and is a byproduct of cellular degradation. The pathogenesis of amiodarone-induced

This iatrogenic hyperpigmentation is associated with lipofuscin rather than melanin deposits.

hyperpigmentation may be related to the basic action of the drug on the lysosome and to extra phototoxic-induced lysosomal damage. Ultrastructural studies show membrane-bound dense lysosomal bodies within macrophages that probably contain degradation products of the drug bound to lipofuscin. The cutaneous pigmentation slowly fades after discontinuation of
5

therapy but may persist for months to years.

Photo Quiz

Palpable Shin Lesions

A 41-year-old woman presented complaining of the progressive development of lesions on her lower extremities (see accompanying photos). She had also noted swelling of her right wrist and ankle with associated mild pain. The lesions were located primarily over the shins and medial aspects of both lower extremities, and consisted of erythematous macules, some of which had confluent borders. The lesions were palpable, did not blanch on pressure, and had no overlying warmth or tenderness. Mild swelling of the right ankle was present, although the patient maintained full range of motion. The remainder of the physical examination was unremarkable. The patient had been recently diagnosed with hypertension for which she had been taking an angiotensin-converting enzyme inhibitor (ramipril) for two weeks. The patient had no other chronic medical illnesses. She had a history of intravenous drug use during adolescence. On laboratory evaluation, she was noted to have proteinuria (1.2 g per day), with a creatinine clearance
C. Mixed cryoglobulinemia. D. Lichen planus. E. Porphyria cutanea tarda. A. Drug-induced vasculitis. B. Cellulitis. Question Given the patient's history and the results of the physical examination, which one of the following is the correct diagnosis for the disorder shown above?

of 56 mL per minute (0.93 mL per second). Serum aminotransferase levels were mildly elevated: alanine aminotransferase was 123 U per L; aspartate aminotransferase was 139 U per L. The patient tested positive for hepatitis C virus (HCV) infection, most likely contracted during her years of intravenous drug use.

Discussion.
The answer is C: mixed cryoglobulinemia. Her rash is a leukocytoclastic vasculitis caused by cutaneous deposition of cryoimmunoglobulins. Several studies have established a strong link
1,2

between HCV infection and mixed cryoglobulinemia, a multisystem disorder that is characterized by deposition of circulating immune complexes in small and medium-sized blood vessels resulting in arthralgias, Raynaud's syndrome and purpura. Kidney, nerve and brain involvement is possible. It is important to obtain a thorough medication history in any patient who presents with a rash, because drug-induced etiologies are among the most common causes of leukocytoclastic vasculitis. Ramipril has been associated with a rash in a small percentage of patients. It often may not be possible to distinguish between a drug-induced vasculitis and a cryoglobulinemic rash by physical examination alone. However, the coincident clinical findings of positive serum HCV antibody, HCV RNA and serum cryoglobulins make the latter much more likely. In this patient, the rash improved on treatment of HCV infection, despite continued treatment with ramipril. Cellulitis was ruled out by the absence of warmth or tenderness on examination of the leg, as well as absence of systemic manifestations such as a fever or elevated white blood cell count. Lichen planus, a skin rash that occurs in less than 1 percent of the general population, persists for a long time. It presents as flat-topped, violaceous, pruritic papules in a generalized distribution. There is a high incidence of mucosal involvement, and it can involve the hair and nails. Antibodies to HCV are present in 10 to 38 percent of patients with lichen planus. Porphyria cutanea tarda presents with photosensitivity, skin fragility, bruising, and vesicles and bullae that can become hemorrhagic. The so-called sporadic variety is the most common type, although rare familial forms exist. There is a high prevalence (62 to 91 percent) of HCV antibody positivity in patients with the sporadic form of porphyria cutanea tarda. Antiviral
3

therapy with alpha-interferon for the underlying HCV infection can be effective in treating the associated mixed cryoglobulinemia. Patients who have no detectable HCV RNA at the end of
4

a course of treatment have significantly improved purpura and serum cryoglobulin levels;

however, a rebound phenomenon of clinical and serologic variables has been noted after discontinuation of this therapy.
4

Although cryoglobulins are found in 19 to 54 percent of patients with HCV infection, symptoms occur in only 25 percent of these. Duration of HCV infection and severity of
5

histologic hepatic inflammation do not appear to be related. In addition to cryoglobulinemia,

5

other important extrahepatic manifestations of HCV infection include membranoproliferative glomerulonephritis, thyroiditis, porphyria cutanea tarda and lichen planus.
6

