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The Diagnosis: Bilateral Auricular Tophaceous Gout

Histopathologic evaluation with hematoxylin and eosin staining demonstrated clusters of abundant granular amorphous material within the subcutaneous tissue (Figure 1). The overlying epidermis and dermis were unremarkable. The granular amorphous material demonstrated numerous monosodium urate crystals under polarized light (Figure 2). At a return visit following the biopsy results, the patient reported a history of a single episode of monoarticular gouty arthritis involving the right hallux approximately 6 months after the onset of the skin lesions. With the added clinical history and the biopsy results, his serum uric acid level was obtained and was found to be elevated at 9.2 mg/dL (reference range, 3.5–8 mg/dL).

In our patient, the clinical differential diagnosis included calcium deposits, weathering nodules, and tophaceous gout. The differential diagnosis of auricular lesions is broad, and benign lesions may mimic cancerous entities such as basal cell carcinoma and squamous cell carcinoma.¹ Therefore a detailed history, thorough physical examination, and tissue sampling are key to establishing the correct diagnosis. Our patient’s history of monoarticular gouty arthritis was only elucidated after a diagnosis of bilateral auricular tophaceous gout was made based on the biopsy results.

Subcutaneous tophi represent a chronic state of hyperuricemia and tend to manifest after long-standing polyarthritis and repeated acute gout attacks.^2-5 These lesions develop in approximately 50% of gout patients and usually occur an average of 11.6 years after the onset of disease.² There is a subset of individuals that are at higher risk for developing tophi, including elderly and female patients, diuretic and chronic nonsteroidal anti-inflammatory drug users, patients with a history of cyclosporine therapy, and patients with underlying chronic renal insufficiency.^2,6,7 The most commonly affected tissues are those with poor blood supply and lower temperatures, such as the ear helix and first metacarpal joint.⁴ The auricle is the most common site of tophi on the head and neck. Tophi of the helices are generally asymptomatic and nontender; however, tophi can become large, inflamed, and ulcerated, causing pressure and discomfort.² Combination treatment with dietary modification and antihyperuricemic therapy (eg, allopurinol) has been shown to reduce the size of lesions and prevent future tophi formation. However, these results may take months, warranting excision of large and symptomatic lesions.^4,8

Our case is unusual in that the onset of the auricular lesions predated the articular gout by 6 months. Gouty tophi as the initial presentation of hyperuricemia is rare; however, tophi formation without concomitant arthritis has been reported.^2,3,7,9 Wernick et al⁷ described 6 patients presenting with tophi before the onset of inflammatory arthritis that they attributed to changes in active inflammation by age (eg, elderly patients were more commonly immunosuppressed), chronic illnesses, and anti-inflammatory medications (eg, nonsteroidal anti-inflammatory drugs). Another possible explanation for this atypical presentation is misdiagnosis caused by other forms of arthritis (eg, rheumatoid arthritis, osteoarthritis) masking acute gout episodes. It also has been reported that monosodium urate crystals can be found in synovial fluid with no inflammation and therefore no symptoms.⁷

Tophi, although rare, may be the sole clinical manifestation of underlying gouty disease. It is important to be aware of this atypical presentation to prevent misdiagnosis and provide appropriate treatment.

The Diagnosis: Bilateral Auricular Tophaceous Gout

Histopathologic evaluation with hematoxylin and eosin staining demonstrated clusters of abundant granular amorphous material within the subcutaneous tissue (Figure 1). The overlying epidermis and dermis were unremarkable. The granular amorphous material demonstrated numerous monosodium urate crystals under polarized light (Figure 2). At a return visit following the biopsy results, the patient reported a history of a single episode of monoarticular gouty arthritis involving the right hallux approximately 6 months after the onset of the skin lesions. With the added clinical history and the biopsy results, his serum uric acid level was obtained and was found to be elevated at 9.2 mg/dL (reference range, 3.5–8 mg/dL).

In our patient, the clinical differential diagnosis included calcium deposits, weathering nodules, and tophaceous gout. The differential diagnosis of auricular lesions is broad, and benign lesions may mimic cancerous entities such as basal cell carcinoma and squamous cell carcinoma.¹ Therefore a detailed history, thorough physical examination, and tissue sampling are key to establishing the correct diagnosis. Our patient’s history of monoarticular gouty arthritis was only elucidated after a diagnosis of bilateral auricular tophaceous gout was made based on the biopsy results.

Subcutaneous tophi represent a chronic state of hyperuricemia and tend to manifest after long-standing polyarthritis and repeated acute gout attacks.^2-5 These lesions develop in approximately 50% of gout patients and usually occur an average of 11.6 years after the onset of disease.² There is a subset of individuals that are at higher risk for developing tophi, including elderly and female patients, diuretic and chronic nonsteroidal anti-inflammatory drug users, patients with a history of cyclosporine therapy, and patients with underlying chronic renal insufficiency.^2,6,7 The most commonly affected tissues are those with poor blood supply and lower temperatures, such as the ear helix and first metacarpal joint.⁴ The auricle is the most common site of tophi on the head and neck. Tophi of the helices are generally asymptomatic and nontender; however, tophi can become large, inflamed, and ulcerated, causing pressure and discomfort.² Combination treatment with dietary modification and antihyperuricemic therapy (eg, allopurinol) has been shown to reduce the size of lesions and prevent future tophi formation. However, these results may take months, warranting excision of large and symptomatic lesions.^4,8

Our case is unusual in that the onset of the auricular lesions predated the articular gout by 6 months. Gouty tophi as the initial presentation of hyperuricemia is rare; however, tophi formation without concomitant arthritis has been reported.^2,3,7,9 Wernick et al⁷ described 6 patients presenting with tophi before the onset of inflammatory arthritis that they attributed to changes in active inflammation by age (eg, elderly patients were more commonly immunosuppressed), chronic illnesses, and anti-inflammatory medications (eg, nonsteroidal anti-inflammatory drugs). Another possible explanation for this atypical presentation is misdiagnosis caused by other forms of arthritis (eg, rheumatoid arthritis, osteoarthritis) masking acute gout episodes. It also has been reported that monosodium urate crystals can be found in synovial fluid with no inflammation and therefore no symptoms.⁷

Tophi, although rare, may be the sole clinical manifestation of underlying gouty disease. It is important to be aware of this atypical presentation to prevent misdiagnosis and provide appropriate treatment.

The Diagnosis: Bilateral Auricular Tophaceous Gout

Histopathologic evaluation with hematoxylin and eosin staining demonstrated clusters of abundant granular amorphous material within the subcutaneous tissue (Figure 1). The overlying epidermis and dermis were unremarkable. The granular amorphous material demonstrated numerous monosodium urate crystals under polarized light (Figure 2). At a return visit following the biopsy results, the patient reported a history of a single episode of monoarticular gouty arthritis involving the right hallux approximately 6 months after the onset of the skin lesions. With the added clinical history and the biopsy results, his serum uric acid level was obtained and was found to be elevated at 9.2 mg/dL (reference range, 3.5–8 mg/dL).

In our patient, the clinical differential diagnosis included calcium deposits, weathering nodules, and tophaceous gout. The differential diagnosis of auricular lesions is broad, and benign lesions may mimic cancerous entities such as basal cell carcinoma and squamous cell carcinoma.¹ Therefore a detailed history, thorough physical examination, and tissue sampling are key to establishing the correct diagnosis. Our patient’s history of monoarticular gouty arthritis was only elucidated after a diagnosis of bilateral auricular tophaceous gout was made based on the biopsy results.

Subcutaneous tophi represent a chronic state of hyperuricemia and tend to manifest after long-standing polyarthritis and repeated acute gout attacks.^2-5 These lesions develop in approximately 50% of gout patients and usually occur an average of 11.6 years after the onset of disease.² There is a subset of individuals that are at higher risk for developing tophi, including elderly and female patients, diuretic and chronic nonsteroidal anti-inflammatory drug users, patients with a history of cyclosporine therapy, and patients with underlying chronic renal insufficiency.^2,6,7 The most commonly affected tissues are those with poor blood supply and lower temperatures, such as the ear helix and first metacarpal joint.⁴ The auricle is the most common site of tophi on the head and neck. Tophi of the helices are generally asymptomatic and nontender; however, tophi can become large, inflamed, and ulcerated, causing pressure and discomfort.² Combination treatment with dietary modification and antihyperuricemic therapy (eg, allopurinol) has been shown to reduce the size of lesions and prevent future tophi formation. However, these results may take months, warranting excision of large and symptomatic lesions.^4,8

Our case is unusual in that the onset of the auricular lesions predated the articular gout by 6 months. Gouty tophi as the initial presentation of hyperuricemia is rare; however, tophi formation without concomitant arthritis has been reported.^2,3,7,9 Wernick et al⁷ described 6 patients presenting with tophi before the onset of inflammatory arthritis that they attributed to changes in active inflammation by age (eg, elderly patients were more commonly immunosuppressed), chronic illnesses, and anti-inflammatory medications (eg, nonsteroidal anti-inflammatory drugs). Another possible explanation for this atypical presentation is misdiagnosis caused by other forms of arthritis (eg, rheumatoid arthritis, osteoarthritis) masking acute gout episodes. It also has been reported that monosodium urate crystals can be found in synovial fluid with no inflammation and therefore no symptoms.⁷

Tophi, although rare, may be the sole clinical manifestation of underlying gouty disease. It is important to be aware of this atypical presentation to prevent misdiagnosis and provide appropriate treatment.

The Diagnosis: Acquired Acrodermatitis Enteropathica

Acquired acrodermatitis enteropathica (AAE) is a rare disorder caused by severe zinc deficiency. Although acrodermatitis enteropathica is an autosomal-recessive disorder that typically manifests in infancy, AAE also can result from poor zinc intake, impaired absorption, or accelerated losses. There are reports of AAE in patients with zinc-deficient diets,¹ eating disorders,² bariatric and other gastrointestinal surgeries,³ malabsorptive diseases,⁴ and nephrotic syndrome.⁵

Zinc plays an important role in DNA and RNA synthesis, reactive oxygen species attenuation, and energy metabolism, allowing for proper wound healing, skin differentiation, and proliferation.⁶ Zinc is found in most foods, but animal protein contains higher concentrations (Table).⁷ Approximately 85% of zinc is stored in muscles and bones, with only a small amount of accessible zinc available in the liver. Liver stores can be depleted as quickly as 1 week.⁸ Total parenteral nutrition without trace element supplementation can quickly predispose patients to AAE.

Diagnosis of this condition requires triangulation of clinical presentation, histopathology examination, and laboratory findings. Acrodermatitis enteropathica typically is characterized by dermatitis, diarrhea, and epidermal appendage findings. In its early stages, the dermatitis often manifests with angular cheilitis and paronychia.⁹ Patients then develop erythema, erosions, and occasionally vesicles or psoriasiform plaques in periorificial, perineal, and acral sites (Figure 1). Epidermal appendage effects include generalized alopecia and thinning nails with white transverse ridges. Although dermatologic and gastrointestinal manifestations are the most obvious, severe AAE may cause other symptoms, including mental slowing, hypogonadism, and impaired immune function.⁹

Histopathology of AAE skin lesions is similar to other nutritional deficiencies. Early changes are more specific to deficiency dermatitis and include cytoplasmic pallor and ballooning degeneration of keratinocytes in the stratum spinosum and granulosum.⁹ Necrolysis results in confluent keratinocyte necrosis developing into subcorneal bulla. Later in the disease course, the presentation becomes psoriasiform with keratinocyte dyskeratosis and confluent parakeratosis¹⁰ (Figure 2). Dermal edema with dilated tortuous vessels and a neutrophilic infiltrate may be present throughout disease progression.

Common laboratory abnormalities used to confirm zinc deficiency are decreased plasma zinc and alkaline phosphatase levels. Plasma zinc levels should be drawn after fasting because zinc levels decrease after food intake.⁹ Concurrent albumin levels should be drawn to correct for low levels caused by hypoalbuminemia. Acquired acrodermatitis enteropathica has been seen in patients with only mildly decreased plasma zinc levels or even zinc levels within reference range.¹¹ Alkaline phosphatase metalloenzyme synthesis requires zinc and a decreased level suggests zinc deficiency even with a plasma zinc level within reference range. Alkaline phosphatase levels usually can be ascertained in a matter of hours, while the zinc levels take much longer to result.