Several types of cryoglobulinemias are recognized. Type I (monoclonal immunoglobulin) is associated primarily with malignant processes of the immune system. Type II (at least one monoclonal immunoglobulin, usually IgM mixed with polyclonal immunoglobulins) and type III (polyclonal only) are also known as mixed cryoglobulinemias. HCV has become one of the most common causes of mixed cryoglobulinemia, although mixed cryoglobulins are also observed with other chronic infections (e.g., hepatitis B, endocarditis) as well as autoimmune and malignant disorders.
7

The clinical presentation of mixed cryoglobulinemia is quite variable. Cutaneous leukocytoclastic vasculitis is the most clinically evident manifestation. It usually presents with palpable purpura and petechiae that involve the lower extremities. Skin lesions are not
8

always obvious and are sometimes not present. Arthralgias and arthritis may be prominent. The joint involvement is usually a symmetric, nonmigratory polyarthritis involving ankles, wrists, elbows, hands and toes. The most serious manifestation is renal damage due to deposition of the circulating cryoimmunoglobulins. This can present as nephrotic syndrome, glomerulonephritis or acute renal failure. Renal biopsy usually reveals IgM and IgG deposition within subendothelial immune deposits. Treatment of the underlying chronic infection can ameliorate cryoglobulinemia. Corticosteroids and cytotoxic agents are sometimes used in severe cases.

Koebner Streak
The editors of AFP welcome submission of photographs and material for the Photo Quiz department. Contributing editor is Marc S. Berger, M.D., C.M. Send photograph and discussion to Marc S. Berger, M.D., C.M., P.O. Box 219, Crystal Beach, FL 34681-0219.

A 45-year-old woman presented with a pruritic eruption of one month duration. Her medications included triamcinolone inhaler, albuterol inhaler, and beclomethasone nasal spray for asthma; carbamazepine and clonazepam for seizures; cyclobenzaprine and tramadol for back pain; estrogen replacement; furosemide; and potassium replacement. On physical examination, there were multiple flat-topped papules with white scale on her hands, wrists, and shins. She also had lacy, white reticulations on her buccal mucosa.
FIGURE 1.

Question Based on the patient's history and physical examination, which one of the following is the correct diagnosis? A. Poison ivy rash. B. Discoid lupus erythematosus. C. Guttate psoriasis. D. Lichen planus. E. Flat warts.

Discussion
The answer is D: lichen planus, which was established by skin biopsy. It was not consistent with a drug-induced lichen planus, because there were no eosinophils and no parakeratosis. An inflammatory dermatosis of unknown etiology, lichen planus classically presents as shiny, violaceous, flat-topped, polygonal papules, 2 mm to 10 mm in diameter. Fine, lacy, white

scale (Wickham's striae) adhere to well-developed papules, resembling a reticulate network of lichen. These are easier to appreciate if a drop of microscope lens oil is placed on the papule and a glass slide is pressed gently over the lesion. Contact dermatitis due to poison ivy can also present as a linear distribution of pruritic lesions. However, instead of flat-topped papules as seen in lichen planus, the lesions of contact dermatitis are often vesicular. Discoid lupus erythematosus typically presents as atrophic or scarring plaques on the head and neck. They are usually not pruritic. Guttate psoriasis is characterized by erythematous plaques with thick white scale, unlike lichen planus, which has a fine, lacy scale. Verruca plana, or flat warts, are flat-topped like the lesions of lichen planus, but are smooth instead of scaly, and are usually skin-colored, pink, or light brown instead of violaceous. Affecting less than 1 percent of the population worldwide, lichen planus occurs in both sexes, most often between 30 and 60 years of age. The initial lesions are usually located on the flexural surfaces of the wrists, arms, and legs, but the trunk, thighs, and genitalia also may be involved. Evolving over several weeks, lesions may be grouped, annular, or generalized in arrangement. Trauma during the early stages of evolution may induce the isomorphic (Koebner) phenomenon to produce a linear distribution of papules. While some patients remain asymptomatic, the eruption is often pruritic with severity related to the degree of involvement.
1

Involvement of the oral mucosa occurs in 60 percent of patients and may be the only manifestation of the disease. The most common pattern of oral disease reveals a reticular network of white hyperkeratosis on the buccal mucosa. Involvement of the lips, gums, and tongue is not uncommon. While most cases of mucosal lichen planus are nonerosive and asymptomatic, ulcerative and atrophic variants may cause painful erosions and marked distress. The appearance of the typical lichen planus papule, characterized by the four Ps (purple, pruritic, polygonal, papule), often allows a clinical diagnosis of the lesion. Histopathologic
1

examination of a biopsy specimen can confirm the diagnosis in atypical cases. Other papulosquamous disorders should be considered in the differential diagnosis, including guttate psoriasis, pityriasis rosea, and discoid lupus erythematosus. Annular lesions may mimic those of granuloma annulare or sarcoid; however, the lesions of these granulomatous disorders lack the fine scale of lichen planus papules. The white buccal lesions of oral lichen planus may necessitate biopsy to exclude leukoplakia, candidiasis, and secondary syphilis.
2

Lichen planus-like eruptions may occur following exposure to industrial compounds such as color film developer or with use of many commonly prescribed medications, including

diuretics, antihypertensives, and hypoglycemic agents. Exposure and medication history should be reviewed as these lesions resolve after discontinuation of the offending agent.
1

Most localized cutaneous eruptions of lichen planus resolve within 12 to 18 months, leaving residual hyperpigmentation that fades with time. Patients with generalized eruptions or mucosal lesions have a more prolonged course. Topical or intralesional steroids suppress inflammation and cause regression of lesions in mild cases, while more severe cases may require systemic corticosteroids, retinoids, or cyclosporine. Antihistamines can be useful for
3

pruritus with recurrence in less than 20 percent of patients.

Photo Quiz
Leg Rash
A 71-year-old woman presented to the dermatology clinic with a 15-year history of a recurrent erythematous rash on her left knee and lower leg (see accompanying figure). On physical examination, a 5-cm erythematous ring was noted on her left central knee and a serpiginous, papular, erythematous lesion was noted on the medial aspect of the knee. The patient had been treated with ivermectin four years earlier, and reported that the lesions resolved at that time. The lesions reappeared approximately one year later, this time with mild pruritus and slight hypersensitivity to touch.

Question
Based on the patient's history and physical appearance of the rash, which one of the following is the correct diagnosis? A. Hansen's disease. B. Granuloma annulare. C. Sarcoidosis.

D. Cutanea larvae migrans. E. Tinea corporis.

Discussion
The answer is B: granuloma annulare. A skin biopsy showed interstitial lymphocytic and histiocytic infiltrates with collagenolysis, consistent with granuloma annulare. The patient was treated with clobetasol steroid cream and instructed to follow up in four weeks.

Selected Differential Diagnosis of Raised Leg Rash

Condition

Characteristics

Hansen's disease

Well-defined, hypopigmented papules with or without scale, hypesthesia, bacilli, travel history

Granuloma annulare Circular, flesh-colored or erythematous plaques and papules, usually asymptomatic Sarcoidosis Cutanea larvae migrans Tinea corporis Brown-red plaques that wax and wane, clinical symptoms present Thin, erythematous, serpiginous papules, pruritic, travel history

Flat, scaly, circular lesions with or without raised erythematous border

Granuloma annulare is a benign, self-limited cutaneous condition. It is characterized by annular, flesh-colored or slightly erythematous plaques and papules that are generally asymptomatic.1,2 Some patients may report mild pruritus, as noted in this case.3,4 There are several forms of granuloma annulare, including localized, generalized, perforating, subcutaneous, and actinic.3 The localized form accounts for approximately 75 percent of all cases.3 The lesions of granuloma annulare can occur anywhere on the body, but most often involve the dorsal surfaces of the hands, feet, elbows, or knees.2 The condition usually begins with an asymptomatic, flesh-colored papule that undergoes central involution and slowly develops into a ring-shaped lesion.1 Over several months, the lesion gradually may increase in diameter, with a final size of 0.5 to 5 cm.1 The duration of the disease is highly variable. Approximately one half of patients experience spontaneous resolution without scarring, whereas, in other patients, lesions may last for years.1,3 Among those who experience resolution of lesions, the disease commonly recurs.2,3