Acquired acrodermatitis enteropathica is treated with oral elemental zinc supplementation at 1 to 2 mg/kg daily.¹² Diarrhea typically resolves within 24 hours, but skin lesions heal in 1 to 2 weeks or longer. Although there is no consensus on when to discontinue zinc replacement therapy, therapy generally is not lifelong. Once the patient is zinc replete and the inciting factor has resolved, patients can discontinue supplementation without risk for recurrence.

Trace elements had not been added to our patient’s total parenteral nutrition prior to admission. Basic nutrition laboratory results and zinc levels returned markedly low: 14 μg/dL (reference range, 60–120 μg/dL). Alkaline phosphatase, a zinc-dependent protein, also was low at 12 U/L (reference range, 40–150 U/L). We added trace elements and vitamins and began empiric zinc replacement with 440 mg oral zinc sulfate daily (100 mg elemental zinc). Cephalexin was prescribed for impetiginized skin lesions. The patient noted skin improvement after 3 days on zinc replacement therapy.

The Diagnosis: Acquired Acrodermatitis Enteropathica

Acquired acrodermatitis enteropathica (AAE) is a rare disorder caused by severe zinc deficiency. Although acrodermatitis enteropathica is an autosomal-recessive disorder that typically manifests in infancy, AAE also can result from poor zinc intake, impaired absorption, or accelerated losses. There are reports of AAE in patients with zinc-deficient diets,¹ eating disorders,² bariatric and other gastrointestinal surgeries,³ malabsorptive diseases,⁴ and nephrotic syndrome.⁵

Zinc plays an important role in DNA and RNA synthesis, reactive oxygen species attenuation, and energy metabolism, allowing for proper wound healing, skin differentiation, and proliferation.⁶ Zinc is found in most foods, but animal protein contains higher concentrations (Table).⁷ Approximately 85% of zinc is stored in muscles and bones, with only a small amount of accessible zinc available in the liver. Liver stores can be depleted as quickly as 1 week.⁸ Total parenteral nutrition without trace element supplementation can quickly predispose patients to AAE.

Diagnosis of this condition requires triangulation of clinical presentation, histopathology examination, and laboratory findings. Acrodermatitis enteropathica typically is characterized by dermatitis, diarrhea, and epidermal appendage findings. In its early stages, the dermatitis often manifests with angular cheilitis and paronychia.⁹ Patients then develop erythema, erosions, and occasionally vesicles or psoriasiform plaques in periorificial, perineal, and acral sites (Figure 1). Epidermal appendage effects include generalized alopecia and thinning nails with white transverse ridges. Although dermatologic and gastrointestinal manifestations are the most obvious, severe AAE may cause other symptoms, including mental slowing, hypogonadism, and impaired immune function.⁹

Histopathology of AAE skin lesions is similar to other nutritional deficiencies. Early changes are more specific to deficiency dermatitis and include cytoplasmic pallor and ballooning degeneration of keratinocytes in the stratum spinosum and granulosum.⁹ Necrolysis results in confluent keratinocyte necrosis developing into subcorneal bulla. Later in the disease course, the presentation becomes psoriasiform with keratinocyte dyskeratosis and confluent parakeratosis¹⁰ (Figure 2). Dermal edema with dilated tortuous vessels and a neutrophilic infiltrate may be present throughout disease progression.

Common laboratory abnormalities used to confirm zinc deficiency are decreased plasma zinc and alkaline phosphatase levels. Plasma zinc levels should be drawn after fasting because zinc levels decrease after food intake.⁹ Concurrent albumin levels should be drawn to correct for low levels caused by hypoalbuminemia. Acquired acrodermatitis enteropathica has been seen in patients with only mildly decreased plasma zinc levels or even zinc levels within reference range.¹¹ Alkaline phosphatase metalloenzyme synthesis requires zinc and a decreased level suggests zinc deficiency even with a plasma zinc level within reference range. Alkaline phosphatase levels usually can be ascertained in a matter of hours, while the zinc levels take much longer to result.

Acquired acrodermatitis enteropathica is treated with oral elemental zinc supplementation at 1 to 2 mg/kg daily.¹² Diarrhea typically resolves within 24 hours, but skin lesions heal in 1 to 2 weeks or longer. Although there is no consensus on when to discontinue zinc replacement therapy, therapy generally is not lifelong. Once the patient is zinc replete and the inciting factor has resolved, patients can discontinue supplementation without risk for recurrence.

Trace elements had not been added to our patient’s total parenteral nutrition prior to admission. Basic nutrition laboratory results and zinc levels returned markedly low: 14 μg/dL (reference range, 60–120 μg/dL). Alkaline phosphatase, a zinc-dependent protein, also was low at 12 U/L (reference range, 40–150 U/L). We added trace elements and vitamins and began empiric zinc replacement with 440 mg oral zinc sulfate daily (100 mg elemental zinc). Cephalexin was prescribed for impetiginized skin lesions. The patient noted skin improvement after 3 days on zinc replacement therapy.

The Diagnosis: Acquired Acrodermatitis Enteropathica

Acquired acrodermatitis enteropathica (AAE) is a rare disorder caused by severe zinc deficiency. Although acrodermatitis enteropathica is an autosomal-recessive disorder that typically manifests in infancy, AAE also can result from poor zinc intake, impaired absorption, or accelerated losses. There are reports of AAE in patients with zinc-deficient diets,¹ eating disorders,² bariatric and other gastrointestinal surgeries,³ malabsorptive diseases,⁴ and nephrotic syndrome.⁵

Zinc plays an important role in DNA and RNA synthesis, reactive oxygen species attenuation, and energy metabolism, allowing for proper wound healing, skin differentiation, and proliferation.⁶ Zinc is found in most foods, but animal protein contains higher concentrations (Table).⁷ Approximately 85% of zinc is stored in muscles and bones, with only a small amount of accessible zinc available in the liver. Liver stores can be depleted as quickly as 1 week.⁸ Total parenteral nutrition without trace element supplementation can quickly predispose patients to AAE.

Diagnosis of this condition requires triangulation of clinical presentation, histopathology examination, and laboratory findings. Acrodermatitis enteropathica typically is characterized by dermatitis, diarrhea, and epidermal appendage findings. In its early stages, the dermatitis often manifests with angular cheilitis and paronychia.⁹ Patients then develop erythema, erosions, and occasionally vesicles or psoriasiform plaques in periorificial, perineal, and acral sites (Figure 1). Epidermal appendage effects include generalized alopecia and thinning nails with white transverse ridges. Although dermatologic and gastrointestinal manifestations are the most obvious, severe AAE may cause other symptoms, including mental slowing, hypogonadism, and impaired immune function.⁹

Histopathology of AAE skin lesions is similar to other nutritional deficiencies. Early changes are more specific to deficiency dermatitis and include cytoplasmic pallor and ballooning degeneration of keratinocytes in the stratum spinosum and granulosum.⁹ Necrolysis results in confluent keratinocyte necrosis developing into subcorneal bulla. Later in the disease course, the presentation becomes psoriasiform with keratinocyte dyskeratosis and confluent parakeratosis¹⁰ (Figure 2). Dermal edema with dilated tortuous vessels and a neutrophilic infiltrate may be present throughout disease progression.

Common laboratory abnormalities used to confirm zinc deficiency are decreased plasma zinc and alkaline phosphatase levels. Plasma zinc levels should be drawn after fasting because zinc levels decrease after food intake.⁹ Concurrent albumin levels should be drawn to correct for low levels caused by hypoalbuminemia. Acquired acrodermatitis enteropathica has been seen in patients with only mildly decreased plasma zinc levels or even zinc levels within reference range.¹¹ Alkaline phosphatase metalloenzyme synthesis requires zinc and a decreased level suggests zinc deficiency even with a plasma zinc level within reference range. Alkaline phosphatase levels usually can be ascertained in a matter of hours, while the zinc levels take much longer to result.

Acquired acrodermatitis enteropathica is treated with oral elemental zinc supplementation at 1 to 2 mg/kg daily.¹² Diarrhea typically resolves within 24 hours, but skin lesions heal in 1 to 2 weeks or longer. Although there is no consensus on when to discontinue zinc replacement therapy, therapy generally is not lifelong. Once the patient is zinc replete and the inciting factor has resolved, patients can discontinue supplementation without risk for recurrence.

Trace elements had not been added to our patient’s total parenteral nutrition prior to admission. Basic nutrition laboratory results and zinc levels returned markedly low: 14 μg/dL (reference range, 60–120 μg/dL). Alkaline phosphatase, a zinc-dependent protein, also was low at 12 U/L (reference range, 40–150 U/L). We added trace elements and vitamins and began empiric zinc replacement with 440 mg oral zinc sulfate daily (100 mg elemental zinc). Cephalexin was prescribed for impetiginized skin lesions. The patient noted skin improvement after 3 days on zinc replacement therapy.

The Diagnosis: Cutaneous Larva Migrans

Three punch biopsies were obtained. Spongiotic dermatitis with eosinophils was seen. There was a single specimen of tissue that showed a possible intraepidermal larva with a tract in the epidermis. The differential diagnosis included allergic contact dermatitis and arthropod bite eruption, among others, but clinical correlation made cutaneous larva migrans (CLM) the likely diagnosis.

The patient was treated empirically with albendazole 400 mg once daily for 3 days. In addition, he was prescribed triamcinolone for symptomatic relief and remained asymptomatic for 8 weeks at which time he presented again to the dermatology clinic with a similar rash in the same distribution. He was treated with a repeat course of albendazole and further educated on the etiology of the infection. The patient has not exhibited a recurrence after treatment of the second episode of CLM.

Cutaneous larva migrans is a dermatosis of the skin caused by the larvae of parasitic nematodes from the hookworm family, most commonly Ancylostoma caninum and Ancylostoma braziliense.^1,2 These hookworms thrive in warm moist climates and are most frequently found in tropical coastal regions. They normally inhabit the intestines of animals such as dogs and cats and are transmitted to soil and sand via feces. Humans become accidental hosts through contact with the contaminated sand or soil³; however, the larvae are unable to penetrate deeper than the upper dermis of the skin in humans, subsequently limiting the infection. Because humans are accidental hosts, the larvae are unable to complete their life cycle and larval death occurs within weeks to months after the initial infection³; thus treatment may be unnecessary unless complications arise.

Cutaneous larva migrans is most commonly observed in travelers or inhabitants of tropical coastal regions but can occur anywhere in the world.¹ Clinically, CLM presents as an enlarging, intensely pruritic, erythematous linear or serpiginous tract,³ most commonly on the hands, feet, abdomen, and buttocks.¹ Complications may include allergic reactions, secondary bacterial infections, and hookworm folliculitis.⁴ Although rare, migration to the intestinal tract⁵ and/or hematological spread with Löffler syndrome has been described.⁶ Although this dermatological disease has been well described in the medical literature, it is not well recognized by Western physicians and is consequently either not diagnosed or misdiagnosed, leading to delays in treatment.⁴ Although the infection is usually self-limiting without treatment, the risk for prolonged active disease may occur, with 1 reported case lasting up to 18 months.^4,5 The first indicator of CLM is intense pruritus localized to the site of infection.⁴ As the larvae migrate or creep, they create a lesion that may appear edematous with vesiculobullous lesions that are either serpiginous or linear.⁴ The differential diagnosis may include fungal infection, bacterial infection, and atypical herpes simplex infections; however, the key finding in CLM is the presence of undulating tracts localized to the borders of the lesion.² Patients may report experiencing a stinging sensation prior to the formation of the erythematous scaly papule,⁵ which is attributed to the initial penetration of the larva into the skin. This development, accompanied with a history of travel to tropical or subtropical regions, should elicit CLM as a likely diagnosis. Because hookworms are a type of helminth, they likely elicit an eosinophilic immune response and thus peripheral eosinophilia may be present.⁵

Effective treatment of CLM is accomplished with oral albendazole 400 mg once daily for 3 to 7 days.^2,7 Alternatively, oral ivermectin, topical thiabendazole, and cryosurgery can be used,² though albendazole currently is the preferred treatment of CLM.⁷

The Diagnosis: Cutaneous Larva Migrans

Three punch biopsies were obtained. Spongiotic dermatitis with eosinophils was seen. There was a single specimen of tissue that showed a possible intraepidermal larva with a tract in the epidermis. The differential diagnosis included allergic contact dermatitis and arthropod bite eruption, among others, but clinical correlation made cutaneous larva migrans (CLM) the likely diagnosis.