The diagnosis of granuloma annulare often may be made by its characteristic clinical presentation. In uncertain cases where biopsy is necessary, the histology shows collagen degeneration caused by an inflammatory reaction that occurs around the blood vessels.1,2 Although the etiology of granuloma annulare is unknown, theories include vasculitis, trauma, monocyte activation, and type IV delayed hypersensitivity.3 Because lesions are usually asymptomatic, they are best left untreated. If cosmetic appearance is a concern, these lesions may be treated with intralesional corticosteroid injections, topical corticosteroids, electrodesiccation, cryotherapy, ultraviolet light therapy, or even systemic agents (e.g., dapsone, colchicine, chloroquine) for patients who have widespread lesions.1-3 None of these methods are curative. Hansen's disease (leprosy) is a chronic granulomatous disease that affects the skin and nerves.2 These lesions are typically well-defined, hypopigmented papules and may have slight scale.2,3 Additional clinical features that help distinguish this diagnosis are perilesional cutaneous anesthesia and exposure to an endemic area (especially Brazil, India, southern Africa, Myanmar, and Nepal).2,3 Diagnosis is made by demonstrating leprosy bacilli in the skin.2 Sarcoidosis can present with a number of different skin findings, including brownish-red plaques that wax and wane.2 The face is most commonly involved, but plaques also may occur on the trunk or the dorsal surfaces of the arms or legs.3 Diagnosis often is obvious from the usual clinical presentation (cough, dyspnea) and radiologic findings (hilar lymphadenopathy), but biopsy of cutaneous lesions may provide confirmatory information in unclear cases.2,3 Cutaneous larvae migrans is characterized by a thin, erythematous, serpiginous papular eruption caused by hookworm larvae traveling through the skin.1,2 Infection is acquired by skin contact with soil contaminated by dog or cat feces.1 It occurs most commonly in travelers returning from tropical locations.1 During larval migration, a local inflammatory response is provoked, which causes moderate to intense pruritus.1,2 If untreated, the larvae usually die within two to eight weeks, but may persist for up to one year.1,2 Tinea corporis classically begins as a flat, scaly spot that later develops a raised advancing border.1,2 The border may develop red, raised papules or vesicles, while the central area becomes hypopigmented and less scaly.1 A potassium hydroxide examination of skin scrapings may reveal hyphae, but this is often difficult to demonstrate because of the low fungal load.2 Resolution of lesions after empiric antifungal treatment is the most common means by which tineal infection is verified.

Photo Quiz
Tiny, Skin-Colored Papules on the Arms and Hands
A 27-year-old man presents with a 10-year history of asymptomatic lesions on his hands and elbows. Hundreds of pinpoint-sized, skin-colored papules appear on the dorsum of his hands and the extensor surface of his upper extremities (see accompanying figure). He is otherwise in good health and is not taking any medications.

Question
Based on the patient's history and physical examination, which one of the following is the correct diagnosis? A. Psoriasis. B. Lichen nitidus. C. Lichen simplex chronicus. D. Prurigo nodularis. E. Lichen planus.

Discussion
The answer is B: lichen nitidus. Lichen nitidus most commonly presents as an incidental finding on physical examination or after the patient notices an insidious onset of the lesions. 1 It is characteristically asymptomatic.2 Physical examination reveals pinpoint- to pinhead-sized skin-colored papules that may be scaly or have a central depression.3 They usually are found on the forearms, trunk, and the glans and shaft of the penis. Lichen nitidus can be discrete or generalized. In the discrete form, papules typically do not coalesce; however, they may form or group at sites of trauma or skin pressure (the isomorphic or "Koebner phenomenon).2 In the generalized (confluent) form, papules coalesce into redyellow to brown plaques, especially in joint flexures, wrist and forearm ventral surfaces, or inframammary areas, making the clinical diagnosis more challenging.3 Biopsy may be helpful because lichen nitidus has a characteristic histologic appearance.3 The etiology of lichen nitidus is unknown, and no laboratory abnormalities or associations with systemic disease have been established. Because lichen nitidus is rare, definitive establishment of the epidemiology is difficult. One study2 of 43 cases demonstrated a male-tofemale ratio of almost 4:1, although the generalized (confluent) form may be more common in women.3 No racial predisposition or known genetic inheritance pattern has been noted.1,2 Lichen nitidus primarily affects children and young adults, with a median age of seven years in males and 13 years in females.2 Lichen nitidus may resolve spontaneously at any time without residual atrophy or pigmentary changes. This, along with its asymptomatic nature, makes clinical observation a reasonable treatment option. In one series,2 69 percent of eruptions resolved within one year; however, they can last for many years and new lesions may continue to appear as old lesions disappear.2

The evidence base for other treatments is limited. Topical steroids may cause lesions to flatten or resolve.4 Short courses of systemic corticosteroids, psoralen with long-wavelength ultraviolet light therapy,5 long-wavelength ultraviolet light/medium wavelength ultraviolet light with systemic corticosteroids,6 and sun exposure7 have been used to treat generalized disease. Selected Differential Diagnosis of Lichen Nitidus

Condition Psoriasis Lichen simplex chronicus Prurigo nodularis Lichen planus

Characteristics Erythematous plaques with thick, white scale Thick plaques with increased skin markings that develop after chronic rubbing Skin-colored to hyperpigmented nodules that develop after external manipulation Pruritic, violaceous, flat-topped, polygonal papules

The differential diagnosis includes psoriasis, lichen simplex chronicus, prurigo nodularis, and lichen planus. Psoriasis typically presents as erythematous plaques with thick, white scale on the elbows, knees, scalp, and lower lumbar area. Lichen simplex chronicus is a thickening of the skin caused by chronic rubbing, and typically presents as thick plaques. Prurigo nodularis is similar to lichen simplex chronicus in that the lesions develop because of external manipulation. These papules or nodules develop in areas that the patient can reach. Lichen planus may appear similar to lichen nitidus. However, lichen planus often is pruritic, which may help to distinguish it from lichen nitidus.2 Characteristically, lichen planus lesions are violaceous and larger than those of lichen nitidus. Finally, lichen planus has a predilection for the ventral wrists and the buccal mucosa.

Photo Quiz
Question
A 67-year-old woman presented after three years of progressive hyperpigmentation, which was worse in the sun-exposed areas of her skin but involved sun-protected areas as well. Appropriate initial management of this patient may include all of the following except: A. Medication history.

FIGURE 1.

B. Oral and genital examination. C. General health history. D. Nd:Yag laser treatment using 532 nm wavelength. E. Punch biopsy at border of lesion.

Discussion
The answer is D: Nd:Yag laser treatment using 532 nm wavelength. Erythema dyschromicum perstans, commonly known as ashy dermatosis, was first described by Ramirez in 1957. This uncommon disorder occurs predominately in dark-skinned Latin Americans, particularly women in the first through third decades of life. Ashy dermatosis is a chronic condition characterized by asymptomatic, slate-gray or violaceous hyperpigmented macules distributed most commonly over the trunk and proximal extremities, and less frequently over the face and neck. Lesions, which occur in otherwise healthy persons, may initially present as erythematous macules that slowly progress to a blue-gray hue. The macules of erythema dyschromicum perstans vary in size and may occasionally demonstrate an erythematous raised border.1-3 The etiology of erythema dyschromicum perstans remains unknown. Melanin complexes in the dermis and epidermis are responsible for the ashen-gray color that occurs in sun-exposed and sun-protected areas.1 It is important to obtain a thorough general health and medication history, perform an oral and genital examination, and obtain a punch biopsy at the border of the lesion to rule out other possible causes of hyperpigmentation. Several authors speculate that erythema dyschromicum perstans may be a variant of lichen planus, and the sequela of resolving lichen planus may cause hyperpigmented lesions. Thus, the patient should be examined for the characteristic lacy white patterned and erosive lesions of the oral and genital mucosa to rule out lichen planus. Review of medications may indicate a drug hypersensitivity reaction, particularly a fixed drug eruption, as a cause of hyperpigmented macules. Certain drugs, such as chlorpromazine, amiodarone, thiazides, and tetracyclines are the most common culprits. A general health history can help distinguish diffuse hyperpigmentation caused by internal disease entities, such as Addison's disease and hemochromatosis. A punch biopsy at the border of the lesion is necessary to rule out melanosis secondary to malignant melanoma that manifests as a generalized blue-gray skin discoloration. Finally, melasma, which presents in sun-exposed areas, particularly the face, and postinflammatory hyperpigmentation, which occurs after inflammatory dermatoses, are other benign causes of hyperpigmented lesions.1,2 Unfortunately, no effective treatment of erythema dyschromicum perstans is available at this time. Several medications, such as hydroquinone, topical steroids, tretinoin, griseofulvin, dapsone, and sunscreen, have been tried but have had poor clinical results. Clofazimine, an

antileprosy drug, has recently been studied in six patients who demonstrated marked improvement with treatment.3 Nd:Yag laser has been attempted for the treatment of postinflammatory hyperpigmentation and melasma with disappointing results and is not recommended in the treatment of ashy dermatosis.1

Photo Quiz
Skin Rash in a Patient with Diabetes
The editors of AFP welcome submission of photographs and material for the Photo Quiz department. Contributing editor is Marc S. Berger, M.D., C.M. Send photograph and discussion to Marc S. Berger, M.D., C.M., P.O. Box 219, Crystal Beach, FL 34681-0219.