The patient was treated empirically with albendazole 400 mg once daily for 3 days. In addition, he was prescribed triamcinolone for symptomatic relief and remained asymptomatic for 8 weeks at which time he presented again to the dermatology clinic with a similar rash in the same distribution. He was treated with a repeat course of albendazole and further educated on the etiology of the infection. The patient has not exhibited a recurrence after treatment of the second episode of CLM.

Cutaneous larva migrans is a dermatosis of the skin caused by the larvae of parasitic nematodes from the hookworm family, most commonly Ancylostoma caninum and Ancylostoma braziliense.^1,2 These hookworms thrive in warm moist climates and are most frequently found in tropical coastal regions. They normally inhabit the intestines of animals such as dogs and cats and are transmitted to soil and sand via feces. Humans become accidental hosts through contact with the contaminated sand or soil³; however, the larvae are unable to penetrate deeper than the upper dermis of the skin in humans, subsequently limiting the infection. Because humans are accidental hosts, the larvae are unable to complete their life cycle and larval death occurs within weeks to months after the initial infection³; thus treatment may be unnecessary unless complications arise.

Cutaneous larva migrans is most commonly observed in travelers or inhabitants of tropical coastal regions but can occur anywhere in the world.¹ Clinically, CLM presents as an enlarging, intensely pruritic, erythematous linear or serpiginous tract,³ most commonly on the hands, feet, abdomen, and buttocks.¹ Complications may include allergic reactions, secondary bacterial infections, and hookworm folliculitis.⁴ Although rare, migration to the intestinal tract⁵ and/or hematological spread with Löffler syndrome has been described.⁶ Although this dermatological disease has been well described in the medical literature, it is not well recognized by Western physicians and is consequently either not diagnosed or misdiagnosed, leading to delays in treatment.⁴ Although the infection is usually self-limiting without treatment, the risk for prolonged active disease may occur, with 1 reported case lasting up to 18 months.^4,5 The first indicator of CLM is intense pruritus localized to the site of infection.⁴ As the larvae migrate or creep, they create a lesion that may appear edematous with vesiculobullous lesions that are either serpiginous or linear.⁴ The differential diagnosis may include fungal infection, bacterial infection, and atypical herpes simplex infections; however, the key finding in CLM is the presence of undulating tracts localized to the borders of the lesion.² Patients may report experiencing a stinging sensation prior to the formation of the erythematous scaly papule,⁵ which is attributed to the initial penetration of the larva into the skin. This development, accompanied with a history of travel to tropical or subtropical regions, should elicit CLM as a likely diagnosis. Because hookworms are a type of helminth, they likely elicit an eosinophilic immune response and thus peripheral eosinophilia may be present.⁵

Effective treatment of CLM is accomplished with oral albendazole 400 mg once daily for 3 to 7 days.^2,7 Alternatively, oral ivermectin, topical thiabendazole, and cryosurgery can be used,² though albendazole currently is the preferred treatment of CLM.⁷

The Diagnosis: Cutaneous Larva Migrans

Three punch biopsies were obtained. Spongiotic dermatitis with eosinophils was seen. There was a single specimen of tissue that showed a possible intraepidermal larva with a tract in the epidermis. The differential diagnosis included allergic contact dermatitis and arthropod bite eruption, among others, but clinical correlation made cutaneous larva migrans (CLM) the likely diagnosis.

The patient was treated empirically with albendazole 400 mg once daily for 3 days. In addition, he was prescribed triamcinolone for symptomatic relief and remained asymptomatic for 8 weeks at which time he presented again to the dermatology clinic with a similar rash in the same distribution. He was treated with a repeat course of albendazole and further educated on the etiology of the infection. The patient has not exhibited a recurrence after treatment of the second episode of CLM.

Cutaneous larva migrans is a dermatosis of the skin caused by the larvae of parasitic nematodes from the hookworm family, most commonly Ancylostoma caninum and Ancylostoma braziliense.^1,2 These hookworms thrive in warm moist climates and are most frequently found in tropical coastal regions. They normally inhabit the intestines of animals such as dogs and cats and are transmitted to soil and sand via feces. Humans become accidental hosts through contact with the contaminated sand or soil³; however, the larvae are unable to penetrate deeper than the upper dermis of the skin in humans, subsequently limiting the infection. Because humans are accidental hosts, the larvae are unable to complete their life cycle and larval death occurs within weeks to months after the initial infection³; thus treatment may be unnecessary unless complications arise.

Cutaneous larva migrans is most commonly observed in travelers or inhabitants of tropical coastal regions but can occur anywhere in the world.¹ Clinically, CLM presents as an enlarging, intensely pruritic, erythematous linear or serpiginous tract,³ most commonly on the hands, feet, abdomen, and buttocks.¹ Complications may include allergic reactions, secondary bacterial infections, and hookworm folliculitis.⁴ Although rare, migration to the intestinal tract⁵ and/or hematological spread with Löffler syndrome has been described.⁶ Although this dermatological disease has been well described in the medical literature, it is not well recognized by Western physicians and is consequently either not diagnosed or misdiagnosed, leading to delays in treatment.⁴ Although the infection is usually self-limiting without treatment, the risk for prolonged active disease may occur, with 1 reported case lasting up to 18 months.^4,5 The first indicator of CLM is intense pruritus localized to the site of infection.⁴ As the larvae migrate or creep, they create a lesion that may appear edematous with vesiculobullous lesions that are either serpiginous or linear.⁴ The differential diagnosis may include fungal infection, bacterial infection, and atypical herpes simplex infections; however, the key finding in CLM is the presence of undulating tracts localized to the borders of the lesion.² Patients may report experiencing a stinging sensation prior to the formation of the erythematous scaly papule,⁵ which is attributed to the initial penetration of the larva into the skin. This development, accompanied with a history of travel to tropical or subtropical regions, should elicit CLM as a likely diagnosis. Because hookworms are a type of helminth, they likely elicit an eosinophilic immune response and thus peripheral eosinophilia may be present.⁵

Effective treatment of CLM is accomplished with oral albendazole 400 mg once daily for 3 to 7 days.^2,7 Alternatively, oral ivermectin, topical thiabendazole, and cryosurgery can be used,² though albendazole currently is the preferred treatment of CLM.⁷

The Diagnosis: Stinkbug Staining

After discussing management options with the patient including biopsy, we decided that we would photograph the lesion and follow-up in clinic. While dressing, the patient discovered the source of the pigment, a stinkbug, stuck to the corresponding area of the sock.

The brown marmorated stinkbug (Halyomorpha halys)(Figure) is a member of the Pentatomidae family. This insect is native to East Asia and has become an invasive species in the United States. Their presence has recently increased in the eastern United States and they have become an important agricultural pest as well as a household nuisance. Stinkbugs most commonly interact with humans during the fall and winter months when they enter homes because of cooler temperatures outdoors. They can fit into many unexpected places because of their thin profile.¹

Stinkbugs earned their name because of their defensive release of a malodorous chemical. This chemical is comprised of trans-2-decenal and trans-2-octenal, which are both aldehydes and are chemically related to formaldehyde. Based on the material safety data sheet, trans-2-decenal also may be responsible for the orange-brown color seen on the patient’s skin.² Contact dermatitis caused by direct excretion of this chemical onto human skin has been reported³; anecdotal reports of irritation in agricultural workers have been noted. Stinkbugs are becoming a more common household and agricultural pest and should be recognized as possible causes of some presentations in the dermatology clinic.

The Diagnosis: Stinkbug Staining

After discussing management options with the patient including biopsy, we decided that we would photograph the lesion and follow-up in clinic. While dressing, the patient discovered the source of the pigment, a stinkbug, stuck to the corresponding area of the sock.

The brown marmorated stinkbug (Halyomorpha halys)(Figure) is a member of the Pentatomidae family. This insect is native to East Asia and has become an invasive species in the United States. Their presence has recently increased in the eastern United States and they have become an important agricultural pest as well as a household nuisance. Stinkbugs most commonly interact with humans during the fall and winter months when they enter homes because of cooler temperatures outdoors. They can fit into many unexpected places because of their thin profile.¹

Stinkbugs earned their name because of their defensive release of a malodorous chemical. This chemical is comprised of trans-2-decenal and trans-2-octenal, which are both aldehydes and are chemically related to formaldehyde. Based on the material safety data sheet, trans-2-decenal also may be responsible for the orange-brown color seen on the patient’s skin.² Contact dermatitis caused by direct excretion of this chemical onto human skin has been reported³; anecdotal reports of irritation in agricultural workers have been noted. Stinkbugs are becoming a more common household and agricultural pest and should be recognized as possible causes of some presentations in the dermatology clinic.

The Diagnosis: Stinkbug Staining

After discussing management options with the patient including biopsy, we decided that we would photograph the lesion and follow-up in clinic. While dressing, the patient discovered the source of the pigment, a stinkbug, stuck to the corresponding area of the sock.

The brown marmorated stinkbug (Halyomorpha halys)(Figure) is a member of the Pentatomidae family. This insect is native to East Asia and has become an invasive species in the United States. Their presence has recently increased in the eastern United States and they have become an important agricultural pest as well as a household nuisance. Stinkbugs most commonly interact with humans during the fall and winter months when they enter homes because of cooler temperatures outdoors. They can fit into many unexpected places because of their thin profile.¹

Stinkbugs earned their name because of their defensive release of a malodorous chemical. This chemical is comprised of trans-2-decenal and trans-2-octenal, which are both aldehydes and are chemically related to formaldehyde. Based on the material safety data sheet, trans-2-decenal also may be responsible for the orange-brown color seen on the patient’s skin.² Contact dermatitis caused by direct excretion of this chemical onto human skin has been reported³; anecdotal reports of irritation in agricultural workers have been noted. Stinkbugs are becoming a more common household and agricultural pest and should be recognized as possible causes of some presentations in the dermatology clinic.

The Diagnosis: Bullous Henoch-Schönlein Purpura

Laboratory tests in this patient showed no abnormalities for complete blood cell count, immunoglobulins, anti–double-stranded DNA, antinuclear antibody, p–antineutrophil cytoplasmic antibodies, lupus anticoagulant, Sjögren antibodies, liver enzymes, and erythrocyte sedimentation rate. Urinalysis was normal. Punch biopsies were obtained and a histologic examination showed an intense inflammatory infiltrate of neutrophils around blood vessels within the dermis (Figure). These blood vessels showed swollen endothelium and narrowing of the vessel lumina with leukocytoclasia. Direct immunofluorescence revealed granular IgA, C3, fibrin, and weak IgM deposits in blood vessels in the papillary dermis consistent with Henoch-Schönlein purpura (HSP).

Henoch-Schönlein purpura is the most common vasculitis in children.^1-6 However, its bullous variant is rare, with few pediatric cases reported. Bullous HSP affects arterioles through an IgA-mediated pathway.^1-6 It is believed that the bullae are formed secondary to neutrophilic release of matrix metalloproteinase 9 (MMP-9), which degrades extracellular collagen.² Additionally, bullous fluid from HSP has been noted to have markedly elevated levels of soluble CD23, a form of the CD23 B-cell surface receptor used in antibody feedback regulation and B-cell recruitment, which also has been found to be elevated in the fluid of bullous pemphigoid, suggesting a similar pathogenesis of exaggerated humoral immunity.³

The most common sign of HSP is palpable purpura; however, other cutaneous findings can be present including targetoid plaques, macules, papules, petechiae, and bullae that may become hemorrhagic, ulcerated, necrotic, or scarred.^1-6 Bullae appear in the most dependent parts of the body, such as the feet and lower legs. Hydrostatic pressure may play a role in the pathogenesis of this phenomenon.¹ When other classic signs of HSP are absent, the presence of bullae clouds the diagnosis and creates controversy regarding treatment, as there is a dearth of literature on proper therapy for severe cutaneous manifestations of HSP.⁶

Our patient was treated with morphine for pain management along with topical mupirocin and nonadherent dressings for wound care. She also received pulse intravenous methylprednisolone 2 mg/kg daily for 3 days and then was transitioned to oral prednisone 1 mg/kg daily, which was tapered over 3 weeks after discharge. This regimen resulted in resolution of symptoms with rapid regression of bullae and subsequent postinflammatory hyperpigmentation. Prior reports have noted that the presence of bullae does not alter the prognosis or predict probability of renal involvement of this self-limited disease, leading to controversy in determining if treatment offers more favorable outcomes.^1,3 One study suggested that steroids only improve symptoms, arthralgia, and abdominal pain, but they do not aid in the resolution of cutaneous lesions or prevent the progression of renal disease.³ Contrarily, others have suggested that the presence of bullae and renal disease is an indication to start treatment.⁶ This claim is based on the mechanistic finding that immunosuppression with corticosteroids decreases inflammation by inhibiting activator protein 1, a transcription factor for MMP-9, thereby reducing MMP-9 activity and the formation of bullae.⁴ Clinical anecdotes, including our own, that demonstrate dramatic improvement of hemorrhagic bullae with the administration of corticosteroids substantiate this mechanism. Through the inhibition of neutrophil interactions and IgA production, other anti-inflammatory and immunosuppressive medications such as colchicine, dapsone, and azathioprine also have been reported to aid in resolution of the cutaneous lesions.^1,5,6 Although there is a clear drawback to the lack of controlled trials and prospective studies regarding the treatment of bullous HSP, it is nearly impossible to expect such studies to be carried out given the rare and unpredictable nature of the disease. For now, claims derived from case series and case reports guide our understanding of treatment efficacy.