A 54-year-old man with type 2 diabetes mellitus complained of asymptomatic, slowly enlarging, brownish plaques on the anterior surfaces of both lower legs (see accompanying figure). These lesions developed over the past three years, and various creams had failed to help. These reddish-brown plaques had depressed shiny centers, and dilated deep subcutaneous vessels could be seen through the atrophic skin. Small ulcerations had recently developed on the involved skin.

Question Given the patient's medical history and the physical appearance of the lesions, which one of the following is the most likely diagnosis? A. Granuloma annulare. B. Erythema nodosum. C. Pretibial myxedema. D. Necrobiosis lipoidica.

E. Diabetic dermopathy.

Discussion
The answer is D: necrobiosis lipoidica. Necrobiosis lipoidica is an unusual skin disorder that is strongly associated with diabetes mellitus. The female-to-male ratio is 3:1. The condition develops only in a small proportion of patients with diabetes (0.3 percent),1 but its presence is said to be a strong marker for the disease (65 and 42 percent of patients in two series 1,2 were diabetic). The condition may precede the diagnosis of diabetes mellitus, but it occurs more commonly in patients with well-established metabolic disease.3 Necrobiosis lipoidica usually develops in the third or fourth decade of life, but it may be seen in younger or older individuals.3 The typical clinical presentation is that of multiple, oval reddish-brown plaques over the anterior portion of the legs (bilateral in 75 percent of cases).3,4 The plaques often slowly enlarge, with the center developing a yellowish sheen and prominent telangiectasias. Ulceration occurs in about one third of diabetic patients with necrobiosis lipoidica,4 and spontaneous remission is relatively uncommon (19 percent). Clinical variants may be solitary and may be seen on the hands, forearms, fingers, face, scalp, and nipples.1 Patients may complain of pruritus, dysesthesia, or pain at the site of lesions. More frequently, however, the lesions of necrobiosis lipoidica are asymptomatic, and it is the cosmetic effect that is of greatest concern to the patient. The histologic features of necrobiosis lipoidica include poorly defined histiocytic granulomas with necrobiosis in the middle to deep dermis, PAS-positive staining in the areas of necrobiosis, degeneration and thickening of collagen bundles in the dermis, and vascular changes consisting of endothelial swelling, fibrosis, and hyalinization.4 There is no universally satisfactory intervention for necrobiosis lipoidica. Moisturizing of the skin, protection against trauma or skin injury, and measures to improve the circulation of the lower limbs are recommended for all patients with this disease. High-potency topical steroids may be useful in the early, inflammatory phase of necrobiosis lipoidica.4 Likewise, injection of triamcinolone in perilesional skin has been used with success,1 but care should be exercised with local steroid use because ulceration may occur. Surgical intervention may be necessary if these measures are unsuccessful and nonhealing ulcers persist. Plastic surgeons advise excision of the involved area down to fascia and ligation of associated perforating blood vessels followed by split-thickness skin grafts, but lesions often recur within or around the graft.5 The admonition to "do no harm" may be well advised in this disorder.4 Erythema nodosum is an inflammatory process of the deep dermis and subcutaneous fat characterized by shiny, tender, deep, red nodules most commonly on the anterior shins. Resembling bruises, the nodules gradually change from pink to bluish to brown. Fever and

arthralgia frequently accompany the rash. Erythema nodosum is most commonly seen following upper respiratory infections, especially those involving Streptococci. Less common causes include other infections, sarcoidosis, inflammatory bowel disease, and drug reactions (especially oral contraceptives). Pretibial myxedema presents as waxy plaques on the shins, with prominent hair follicles that give the peau d'orange appearance. This condition is most commonly associated with Graves' disease, and it is thought to be caused by thyroid-stimulating hormone-induced deposition of mucin. Diabetic dermopathy (skin spots) is the most common dermatosis associated with diabetes. Similar to necrobiosis lipoidica, it presents with reddish-brown patches on the shins, but they are usually much smaller (0.5 to 1.0 cm) in size and greater in number (five to 10, or more lesions). Skin spots gradually resolve to leave a brown, atrophic scar. They are thought to be caused by vascular disease, but there is no correlation with the extent or duration of diabetes. Granuloma annulare may be hard to distinguish from early necrobiosis lipoidica. There are many variants, but granuloma annulare is typically characterized by several papules or nodules that spread to form a ring around normal or slightly depressed skin. Lesions enlarge slowly over a period of months to years and can be yellowish tan, erythematous, bluish, or the color of the surrounding skin. They are usually asymptomatic and occur on the distal portion of the legs, feet, hands, or fingers. Spontaneous resolution is common and no treatment is required.