Acknowledgment—Quiz photograph courtesy of Steve Taylor, BS, Phoenix, Arizona.

The Diagnosis: Bullous Henoch-Schönlein Purpura

Laboratory tests in this patient showed no abnormalities for complete blood cell count, immunoglobulins, anti–double-stranded DNA, antinuclear antibody, p–antineutrophil cytoplasmic antibodies, lupus anticoagulant, Sjögren antibodies, liver enzymes, and erythrocyte sedimentation rate. Urinalysis was normal. Punch biopsies were obtained and a histologic examination showed an intense inflammatory infiltrate of neutrophils around blood vessels within the dermis (Figure). These blood vessels showed swollen endothelium and narrowing of the vessel lumina with leukocytoclasia. Direct immunofluorescence revealed granular IgA, C3, fibrin, and weak IgM deposits in blood vessels in the papillary dermis consistent with Henoch-Schönlein purpura (HSP).

Henoch-Schönlein purpura is the most common vasculitis in children.^1-6 However, its bullous variant is rare, with few pediatric cases reported. Bullous HSP affects arterioles through an IgA-mediated pathway.^1-6 It is believed that the bullae are formed secondary to neutrophilic release of matrix metalloproteinase 9 (MMP-9), which degrades extracellular collagen.² Additionally, bullous fluid from HSP has been noted to have markedly elevated levels of soluble CD23, a form of the CD23 B-cell surface receptor used in antibody feedback regulation and B-cell recruitment, which also has been found to be elevated in the fluid of bullous pemphigoid, suggesting a similar pathogenesis of exaggerated humoral immunity.³

The most common sign of HSP is palpable purpura; however, other cutaneous findings can be present including targetoid plaques, macules, papules, petechiae, and bullae that may become hemorrhagic, ulcerated, necrotic, or scarred.^1-6 Bullae appear in the most dependent parts of the body, such as the feet and lower legs. Hydrostatic pressure may play a role in the pathogenesis of this phenomenon.¹ When other classic signs of HSP are absent, the presence of bullae clouds the diagnosis and creates controversy regarding treatment, as there is a dearth of literature on proper therapy for severe cutaneous manifestations of HSP.⁶

Our patient was treated with morphine for pain management along with topical mupirocin and nonadherent dressings for wound care. She also received pulse intravenous methylprednisolone 2 mg/kg daily for 3 days and then was transitioned to oral prednisone 1 mg/kg daily, which was tapered over 3 weeks after discharge. This regimen resulted in resolution of symptoms with rapid regression of bullae and subsequent postinflammatory hyperpigmentation. Prior reports have noted that the presence of bullae does not alter the prognosis or predict probability of renal involvement of this self-limited disease, leading to controversy in determining if treatment offers more favorable outcomes.^1,3 One study suggested that steroids only improve symptoms, arthralgia, and abdominal pain, but they do not aid in the resolution of cutaneous lesions or prevent the progression of renal disease.³ Contrarily, others have suggested that the presence of bullae and renal disease is an indication to start treatment.⁶ This claim is based on the mechanistic finding that immunosuppression with corticosteroids decreases inflammation by inhibiting activator protein 1, a transcription factor for MMP-9, thereby reducing MMP-9 activity and the formation of bullae.⁴ Clinical anecdotes, including our own, that demonstrate dramatic improvement of hemorrhagic bullae with the administration of corticosteroids substantiate this mechanism. Through the inhibition of neutrophil interactions and IgA production, other anti-inflammatory and immunosuppressive medications such as colchicine, dapsone, and azathioprine also have been reported to aid in resolution of the cutaneous lesions.^1,5,6 Although there is a clear drawback to the lack of controlled trials and prospective studies regarding the treatment of bullous HSP, it is nearly impossible to expect such studies to be carried out given the rare and unpredictable nature of the disease. For now, claims derived from case series and case reports guide our understanding of treatment efficacy.

Acknowledgment—Quiz photograph courtesy of Steve Taylor, BS, Phoenix, Arizona.

The Diagnosis: Bullous Henoch-Schönlein Purpura

Laboratory tests in this patient showed no abnormalities for complete blood cell count, immunoglobulins, anti–double-stranded DNA, antinuclear antibody, p–antineutrophil cytoplasmic antibodies, lupus anticoagulant, Sjögren antibodies, liver enzymes, and erythrocyte sedimentation rate. Urinalysis was normal. Punch biopsies were obtained and a histologic examination showed an intense inflammatory infiltrate of neutrophils around blood vessels within the dermis (Figure). These blood vessels showed swollen endothelium and narrowing of the vessel lumina with leukocytoclasia. Direct immunofluorescence revealed granular IgA, C3, fibrin, and weak IgM deposits in blood vessels in the papillary dermis consistent with Henoch-Schönlein purpura (HSP).

Henoch-Schönlein purpura is the most common vasculitis in children.^1-6 However, its bullous variant is rare, with few pediatric cases reported. Bullous HSP affects arterioles through an IgA-mediated pathway.^1-6 It is believed that the bullae are formed secondary to neutrophilic release of matrix metalloproteinase 9 (MMP-9), which degrades extracellular collagen.² Additionally, bullous fluid from HSP has been noted to have markedly elevated levels of soluble CD23, a form of the CD23 B-cell surface receptor used in antibody feedback regulation and B-cell recruitment, which also has been found to be elevated in the fluid of bullous pemphigoid, suggesting a similar pathogenesis of exaggerated humoral immunity.³

The most common sign of HSP is palpable purpura; however, other cutaneous findings can be present including targetoid plaques, macules, papules, petechiae, and bullae that may become hemorrhagic, ulcerated, necrotic, or scarred.^1-6 Bullae appear in the most dependent parts of the body, such as the feet and lower legs. Hydrostatic pressure may play a role in the pathogenesis of this phenomenon.¹ When other classic signs of HSP are absent, the presence of bullae clouds the diagnosis and creates controversy regarding treatment, as there is a dearth of literature on proper therapy for severe cutaneous manifestations of HSP.⁶

Our patient was treated with morphine for pain management along with topical mupirocin and nonadherent dressings for wound care. She also received pulse intravenous methylprednisolone 2 mg/kg daily for 3 days and then was transitioned to oral prednisone 1 mg/kg daily, which was tapered over 3 weeks after discharge. This regimen resulted in resolution of symptoms with rapid regression of bullae and subsequent postinflammatory hyperpigmentation. Prior reports have noted that the presence of bullae does not alter the prognosis or predict probability of renal involvement of this self-limited disease, leading to controversy in determining if treatment offers more favorable outcomes.^1,3 One study suggested that steroids only improve symptoms, arthralgia, and abdominal pain, but they do not aid in the resolution of cutaneous lesions or prevent the progression of renal disease.³ Contrarily, others have suggested that the presence of bullae and renal disease is an indication to start treatment.⁶ This claim is based on the mechanistic finding that immunosuppression with corticosteroids decreases inflammation by inhibiting activator protein 1, a transcription factor for MMP-9, thereby reducing MMP-9 activity and the formation of bullae.⁴ Clinical anecdotes, including our own, that demonstrate dramatic improvement of hemorrhagic bullae with the administration of corticosteroids substantiate this mechanism. Through the inhibition of neutrophil interactions and IgA production, other anti-inflammatory and immunosuppressive medications such as colchicine, dapsone, and azathioprine also have been reported to aid in resolution of the cutaneous lesions.^1,5,6 Although there is a clear drawback to the lack of controlled trials and prospective studies regarding the treatment of bullous HSP, it is nearly impossible to expect such studies to be carried out given the rare and unpredictable nature of the disease. For now, claims derived from case series and case reports guide our understanding of treatment efficacy.

Acknowledgment—Quiz photograph courtesy of Steve Taylor, BS, Phoenix, Arizona.

The Diagnosis: Plexiform Neurofibroma as a Manifestation of Neurofibromatosis Type I

Physical examination revealed a large 10×8-cm subcutaneous nodule that was boggy and resembled a bag of worms on palpation. It was covered by slightly hyperpigmented skin. He also had numerous (>20) café au lait spots measuring 2 to 3 cm across the body and several others on the axillae. There were no gross eye findings. Otherwise the examination was unremarkable on the rest of the body. The patient’s paternal grandfather and aunt had similar macules and multiple nodules. The patient had mild to moderate learning difficulties. He was subsequently referred for genetic and ophthalmology evaluation.

Plexiform neurofibromas are usually benign nerve sheath tumors that are elongated and are multinodular, forming when the tumor involves either multiple trunks of a plexus or multiple fascicles of a large nerve such as the sciatic. Some plexiform neurofibromas resemble a bag of worms; others produce a massive ropy enlargement of the nerve.^1,2 Plexiform neurofibromas are associated with cases of neurofibromatosis type I (NFI) and are themselves one of the diagnostic criteria for NFI.¹

Plexiform neurofibromas are benign tumors that are the result of a genetic mutation in which loss of heterozygosity occurs, as is the case with the other predominant neoplasms of NFI, that results in unrestricted cell growth.^3,4 Some patients have a loss of heterozygosity of this tumor suppression gene with overgrowth of neurofibromatosis on a Blaschko segment. One study in mouse models showed that stromal mast cells were involved in promoting inflammation and increasing tumor growth by mediation of mitogenic signals involved in vascular ingrowth, collagen deposition, and cellular proliferation.⁵ Plexiform neurofibromas are a presenting feature in 30% of NFI cases within the first year of life. They are extensive nerve sheath tumors with an unpredictable growth pattern that can involve multiple fascicles (ie, large nerves and their branches). Five percent become malignant and the transformation is often heralded by rapid growth and pain.⁶ If malignant transformation is suspected, biopsy is diagnostic. Magnetic resonance imaging with and without contrast can categorize them into 3 growth categories: superficial, displacing, and invasive.⁷ Because plexiform neurofibromas are rare tumors, it previously was common practice to delay surgical intervention until disfigurement or disability arose. Complete surgical resection at more advanced stages is nearly impossible given the networklike growth pattern that commonly encapsulates vital structures.^8,9 Therefore, surgery has been used in the past for debulking the large growths that eventually will recur. A study of 9 small superficial plexiform neurofibromas in children aged 3 to 15 years documented treatment with early surgical resection, which showed complete resection and no relapse at 4 years. This study showed a promising strategy to prevent future extension of these fast-growing tumors into vital structures.⁸ There also are current clinical trials investigating sirolimus and peginterferon alfa-2b in patients with more invasive plexiform neurofibromas that are unable to undergo surgical resection due to encapsulation or proximity to essential anatomical structures (registered at www.clinicaltrials.gov with the identifiers NCT00652990 and NCT00678951, respectively).