Photo Quiz

FIGURE 1.

A 50-year-old white woman presented with a rash that first erupted on her trunk three years earlier and never fully cleared (see accompanying figure). The lesions became pruritic after a

warm shower or strenuous physical exercise, but were otherwise asymptomatic. Physical examination revealed many discrete erythematous papules spread over the abdomen, upper chest, and back. On vigorous rubbing of a papule, a wheal formed at the site. The patient did not have hepatosplenomegaly, gastrointestinal complaints, or any palpable lymphadenopathy.

Question
Based on the patient's history and physical examination, which one of the following is the correct diagnosis? A. Lichen planus. B.Pityriasis rosea. C. Scabies. D. Urticaria. E. Urticaria pigmentosa.

Discussion
The answer is E: urticaria pigmentosa. Biopsy of a skin lesion revealed superficial infiltrates of mononuclear cells and some eosinophils. The mononuclear cells stained strongly for tryptase, which confirmed the diagnosis of urticaria pigmentosa. The patient was given hydroxyzine for pruritus and referred to a hematologist for further testing. Urticaria pigmentosa is part of a group of disorders that shares an abnormal growth of mast cells, termed mastocytosis. With urticaria pigmentosa, a type of cutaneous mastocytosis, abnormal mast cell accumulation is limited to the skin. In contrast, systemic mastocytosis affects not only the skin, but also may involve the liver, spleen, lymph nodes, gastrointestinal tract, and bone marrow. Because mast cells often are missed using conventional staining, special stains must be ordered when mastocytosis is suspected. These include the metachromatic stains (e.g., toluidine blue O) or enzymatic stains (e.g., chloroacetate esterase). Urticaria pigmentosa is the most common form of mastocytosis. Approximately one half of cases occur before six months of age, and another one fourth before puberty.1 Onset of urticaria pigmentosa in adulthood, such as occurred with this patient, is less common. Accumulation of mast cells in organs other than the skin occurs primarily in adults. Mast cell degranulation with hormone release and direct organ infiltration lead to the symptoms seen with systemic mastocytosis. Histamine-induced hypersecretion may cause gastritis, peptic ulcers, and diarrhea, and ultimately, malabsorption may occur. Other histamine-induced symptoms include pruritus, urticaria, bronchoconstriction, and vasopermeability (possibly leading to vascular collapse). Release of prostaglandins may cause

skin flushing, intestinal cramping, and cardiovascular abnormalities (e.g., tachycardia, vascular collapse). Adults with urticaria pigmentosa should undergo bone marrow biopsy to look for evidence of systemic mastocytosis.2 In addition, serum tryptase levels greater than 20 ng per mL suggest systemic involvement. The most common symptom in urticaria pigmentosa is pruritus, which may be treated with H1-receptor antagonists. Inhibitors of mast cell degranulation, such as cromolyn and ketotifen, have been found to have a moderate effect on pruritus, whealing, and flushing. Finally, some patients may benefit from topical corticosteroids or psoralens and ultraviolet A (PUVA) therapy. Adults with urticaria pigmentosa usually progress slowly to systemic disease, but rarely develop hematologic disease. Clinical factors associated with poor prognosis include anemia, hypercellular bone marrow, cytologic atypia, hepatosplenomegaly, and an associated hematologic disorder.3 Lichen planus also is a pruritic, often chronic, rash, but the lesions are typically flat-topped, violaceous papules with scale. They usually are less widespread than urticaria pigmentosa and would not wheal when rubbed. Pityriasis rosea may lead to a truncal macular rash, sometimes with pruritus. The eruption may last up to two or three months, but not years. In addition to many small macules, a large patch (i.e., herald patch) may be seen. Scabies, a contagious skin infestation caused by a mite, is typically highly pruritic. Skin lesions may be widespread but tend to cluster in the intertriginous areas, such as the axilla, groin, inframammary area, and finger webs. Urticaria typically presents with larger areas of erythema, but also may occur as small erythematous papules. Unlike urticaria pigmentosa, individual urticarial skin lesions wax and wane over a course of hours and would not persist in the same location as chronic papules.

Photo Quiz
Generalized Pruritus Without Relief

A nine-year-old girl presents with a threemonth history of severe persistent itching and skin lesions throughout most of her body. Physical examination revealed numerous 15 to 20 mm papulonodular lesions over all the extremities and trunk with some confluence (see accompanying figure). Crusting and lichenification also were observed. No lesions were present on the face.