Pain, development of a neurologic deficit, or enlargement of a preexisting plexiform neurofibroma may signal a malignant peripheral nerve sheath tumor (MPNST) and require immediate evaluation.¹⁰ Examination by magnetic resonance imaging and positron emission tomography is useful in distinguishing benign and MPNSTs,^8,11,12 but definitive differentiation can only be made by histologic examination of the tumor. Complete surgical excision, when possible, is the only treatment that offers the possibility of cure of MPNSTs. Adjuvant chemotherapy or radiotherapy also is sometimes used, though benefit has not been clearly established.^8,9,13,14

Death certificate and population-based studies have shown that approximately 10% of patients with NFI have a reduced life expectancy due to MPNSTs; indeed, these tumors arising from plexiform neurofibromas are the main cause of death in adults with NFI. In 2003, Mautner et al⁷ studied 50 individuals with NFI. The objective was to establish magnetic resonance imaging criteria for MPNST and to test their usefulness in detecting early malignant change in plexiform neurofibromas. This study found that MPNST in patients with NFI frequently showed inhomogeneous contrast enhancement. This inhomogeneity was due to necrosis and hemorrhage, as shown by macroscopic and histologic analysis of amputated limbs in 2 patients within the study. The investigators found it to be possible to detect malignant transformation at an early stage in patients with no overt clinical signs of progression.⁷ Careful follow-up will determine how frequently early malignancy can be detected and if it is worthwhile carrying out magnetic resonance imaging at defined intervals.^2,7,10,15,16

The Diagnosis: Plexiform Neurofibroma as a Manifestation of Neurofibromatosis Type I

Physical examination revealed a large 10×8-cm subcutaneous nodule that was boggy and resembled a bag of worms on palpation. It was covered by slightly hyperpigmented skin. He also had numerous (>20) café au lait spots measuring 2 to 3 cm across the body and several others on the axillae. There were no gross eye findings. Otherwise the examination was unremarkable on the rest of the body. The patient’s paternal grandfather and aunt had similar macules and multiple nodules. The patient had mild to moderate learning difficulties. He was subsequently referred for genetic and ophthalmology evaluation.

Plexiform neurofibromas are usually benign nerve sheath tumors that are elongated and are multinodular, forming when the tumor involves either multiple trunks of a plexus or multiple fascicles of a large nerve such as the sciatic. Some plexiform neurofibromas resemble a bag of worms; others produce a massive ropy enlargement of the nerve.^1,2 Plexiform neurofibromas are associated with cases of neurofibromatosis type I (NFI) and are themselves one of the diagnostic criteria for NFI.¹

Plexiform neurofibromas are benign tumors that are the result of a genetic mutation in which loss of heterozygosity occurs, as is the case with the other predominant neoplasms of NFI, that results in unrestricted cell growth.^3,4 Some patients have a loss of heterozygosity of this tumor suppression gene with overgrowth of neurofibromatosis on a Blaschko segment. One study in mouse models showed that stromal mast cells were involved in promoting inflammation and increasing tumor growth by mediation of mitogenic signals involved in vascular ingrowth, collagen deposition, and cellular proliferation.⁵ Plexiform neurofibromas are a presenting feature in 30% of NFI cases within the first year of life. They are extensive nerve sheath tumors with an unpredictable growth pattern that can involve multiple fascicles (ie, large nerves and their branches). Five percent become malignant and the transformation is often heralded by rapid growth and pain.⁶ If malignant transformation is suspected, biopsy is diagnostic. Magnetic resonance imaging with and without contrast can categorize them into 3 growth categories: superficial, displacing, and invasive.⁷ Because plexiform neurofibromas are rare tumors, it previously was common practice to delay surgical intervention until disfigurement or disability arose. Complete surgical resection at more advanced stages is nearly impossible given the networklike growth pattern that commonly encapsulates vital structures.^8,9 Therefore, surgery has been used in the past for debulking the large growths that eventually will recur. A study of 9 small superficial plexiform neurofibromas in children aged 3 to 15 years documented treatment with early surgical resection, which showed complete resection and no relapse at 4 years. This study showed a promising strategy to prevent future extension of these fast-growing tumors into vital structures.⁸ There also are current clinical trials investigating sirolimus and peginterferon alfa-2b in patients with more invasive plexiform neurofibromas that are unable to undergo surgical resection due to encapsulation or proximity to essential anatomical structures (registered at www.clinicaltrials.gov with the identifiers NCT00652990 and NCT00678951, respectively).

Pain, development of a neurologic deficit, or enlargement of a preexisting plexiform neurofibroma may signal a malignant peripheral nerve sheath tumor (MPNST) and require immediate evaluation.¹⁰ Examination by magnetic resonance imaging and positron emission tomography is useful in distinguishing benign and MPNSTs,^8,11,12 but definitive differentiation can only be made by histologic examination of the tumor. Complete surgical excision, when possible, is the only treatment that offers the possibility of cure of MPNSTs. Adjuvant chemotherapy or radiotherapy also is sometimes used, though benefit has not been clearly established.^8,9,13,14

Death certificate and population-based studies have shown that approximately 10% of patients with NFI have a reduced life expectancy due to MPNSTs; indeed, these tumors arising from plexiform neurofibromas are the main cause of death in adults with NFI. In 2003, Mautner et al⁷ studied 50 individuals with NFI. The objective was to establish magnetic resonance imaging criteria for MPNST and to test their usefulness in detecting early malignant change in plexiform neurofibromas. This study found that MPNST in patients with NFI frequently showed inhomogeneous contrast enhancement. This inhomogeneity was due to necrosis and hemorrhage, as shown by macroscopic and histologic analysis of amputated limbs in 2 patients within the study. The investigators found it to be possible to detect malignant transformation at an early stage in patients with no overt clinical signs of progression.⁷ Careful follow-up will determine how frequently early malignancy can be detected and if it is worthwhile carrying out magnetic resonance imaging at defined intervals.^2,7,10,15,16

The Diagnosis: Plexiform Neurofibroma as a Manifestation of Neurofibromatosis Type I

Physical examination revealed a large 10×8-cm subcutaneous nodule that was boggy and resembled a bag of worms on palpation. It was covered by slightly hyperpigmented skin. He also had numerous (>20) café au lait spots measuring 2 to 3 cm across the body and several others on the axillae. There were no gross eye findings. Otherwise the examination was unremarkable on the rest of the body. The patient’s paternal grandfather and aunt had similar macules and multiple nodules. The patient had mild to moderate learning difficulties. He was subsequently referred for genetic and ophthalmology evaluation.

Plexiform neurofibromas are usually benign nerve sheath tumors that are elongated and are multinodular, forming when the tumor involves either multiple trunks of a plexus or multiple fascicles of a large nerve such as the sciatic. Some plexiform neurofibromas resemble a bag of worms; others produce a massive ropy enlargement of the nerve.^1,2 Plexiform neurofibromas are associated with cases of neurofibromatosis type I (NFI) and are themselves one of the diagnostic criteria for NFI.¹

Plexiform neurofibromas are benign tumors that are the result of a genetic mutation in which loss of heterozygosity occurs, as is the case with the other predominant neoplasms of NFI, that results in unrestricted cell growth.^3,4 Some patients have a loss of heterozygosity of this tumor suppression gene with overgrowth of neurofibromatosis on a Blaschko segment. One study in mouse models showed that stromal mast cells were involved in promoting inflammation and increasing tumor growth by mediation of mitogenic signals involved in vascular ingrowth, collagen deposition, and cellular proliferation.⁵ Plexiform neurofibromas are a presenting feature in 30% of NFI cases within the first year of life. They are extensive nerve sheath tumors with an unpredictable growth pattern that can involve multiple fascicles (ie, large nerves and their branches). Five percent become malignant and the transformation is often heralded by rapid growth and pain.⁶ If malignant transformation is suspected, biopsy is diagnostic. Magnetic resonance imaging with and without contrast can categorize them into 3 growth categories: superficial, displacing, and invasive.⁷ Because plexiform neurofibromas are rare tumors, it previously was common practice to delay surgical intervention until disfigurement or disability arose. Complete surgical resection at more advanced stages is nearly impossible given the networklike growth pattern that commonly encapsulates vital structures.^8,9 Therefore, surgery has been used in the past for debulking the large growths that eventually will recur. A study of 9 small superficial plexiform neurofibromas in children aged 3 to 15 years documented treatment with early surgical resection, which showed complete resection and no relapse at 4 years. This study showed a promising strategy to prevent future extension of these fast-growing tumors into vital structures.⁸ There also are current clinical trials investigating sirolimus and peginterferon alfa-2b in patients with more invasive plexiform neurofibromas that are unable to undergo surgical resection due to encapsulation or proximity to essential anatomical structures (registered at www.clinicaltrials.gov with the identifiers NCT00652990 and NCT00678951, respectively).

Pain, development of a neurologic deficit, or enlargement of a preexisting plexiform neurofibroma may signal a malignant peripheral nerve sheath tumor (MPNST) and require immediate evaluation.¹⁰ Examination by magnetic resonance imaging and positron emission tomography is useful in distinguishing benign and MPNSTs,^8,11,12 but definitive differentiation can only be made by histologic examination of the tumor. Complete surgical excision, when possible, is the only treatment that offers the possibility of cure of MPNSTs. Adjuvant chemotherapy or radiotherapy also is sometimes used, though benefit has not been clearly established.^8,9,13,14

Death certificate and population-based studies have shown that approximately 10% of patients with NFI have a reduced life expectancy due to MPNSTs; indeed, these tumors arising from plexiform neurofibromas are the main cause of death in adults with NFI. In 2003, Mautner et al⁷ studied 50 individuals with NFI. The objective was to establish magnetic resonance imaging criteria for MPNST and to test their usefulness in detecting early malignant change in plexiform neurofibromas. This study found that MPNST in patients with NFI frequently showed inhomogeneous contrast enhancement. This inhomogeneity was due to necrosis and hemorrhage, as shown by macroscopic and histologic analysis of amputated limbs in 2 patients within the study. The investigators found it to be possible to detect malignant transformation at an early stage in patients with no overt clinical signs of progression.⁷ Careful follow-up will determine how frequently early malignancy can be detected and if it is worthwhile carrying out magnetic resonance imaging at defined intervals.^2,7,10,15,16

The Diagnosis: Mycosis Fungoides

Physical examination revealed erythematous polycyclic and arcuate plaques with fine overlying scale on the right arm and shoulder (Figure 1). Mild wrinkling and telangiectasias were noted on the skin surrounding the lesions. Laboratory tests showed normal values for antinuclear antibodies, anti–Sjögren syndrome–related antigen A, and anti–Sjögren syndrome–related antigen B.

A skin biopsy of a plaque on the right upper arm showed enlarged pleomorphic lymphocytes arranged along the basal layer and in focal collections within the epidermis (Figure 2). Within the dermis were wiry bundles of collagen, a sparse superficial and patchy infiltrate of lymphocytes, and scattered large mononuclear cells (Figure 3). Immunoperoxidase staining revealed large intraepidermal lymphocytes positive for CD4 (Figure 4A) and CD5. Notably, these lymphocytes also stained positive for CD30 (Figure 4B). Staining for CD8, CD1a, CD56, and anaplastic lymphoma kinase was negative, with aberrant loss of CD3. The morphology and pattern of immunoreactivity supported the diagnosis of mycosis fungoides (MF).

Mycosis fungoides is the most common form of cutaneous T-cell lymphoma.¹ Its progression is classified in 3 stages: (1) early (patch) stage, (2) plaque stage, and (3) tumor stage. Conclusive diagnosis of early stage MF often is difficult due to its clinical features that are similar to more common benign dermatoses (eg, atopic dermatitis, psoriasis, lichen planus), leading to shortcomings in determining prognosis and selecting an appropriate treatment regimen. With this diagnositic difficulty in mind, guidelines have been created to aid in the diagnosis of early stage MF.²

Clinical features consistent with early stage MF include multiple erythematous, well-demarcated lesions with varying shapes that typically are greater than 5 cm in diameter.² Lesions usually are flat or thinly elevated and may exhibit slight scaling. As was noted in our patient, poikiloderma of the surrounding skin is fairly specific for early stage MF, as it is not a feature associated with common clinical mimics of MF (eg, atopic dermatitis, psoriasis, lichen planus). The distribution of skin lesions in non–sun-exposed areas is common. The eruption is persistent, though it may wax and wane in severity.²
 

Histopathologic examination is necessary to confirm a diagnosis of MF. Typically, early stage MF is marked by enlarged T lymphocytes within the epidermis as well as the papillary and superficial reticular dermis. Cerebriform nuclei are a key finding in the diagnosis of MF. Lymphocytes frequently are arranged linearly along the basal layer of the epidermis. Within the epidermis, clusters of atypical lymphocytes (Pautrier microabscesses) without spongiosis are uncommon but are a characteristic finding of MF if present.¹ Papillary dermal fibrosis also may be evident.²
 

Figure 4. Large intraepidermal lymphocytes were highlighted on CD4 (A) and CD30 immunostaining (B)(original magnification ×200 and ×200).

Immunostaining typically reveals positivity for CD3 and CD4, as well as for lymphocyte antigens CD2 and CD5.¹ CD30 positivity in early stage MF rarely has been reported in the literature.^3,4 Such cases appear histologically similarly to CD30‒negative cases in other respects. One study showed that the presence of CD30-positive lymphocytes does not alter the clinical course of MF.³ Another study found that, while epidermal CD30-postive lymphocytes had no prognostic relevance, an increased percentage of dermal CD30-positive cells was linked to a higher stage at diagnosis and worse overall prognosis.⁵ Pathogenesis underlying CD30 positivity in early MF is unknown. It is important to note that CD30-positive cells commonly are seen in lymphomatoid papulosis and anaplastic large cell lymphoma, as well as a variety of nonneoplastic conditions.^3,6,7

The Diagnosis: Mycosis Fungoides

Physical examination revealed erythematous polycyclic and arcuate plaques with fine overlying scale on the right arm and shoulder (Figure 1). Mild wrinkling and telangiectasias were noted on the skin surrounding the lesions. Laboratory tests showed normal values for antinuclear antibodies, anti–Sjögren syndrome–related antigen A, and anti–Sjögren syndrome–related antigen B.

A skin biopsy of a plaque on the right upper arm showed enlarged pleomorphic lymphocytes arranged along the basal layer and in focal collections within the epidermis (Figure 2). Within the dermis were wiry bundles of collagen, a sparse superficial and patchy infiltrate of lymphocytes, and scattered large mononuclear cells (Figure 3). Immunoperoxidase staining revealed large intraepidermal lymphocytes positive for CD4 (Figure 4A) and CD5. Notably, these lymphocytes also stained positive for CD30 (Figure 4B). Staining for CD8, CD1a, CD56, and anaplastic lymphoma kinase was negative, with aberrant loss of CD3. The morphology and pattern of immunoreactivity supported the diagnosis of mycosis fungoides (MF).

Mycosis fungoides is the most common form of cutaneous T-cell lymphoma.¹ Its progression is classified in 3 stages: (1) early (patch) stage, (2) plaque stage, and (3) tumor stage. Conclusive diagnosis of early stage MF often is difficult due to its clinical features that are similar to more common benign dermatoses (eg, atopic dermatitis, psoriasis, lichen planus), leading to shortcomings in determining prognosis and selecting an appropriate treatment regimen. With this diagnositic difficulty in mind, guidelines have been created to aid in the diagnosis of early stage MF.²

Clinical features consistent with early stage MF include multiple erythematous, well-demarcated lesions with varying shapes that typically are greater than 5 cm in diameter.² Lesions usually are flat or thinly elevated and may exhibit slight scaling. As was noted in our patient, poikiloderma of the surrounding skin is fairly specific for early stage MF, as it is not a feature associated with common clinical mimics of MF (eg, atopic dermatitis, psoriasis, lichen planus). The distribution of skin lesions in non–sun-exposed areas is common. The eruption is persistent, though it may wax and wane in severity.²
 

Histopathologic examination is necessary to confirm a diagnosis of MF. Typically, early stage MF is marked by enlarged T lymphocytes within the epidermis as well as the papillary and superficial reticular dermis. Cerebriform nuclei are a key finding in the diagnosis of MF. Lymphocytes frequently are arranged linearly along the basal layer of the epidermis. Within the epidermis, clusters of atypical lymphocytes (Pautrier microabscesses) without spongiosis are uncommon but are a characteristic finding of MF if present.¹ Papillary dermal fibrosis also may be evident.²
 

Figure 4. Large intraepidermal lymphocytes were highlighted on CD4 (A) and CD30 immunostaining (B)(original magnification ×200 and ×200).

Immunostaining typically reveals positivity for CD3 and CD4, as well as for lymphocyte antigens CD2 and CD5.¹ CD30 positivity in early stage MF rarely has been reported in the literature.^3,4 Such cases appear histologically similarly to CD30‒negative cases in other respects. One study showed that the presence of CD30-positive lymphocytes does not alter the clinical course of MF.³ Another study found that, while epidermal CD30-postive lymphocytes had no prognostic relevance, an increased percentage of dermal CD30-positive cells was linked to a higher stage at diagnosis and worse overall prognosis.⁵ Pathogenesis underlying CD30 positivity in early MF is unknown. It is important to note that CD30-positive cells commonly are seen in lymphomatoid papulosis and anaplastic large cell lymphoma, as well as a variety of nonneoplastic conditions.^3,6,7

The Diagnosis: Mycosis Fungoides

Physical examination revealed erythematous polycyclic and arcuate plaques with fine overlying scale on the right arm and shoulder (Figure 1). Mild wrinkling and telangiectasias were noted on the skin surrounding the lesions. Laboratory tests showed normal values for antinuclear antibodies, anti–Sjögren syndrome–related antigen A, and anti–Sjögren syndrome–related antigen B.

A skin biopsy of a plaque on the right upper arm showed enlarged pleomorphic lymphocytes arranged along the basal layer and in focal collections within the epidermis (Figure 2). Within the dermis were wiry bundles of collagen, a sparse superficial and patchy infiltrate of lymphocytes, and scattered large mononuclear cells (Figure 3). Immunoperoxidase staining revealed large intraepidermal lymphocytes positive for CD4 (Figure 4A) and CD5. Notably, these lymphocytes also stained positive for CD30 (Figure 4B). Staining for CD8, CD1a, CD56, and anaplastic lymphoma kinase was negative, with aberrant loss of CD3. The morphology and pattern of immunoreactivity supported the diagnosis of mycosis fungoides (MF).

Mycosis fungoides is the most common form of cutaneous T-cell lymphoma.¹ Its progression is classified in 3 stages: (1) early (patch) stage, (2) plaque stage, and (3) tumor stage. Conclusive diagnosis of early stage MF often is difficult due to its clinical features that are similar to more common benign dermatoses (eg, atopic dermatitis, psoriasis, lichen planus), leading to shortcomings in determining prognosis and selecting an appropriate treatment regimen. With this diagnositic difficulty in mind, guidelines have been created to aid in the diagnosis of early stage MF.²

Clinical features consistent with early stage MF include multiple erythematous, well-demarcated lesions with varying shapes that typically are greater than 5 cm in diameter.² Lesions usually are flat or thinly elevated and may exhibit slight scaling. As was noted in our patient, poikiloderma of the surrounding skin is fairly specific for early stage MF, as it is not a feature associated with common clinical mimics of MF (eg, atopic dermatitis, psoriasis, lichen planus). The distribution of skin lesions in non–sun-exposed areas is common. The eruption is persistent, though it may wax and wane in severity.²
 

Histopathologic examination is necessary to confirm a diagnosis of MF. Typically, early stage MF is marked by enlarged T lymphocytes within the epidermis as well as the papillary and superficial reticular dermis. Cerebriform nuclei are a key finding in the diagnosis of MF. Lymphocytes frequently are arranged linearly along the basal layer of the epidermis. Within the epidermis, clusters of atypical lymphocytes (Pautrier microabscesses) without spongiosis are uncommon but are a characteristic finding of MF if present.¹ Papillary dermal fibrosis also may be evident.²
 

Figure 4. Large intraepidermal lymphocytes were highlighted on CD4 (A) and CD30 immunostaining (B)(original magnification ×200 and ×200).

Immunostaining typically reveals positivity for CD3 and CD4, as well as for lymphocyte antigens CD2 and CD5.¹ CD30 positivity in early stage MF rarely has been reported in the literature.^3,4 Such cases appear histologically similarly to CD30‒negative cases in other respects. One study showed that the presence of CD30-positive lymphocytes does not alter the clinical course of MF.³ Another study found that, while epidermal CD30-postive lymphocytes had no prognostic relevance, an increased percentage of dermal CD30-positive cells was linked to a higher stage at diagnosis and worse overall prognosis.⁵ Pathogenesis underlying CD30 positivity in early MF is unknown. It is important to note that CD30-positive cells commonly are seen in lymphomatoid papulosis and anaplastic large cell lymphoma, as well as a variety of nonneoplastic conditions.^3,6,7

The Diagnosis: Neutrophilic Dermatosis of the Dorsal Hands

Neutrophilic dermatosis of the dorsal hands (NDDH) is considered to be an uncommon localized variant of Sweet syndrome (SS). The term pustular vasculitis originally was used to describe this condition by Strutton et al¹ in 1995 due to the presence of leukocytoclastic vasculitis on histology. In 2000, Galaria et al² suggested this eruption was a localized variant of SS based on clinical presentations that demonstrated associated fever and lack of necrotizing vasculitis and proposed the term neutrophilic dermatosis of the dorsal hands to describe the condition. Cases of similar cutaneous eruptions on the hands associated with fever, leukocytosis, elevated erythrocyte sedimentation rate, and leukocytoclasis have since been reported.^3-5 Some authors have concluded that these eruptions, previously termed atypical pyoderma gangrenosum and pustular vasculitis of the hands, represent a single disease entity and should be designated as NDDH.^3,4

Neutrophilic dermatosis of the dorsal hands characteristically presents with hemorrhagic pustular ulcerations limited to or predominantly located on the dorsal hands, as seen in our patient. Histopathologically, NDDH demonstrates a neutrophil-predominant infiltrate of the upper dermis and marked papillary dermal edema; a punch biopsy specimen from our patient was consistent with these features (Figure). Two punch biopsies were performed and were negative for fungus and acid-fast bacteria and positive for methicillin-sensitive Staphylococcus aureus. Vasculitis, if present, is more commonly seen in eruptions of longer duration (ie, months to years) and is thought to be secondary to the dense neutrophilic infiltrate and not a primary vasculitis.^3,6,7 Similar to classic SS, NDDH is inherently responsive to corticosteroid therapy. Successful treatment also has been reported with dapsone, colchicine, sulfapyridine, potassium iodide, intralesional and topical corticosteroids, and topical tacrolimus.^2-8 Oral minocycline has shown variable results.^3,4

Numerous case series have demonstrated that a majority of cases of NDDH are associated with hematologic or solid organ malignancies, myelodysplastic syndrome (MDS), inflammatory bowel disease, or other underlying systemic diseases.^3,5,9 It is important for dermatologists to recognize NDDH, distinguish it from localized infection, and perform the appropriate workup (eg, basic laboratory tests [complete blood count, complete metabolic panel], age-appropriate malignancy screening, colonoscopy, bone marrow biopsy) to exclude associated systemic diseases.

Our patient demonstrated characteristic clinical and histopathologic findings of NDDH in association with early MDS and possible common bile duct (CBD) malignancy. The lesions showed a rapid response to topical corticosteroid therapy. The initial differential diagnoses included NDDH or other neutrophilic dermatosis, phototoxic drug eruption, and atypical mycobacterial or fungal infection (cultures were negative in our patient). Physical examination and histopathologic findings along with the patient’s clinical course and rapid response to topical corticosteroid therapy supported the diagnosis of NDDH. Our patient’s multiple comorbidities, including macrocytic anemia, MDS, and potential CBD malignancy, presented a therapeutic challenge. Oral dapsone, an ideal steroid-sparing agent for neutrophilic dermatoses including NDDH, was avoided given its associated hematologic side effects including hemolysis, methemoglobinemia, and possible agranulocytosis. To date, the patient has not received any further treatment for MDS or the CBD mass and continues regular follow-up with hematology, gastroenterology, and dermatology.

This case highlights the importance of including NDDH in the differential diagnosis of papules and plaques on the hands, especially in patients with known malignancies, and emphasizes the association of neutrophilic dermatoses with malignancy and systemic disease. 