Question
Based on the patient's history and physical examination, which one of the following is the most likely diagnosis? A. Psoriasis vulgaris. B. Pemphigus vulgaris. C. Severe atopic dermatitis. D. Lichen planus. E. Sweet's syndrome.

Discussion
The answer is C: severe atopic dermatitis. Atopic dermatitis is a form of endogenous dermatitis resulting in pruritic inflammation of the epidermis and dermis, which commonly occurs in infants and children but can be found in adults. Atopic dermatitis affects more than 10 percent of children, and the majority of patients are affected during the first five years of life.1 Psoriasis is an inflammatory epidermal proliferative disorder of the skin, which is usually not intensely pruritic. The most common lesions are papules and nodules like those shown in the photograph, but in psoriasis they are sharply demarcated and covered by silvery white scale. The lesions most commonly involve areas of the body that experience repeated minor trauma, such as elbows, knees, scalp, feet, and hands. Associated findings may include fingernail pitting or thickening (50 percent of cases) and arthritis (up to 10 percent of cases). Pemphigus vulgaris is an autoimmune bullous disease of the skin that usually occurs in adults and is rare in children. There is no pruritus. The lesions are flaccid vesicles or bullae that are initially localized in oral mucosa and later spread randomly to other parts of the body. This can be a serious and potentially fatal disorder.

Lichen planus is characterized by flat-topped, polygonal, violaceous papules, which are much smaller than the confluent papulonodular lesions seen in severe atopic dermatitis. The pruritus is variable. Lichen planus is uncommon in children. The common sites include wrists, shins, mucous membrane, lumbar area, and genitalia. Sweet's syndrome is an uncommon disorder of the skin that generally has associated systemic symptoms like fever, arthralgias, and peripheral leukocytosis. The lesions are red-brown plaques and nodules over the head, neck, and upper extremities, which are painful rather than pruritic. Truncal lesions are uncommon, and approximately 10 percent of patients have an associated underlying malignancy. Atopic dermatitis is frequently accompanied by a personal or family history of asthma, allergic rhinitis, or allergic skin involvement. The onset of the skin lesions is usually subacute or chronic. In infants, the extensor surface of the extremities, face, and trunk are involved, whereas children and adults have predilection for the flexural areas of the extremities, neck, and upper trunk. Patients with atopic dermatitis often have diffusely dry skin. Pruritic papules with vesicles are typical initially; these may become scaly and crusty later. Chronic lesions may have thickened lichenified skin with fibrotic papules and nodules as are seen in this case. The distribution of the lesions may become more diffuse in the chronic condition. Secondary infection is common, especially with Staphylococcus aureus.2 Atopic dermatitis may be confused with a number of the eczematous dermatitides including contact dermatitis, seborrheic dermatitis, and psoriasis. In dark-skinned patients, it is often difficult to differentiate the lesions from the other conditions as outlined above because of the lack of contrast between the lesions and uninvolved skin. In blacks, a subtype of atopic dermatitis occurs frequently where each papule involves a separate hair follicle, and is termed follicular eczema. The diagnosis of atopic dermatitis is based primarily on clinical presentation and history. No laboratory tests are available to definitively establish a diagnosis of atopic dermatitis, although patients may have elevated levels of IgE and peripheral blood eosinophilia. The histopathologic changes seen in biopsy specimens of atopic dermatitis are nonspecific. Common triggers of atopic dermatitis include dry skin, infection, physical or emotional stress, sweating, and skin irritants. These irritants can include soaps, detergents, cosmetics, wool and acrylic clothing, linens, and perfumes. Symptomatic treatment consists of the use of moisturizers to prevent the itching caused by dry skin. Avoidance of any of the irritants or triggers is the cornerstone of therapy. Mild or no soap should be used when bathing. Hot baths or frequent bathing may cause drier skin and should be avoided. Oral antihistamines can help control itching. Use of H2 blockers in cases of severe pruritus may be helpful. Topical steroid ointments or creams in addition to cool wet dressings are useful in acute flares of the disease as well as in maintenance of healing in the

chronic phase. Topical or oral antibiotics should be considered when there is suspicion of secondary infection, because this may be a cause of persistent pruritus. In cases of severe intractable atopic dermatitis, systemic corticosteroids may be used. Other alternatives include phototherapy using ultraviolet radiation, cyclosporin, or recombinant IFN-g.3