The Diagnosis: Neutrophilic Dermatosis of the Dorsal Hands

Neutrophilic dermatosis of the dorsal hands (NDDH) is considered to be an uncommon localized variant of Sweet syndrome (SS). The term pustular vasculitis originally was used to describe this condition by Strutton et al¹ in 1995 due to the presence of leukocytoclastic vasculitis on histology. In 2000, Galaria et al² suggested this eruption was a localized variant of SS based on clinical presentations that demonstrated associated fever and lack of necrotizing vasculitis and proposed the term neutrophilic dermatosis of the dorsal hands to describe the condition. Cases of similar cutaneous eruptions on the hands associated with fever, leukocytosis, elevated erythrocyte sedimentation rate, and leukocytoclasis have since been reported.^3-5 Some authors have concluded that these eruptions, previously termed atypical pyoderma gangrenosum and pustular vasculitis of the hands, represent a single disease entity and should be designated as NDDH.^3,4

Neutrophilic dermatosis of the dorsal hands characteristically presents with hemorrhagic pustular ulcerations limited to or predominantly located on the dorsal hands, as seen in our patient. Histopathologically, NDDH demonstrates a neutrophil-predominant infiltrate of the upper dermis and marked papillary dermal edema; a punch biopsy specimen from our patient was consistent with these features (Figure). Two punch biopsies were performed and were negative for fungus and acid-fast bacteria and positive for methicillin-sensitive Staphylococcus aureus. Vasculitis, if present, is more commonly seen in eruptions of longer duration (ie, months to years) and is thought to be secondary to the dense neutrophilic infiltrate and not a primary vasculitis.^3,6,7 Similar to classic SS, NDDH is inherently responsive to corticosteroid therapy. Successful treatment also has been reported with dapsone, colchicine, sulfapyridine, potassium iodide, intralesional and topical corticosteroids, and topical tacrolimus.^2-8 Oral minocycline has shown variable results.^3,4

Numerous case series have demonstrated that a majority of cases of NDDH are associated with hematologic or solid organ malignancies, myelodysplastic syndrome (MDS), inflammatory bowel disease, or other underlying systemic diseases.^3,5,9 It is important for dermatologists to recognize NDDH, distinguish it from localized infection, and perform the appropriate workup (eg, basic laboratory tests [complete blood count, complete metabolic panel], age-appropriate malignancy screening, colonoscopy, bone marrow biopsy) to exclude associated systemic diseases.

Our patient demonstrated characteristic clinical and histopathologic findings of NDDH in association with early MDS and possible common bile duct (CBD) malignancy. The lesions showed a rapid response to topical corticosteroid therapy. The initial differential diagnoses included NDDH or other neutrophilic dermatosis, phototoxic drug eruption, and atypical mycobacterial or fungal infection (cultures were negative in our patient). Physical examination and histopathologic findings along with the patient’s clinical course and rapid response to topical corticosteroid therapy supported the diagnosis of NDDH. Our patient’s multiple comorbidities, including macrocytic anemia, MDS, and potential CBD malignancy, presented a therapeutic challenge. Oral dapsone, an ideal steroid-sparing agent for neutrophilic dermatoses including NDDH, was avoided given its associated hematologic side effects including hemolysis, methemoglobinemia, and possible agranulocytosis. To date, the patient has not received any further treatment for MDS or the CBD mass and continues regular follow-up with hematology, gastroenterology, and dermatology.

This case highlights the importance of including NDDH in the differential diagnosis of papules and plaques on the hands, especially in patients with known malignancies, and emphasizes the association of neutrophilic dermatoses with malignancy and systemic disease. 

The Diagnosis: Neutrophilic Dermatosis of the Dorsal Hands

Neutrophilic dermatosis of the dorsal hands (NDDH) is considered to be an uncommon localized variant of Sweet syndrome (SS). The term pustular vasculitis originally was used to describe this condition by Strutton et al¹ in 1995 due to the presence of leukocytoclastic vasculitis on histology. In 2000, Galaria et al² suggested this eruption was a localized variant of SS based on clinical presentations that demonstrated associated fever and lack of necrotizing vasculitis and proposed the term neutrophilic dermatosis of the dorsal hands to describe the condition. Cases of similar cutaneous eruptions on the hands associated with fever, leukocytosis, elevated erythrocyte sedimentation rate, and leukocytoclasis have since been reported.^3-5 Some authors have concluded that these eruptions, previously termed atypical pyoderma gangrenosum and pustular vasculitis of the hands, represent a single disease entity and should be designated as NDDH.^3,4

Neutrophilic dermatosis of the dorsal hands characteristically presents with hemorrhagic pustular ulcerations limited to or predominantly located on the dorsal hands, as seen in our patient. Histopathologically, NDDH demonstrates a neutrophil-predominant infiltrate of the upper dermis and marked papillary dermal edema; a punch biopsy specimen from our patient was consistent with these features (Figure). Two punch biopsies were performed and were negative for fungus and acid-fast bacteria and positive for methicillin-sensitive Staphylococcus aureus. Vasculitis, if present, is more commonly seen in eruptions of longer duration (ie, months to years) and is thought to be secondary to the dense neutrophilic infiltrate and not a primary vasculitis.^3,6,7 Similar to classic SS, NDDH is inherently responsive to corticosteroid therapy. Successful treatment also has been reported with dapsone, colchicine, sulfapyridine, potassium iodide, intralesional and topical corticosteroids, and topical tacrolimus.^2-8 Oral minocycline has shown variable results.^3,4

Numerous case series have demonstrated that a majority of cases of NDDH are associated with hematologic or solid organ malignancies, myelodysplastic syndrome (MDS), inflammatory bowel disease, or other underlying systemic diseases.^3,5,9 It is important for dermatologists to recognize NDDH, distinguish it from localized infection, and perform the appropriate workup (eg, basic laboratory tests [complete blood count, complete metabolic panel], age-appropriate malignancy screening, colonoscopy, bone marrow biopsy) to exclude associated systemic diseases.

Our patient demonstrated characteristic clinical and histopathologic findings of NDDH in association with early MDS and possible common bile duct (CBD) malignancy. The lesions showed a rapid response to topical corticosteroid therapy. The initial differential diagnoses included NDDH or other neutrophilic dermatosis, phototoxic drug eruption, and atypical mycobacterial or fungal infection (cultures were negative in our patient). Physical examination and histopathologic findings along with the patient’s clinical course and rapid response to topical corticosteroid therapy supported the diagnosis of NDDH. Our patient’s multiple comorbidities, including macrocytic anemia, MDS, and potential CBD malignancy, presented a therapeutic challenge. Oral dapsone, an ideal steroid-sparing agent for neutrophilic dermatoses including NDDH, was avoided given its associated hematologic side effects including hemolysis, methemoglobinemia, and possible agranulocytosis. To date, the patient has not received any further treatment for MDS or the CBD mass and continues regular follow-up with hematology, gastroenterology, and dermatology.

This case highlights the importance of including NDDH in the differential diagnosis of papules and plaques on the hands, especially in patients with known malignancies, and emphasizes the association of neutrophilic dermatoses with malignancy and systemic disease. 

The Diagnosis: Hyperkeratosis Lenticularis Perstans

A shave biopsy of a lesion on the right leg was performed. Histopathology revealed a discrete papule with overlying compact hyperkeratosis. There was parakeratosis with an absent granular layer and a lichenoid lymphocytic infiltrate within the papillary dermis (Figure). Given the clinical context, these changes were consistent with a diagnosis of hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease.

The patient was started on tretinoin cream 0.1% nightly for 3 months and triamcinolone ointment 0.1% as needed for pruritus but showed no clinical response. Given the benign nature of the condition and because the lesions were asymptomatic, additional treatment options were not pursued.

Originally described by Flegel¹ in 1958, HLP is a rare skin disorder commonly seen in white individuals with onset in the fourth or fifth decades of life.^1,2 While most cases are sporadic,^3-6 HLP also has been associated with autosomal dominant inheritance.^7-10

Patients with HLP typically present with multiple 1- to 5-mm reddish-brown, hyperkeratotic, scaly papules that reveal a moist, erythematous base with pinpoint bleeding upon removal of the scale. Lesions usually are distributed symmetrically and most commonly present on the extensor surfaces of the lower legs and dorsal feet.^1,2,7 Lesions also may appear on the extensor surfaces of the arms, pinna, periocular region, antecubital and popliteal fossae, and oral mucosa and also may present as pits on the palms and soles.^2,4,7,8 Furthermore, unilateral and localized variants of HLP have been described.^11,12 Hyperkeratosis lenticularis perstans usually is asymptomatic but can present with mild pruritus or burning.^3,5,13

The etiology and pathogenesis of HLP are unknown. Exposure to UV light has been implicated as an inciting factor¹⁴; however, reports of spontaneous resolution in the summer¹³ and upon treatment with psoralen plus UVA therapy¹⁵ make the role of UV light unclear. Furthermore, investigators disagree as to whether the primary pathogenic event in HLP is an inflammatory process or one of abnormal keratinization.^1,3,7,10 Fernandez-Flores and Manjon¹⁶ suggested HLP is an inflammatory process with periods of exacerbations and remissions after finding mounds of parakeratosis with neutrophils arranged in different strata in the stratum corneum.

Histologically, compact hyperkeratosis usually is noted, often with associated parakeratosis, epidermal atrophy with thinning or absence of the granular layer, and a bandlike lymphohistiocytic infiltrate in the papillary dermis.^1-3 Histopathologic differences between recent-onset versus longstanding lesions have been found, with old lesions lacking an inflammatory infiltrate.³ Furthermore, new lesions often show abnormalities in quantity and/or morphology of membrane-coating granules, also known as Odland bodies, in keratinocytes on electron microscopy,^3,10,17 while old lesions do not.³ Odland bodies are involved in normal desquamation, leading some to speculate on their role in HLP.¹⁰ Currently, it is unclear whether abnormalities in these organelles cause the retention hyperkeratosis seen in HLP or if such abnormalities are a secondary phenomenon.^3,17

There are questionable associations between HLP and diabetes mellitus type 2, hyperthyroidism, basal and squamous cell carcinomas of the skin, and gastrointestinal malignancy.^4,9,18 Our patient had a history of basal cell carcinoma on the face, diet-controlled diabetes mellitus, and hypothyroidism. Given the high prevalence of these diseases in the general population, however, it is difficult to ascertain whether a true association with HLP exists.

While HLP can slowly progress to involve additional body sites, it is overall a benign condition that does not require treatment. Therapeutic options are based on case reports, with no single treatment showing a consistent response. From review of the literature, therapies that have been most effective include dermabrasion, excision,¹⁹ topical 5-fluorouracil,^2,17,20 and oral retinoids.⁸ Hyperkeratosis lenticularis perstans generally is resistant to topical steroids, retinoids, and vitamin D₃ analogs, although success with betamethasone dipropionate,⁵ isotretinoin  
gel 0.05%,¹¹ and calcipotriol have been reported.⁶ A case of HLP with clinical response to psoralen plus UVA therapy also has been described.¹⁵

The Diagnosis: Hyperkeratosis Lenticularis Perstans

A shave biopsy of a lesion on the right leg was performed. Histopathology revealed a discrete papule with overlying compact hyperkeratosis. There was parakeratosis with an absent granular layer and a lichenoid lymphocytic infiltrate within the papillary dermis (Figure). Given the clinical context, these changes were consistent with a diagnosis of hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease.

The patient was started on tretinoin cream 0.1% nightly for 3 months and triamcinolone ointment 0.1% as needed for pruritus but showed no clinical response. Given the benign nature of the condition and because the lesions were asymptomatic, additional treatment options were not pursued.

Originally described by Flegel¹ in 1958, HLP is a rare skin disorder commonly seen in white individuals with onset in the fourth or fifth decades of life.^1,2 While most cases are sporadic,^3-6 HLP also has been associated with autosomal dominant inheritance.^7-10

Patients with HLP typically present with multiple 1- to 5-mm reddish-brown, hyperkeratotic, scaly papules that reveal a moist, erythematous base with pinpoint bleeding upon removal of the scale. Lesions usually are distributed symmetrically and most commonly present on the extensor surfaces of the lower legs and dorsal feet.^1,2,7 Lesions also may appear on the extensor surfaces of the arms, pinna, periocular region, antecubital and popliteal fossae, and oral mucosa and also may present as pits on the palms and soles.^2,4,7,8 Furthermore, unilateral and localized variants of HLP have been described.^11,12 Hyperkeratosis lenticularis perstans usually is asymptomatic but can present with mild pruritus or burning.^3,5,13

The etiology and pathogenesis of HLP are unknown. Exposure to UV light has been implicated as an inciting factor¹⁴; however, reports of spontaneous resolution in the summer¹³ and upon treatment with psoralen plus UVA therapy¹⁵ make the role of UV light unclear. Furthermore, investigators disagree as to whether the primary pathogenic event in HLP is an inflammatory process or one of abnormal keratinization.^1,3,7,10 Fernandez-Flores and Manjon¹⁶ suggested HLP is an inflammatory process with periods of exacerbations and remissions after finding mounds of parakeratosis with neutrophils arranged in different strata in the stratum corneum.

Histologically, compact hyperkeratosis usually is noted, often with associated parakeratosis, epidermal atrophy with thinning or absence of the granular layer, and a bandlike lymphohistiocytic infiltrate in the papillary dermis.^1-3 Histopathologic differences between recent-onset versus longstanding lesions have been found, with old lesions lacking an inflammatory infiltrate.³ Furthermore, new lesions often show abnormalities in quantity and/or morphology of membrane-coating granules, also known as Odland bodies, in keratinocytes on electron microscopy,^3,10,17 while old lesions do not.³ Odland bodies are involved in normal desquamation, leading some to speculate on their role in HLP.¹⁰ Currently, it is unclear whether abnormalities in these organelles cause the retention hyperkeratosis seen in HLP or if such abnormalities are a secondary phenomenon.^3,17

There are questionable associations between HLP and diabetes mellitus type 2, hyperthyroidism, basal and squamous cell carcinomas of the skin, and gastrointestinal malignancy.^4,9,18 Our patient had a history of basal cell carcinoma on the face, diet-controlled diabetes mellitus, and hypothyroidism. Given the high prevalence of these diseases in the general population, however, it is difficult to ascertain whether a true association with HLP exists.

While HLP can slowly progress to involve additional body sites, it is overall a benign condition that does not require treatment. Therapeutic options are based on case reports, with no single treatment showing a consistent response. From review of the literature, therapies that have been most effective include dermabrasion, excision,¹⁹ topical 5-fluorouracil,^2,17,20 and oral retinoids.⁸ Hyperkeratosis lenticularis perstans generally is resistant to topical steroids, retinoids, and vitamin D₃ analogs, although success with betamethasone dipropionate,⁵ isotretinoin  
gel 0.05%,¹¹ and calcipotriol have been reported.⁶ A case of HLP with clinical response to psoralen plus UVA therapy also has been described.¹⁵

The Diagnosis: Hyperkeratosis Lenticularis Perstans

A shave biopsy of a lesion on the right leg was performed. Histopathology revealed a discrete papule with overlying compact hyperkeratosis. There was parakeratosis with an absent granular layer and a lichenoid lymphocytic infiltrate within the papillary dermis (Figure). Given the clinical context, these changes were consistent with a diagnosis of hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease.

The patient was started on tretinoin cream 0.1% nightly for 3 months and triamcinolone ointment 0.1% as needed for pruritus but showed no clinical response. Given the benign nature of the condition and because the lesions were asymptomatic, additional treatment options were not pursued.

Originally described by Flegel¹ in 1958, HLP is a rare skin disorder commonly seen in white individuals with onset in the fourth or fifth decades of life.^1,2 While most cases are sporadic,^3-6 HLP also has been associated with autosomal dominant inheritance.^7-10

Patients with HLP typically present with multiple 1- to 5-mm reddish-brown, hyperkeratotic, scaly papules that reveal a moist, erythematous base with pinpoint bleeding upon removal of the scale. Lesions usually are distributed symmetrically and most commonly present on the extensor surfaces of the lower legs and dorsal feet.^1,2,7 Lesions also may appear on the extensor surfaces of the arms, pinna, periocular region, antecubital and popliteal fossae, and oral mucosa and also may present as pits on the palms and soles.^2,4,7,8 Furthermore, unilateral and localized variants of HLP have been described.^11,12 Hyperkeratosis lenticularis perstans usually is asymptomatic but can present with mild pruritus or burning.^3,5,13

The etiology and pathogenesis of HLP are unknown. Exposure to UV light has been implicated as an inciting factor¹⁴; however, reports of spontaneous resolution in the summer¹³ and upon treatment with psoralen plus UVA therapy¹⁵ make the role of UV light unclear. Furthermore, investigators disagree as to whether the primary pathogenic event in HLP is an inflammatory process or one of abnormal keratinization.^1,3,7,10 Fernandez-Flores and Manjon¹⁶ suggested HLP is an inflammatory process with periods of exacerbations and remissions after finding mounds of parakeratosis with neutrophils arranged in different strata in the stratum corneum.

Histologically, compact hyperkeratosis usually is noted, often with associated parakeratosis, epidermal atrophy with thinning or absence of the granular layer, and a bandlike lymphohistiocytic infiltrate in the papillary dermis.^1-3 Histopathologic differences between recent-onset versus longstanding lesions have been found, with old lesions lacking an inflammatory infiltrate.³ Furthermore, new lesions often show abnormalities in quantity and/or morphology of membrane-coating granules, also known as Odland bodies, in keratinocytes on electron microscopy,^3,10,17 while old lesions do not.³ Odland bodies are involved in normal desquamation, leading some to speculate on their role in HLP.¹⁰ Currently, it is unclear whether abnormalities in these organelles cause the retention hyperkeratosis seen in HLP or if such abnormalities are a secondary phenomenon.^3,17

There are questionable associations between HLP and diabetes mellitus type 2, hyperthyroidism, basal and squamous cell carcinomas of the skin, and gastrointestinal malignancy.^4,9,18 Our patient had a history of basal cell carcinoma on the face, diet-controlled diabetes mellitus, and hypothyroidism. Given the high prevalence of these diseases in the general population, however, it is difficult to ascertain whether a true association with HLP exists.

While HLP can slowly progress to involve additional body sites, it is overall a benign condition that does not require treatment. Therapeutic options are based on case reports, with no single treatment showing a consistent response. From review of the literature, therapies that have been most effective include dermabrasion, excision,¹⁹ topical 5-fluorouracil,^2,17,20 and oral retinoids.⁸ Hyperkeratosis lenticularis perstans generally is resistant to topical steroids, retinoids, and vitamin D₃ analogs, although success with betamethasone dipropionate,⁵ isotretinoin  
gel 0.05%,¹¹ and calcipotriol have been reported.⁶ A case of HLP with clinical response to psoralen plus UVA therapy also has been described.¹⁵

The Diagnosis: Herpes Zoster

Herpes zoster is a common infection that clinically presents with moderate to intense pain in the involved dermatome (1–3 days before the outbreak¹) followed by a unilateral dermatomal eruption. The most common sites of involvement include the trunk (dermatomes T3–L2) and upper face (dermatome V1).² Herpes zoster characteristically begins as erythematous macules and papules that progress to vesicles and sometimes pustules, which subsequently crust over (7–10 days after the initial outbreak).¹ Regional lymphadenopathy is present in most cases. Due to the classic presentation of herpes zoster, clinical diagnosis is the mainstay for most cases. Although it can present in any age group, herpes zoster is most commonly associated with advancing age.³

During the course of primary varicella infection, the herpes virus spreads from infected lesions to the contiguous endings of sensory nerves and travels to the dorsal root ganglion cells where it remains latent.¹ It is hypothesized that cell-mediated immunity suppresses viral activity and maintains viral latency. A decline in varicella zoster virus–specific cell-mediated immunity can result in reactivation of the latent virus.¹ The virus is then transported to the skin from the dorsal root ganglion via myelinated nerves, which terminate at the isthmus of hair follicles, and subsequent infection of the folliculosebaceous unit occurs.⁴

Laboratory tests that can assist in the diagnosis of herpes zoster, especially atypical cases, include Tzanck smear and viral culture of the vesicle fluid.¹ When vesicles are not present, biopsy of the lesion followed by immunohistochemical staining and polymerase chain reaction assay can aid in the diagnosis. The differential diagnosis for our patient included pseudolymphoma, herpes simplex virus, lymphomatoid papulosis, sarcoidosis, trigeminal trophic syndrome, and Sweet syndrome.

Vesicles were not present in our patient, but the dermatomal nature of the eruption and the pain she experienced made the clinical scenario suspicious for herpes zoster. A 4-mm punch biopsy of a single folliculosebaceous unit revealed herpetic, cytopathic features including prominent keratinocyte necrosis involving sebaceous, isthmic, and infundibular epithelium; ballooning of epithelial cells with steel gray nuclei; and multinucleation with nuclear molding (Figure 1). Strong nuclear and cytoplasmic staining was seen in the affected keratinocytes under anti–varicella zoster virus immunohistochemical analysis (Figure 2). Staining for herpes simplex virus types 1 and 2 was negative. Within days of starting valacyclovir 1000 mg (every 8 hours for 1 week), the patient’s symptoms resolved.
 

Atypical presentations of herpes zoster (eg, presentations that are not completely dermatomal) are becoming more common. Herpetic infections should always be in the differential diagnosis for cutaneous ulcerations. Misdiagnosis of herpes zoster due to atypical features is common and can delay prompt and adequate treatment.

The Diagnosis: Herpes Zoster

Herpes zoster is a common infection that clinically presents with moderate to intense pain in the involved dermatome (1–3 days before the outbreak¹) followed by a unilateral dermatomal eruption. The most common sites of involvement include the trunk (dermatomes T3–L2) and upper face (dermatome V1).² Herpes zoster characteristically begins as erythematous macules and papules that progress to vesicles and sometimes pustules, which subsequently crust over (7–10 days after the initial outbreak).¹ Regional lymphadenopathy is present in most cases. Due to the classic presentation of herpes zoster, clinical diagnosis is the mainstay for most cases. Although it can present in any age group, herpes zoster is most commonly associated with advancing age.³

During the course of primary varicella infection, the herpes virus spreads from infected lesions to the contiguous endings of sensory nerves and travels to the dorsal root ganglion cells where it remains latent.¹ It is hypothesized that cell-mediated immunity suppresses viral activity and maintains viral latency. A decline in varicella zoster virus–specific cell-mediated immunity can result in reactivation of the latent virus.¹ The virus is then transported to the skin from the dorsal root ganglion via myelinated nerves, which terminate at the isthmus of hair follicles, and subsequent infection of the folliculosebaceous unit occurs.⁴

Laboratory tests that can assist in the diagnosis of herpes zoster, especially atypical cases, include Tzanck smear and viral culture of the vesicle fluid.¹ When vesicles are not present, biopsy of the lesion followed by immunohistochemical staining and polymerase chain reaction assay can aid in the diagnosis. The differential diagnosis for our patient included pseudolymphoma, herpes simplex virus, lymphomatoid papulosis, sarcoidosis, trigeminal trophic syndrome, and Sweet syndrome.

Vesicles were not present in our patient, but the dermatomal nature of the eruption and the pain she experienced made the clinical scenario suspicious for herpes zoster. A 4-mm punch biopsy of a single folliculosebaceous unit revealed herpetic, cytopathic features including prominent keratinocyte necrosis involving sebaceous, isthmic, and infundibular epithelium; ballooning of epithelial cells with steel gray nuclei; and multinucleation with nuclear molding (Figure 1). Strong nuclear and cytoplasmic staining was seen in the affected keratinocytes under anti–varicella zoster virus immunohistochemical analysis (Figure 2). Staining for herpes simplex virus types 1 and 2 was negative. Within days of starting valacyclovir 1000 mg (every 8 hours for 1 week), the patient’s symptoms resolved.
 

Atypical presentations of herpes zoster (eg, presentations that are not completely dermatomal) are becoming more common. Herpetic infections should always be in the differential diagnosis for cutaneous ulcerations. Misdiagnosis of herpes zoster due to atypical features is common and can delay prompt and adequate treatment.

The Diagnosis: Herpes Zoster

Herpes zoster is a common infection that clinically presents with moderate to intense pain in the involved dermatome (1–3 days before the outbreak¹) followed by a unilateral dermatomal eruption. The most common sites of involvement include the trunk (dermatomes T3–L2) and upper face (dermatome V1).² Herpes zoster characteristically begins as erythematous macules and papules that progress to vesicles and sometimes pustules, which subsequently crust over (7–10 days after the initial outbreak).¹ Regional lymphadenopathy is present in most cases. Due to the classic presentation of herpes zoster, clinical diagnosis is the mainstay for most cases. Although it can present in any age group, herpes zoster is most commonly associated with advancing age.³

During the course of primary varicella infection, the herpes virus spreads from infected lesions to the contiguous endings of sensory nerves and travels to the dorsal root ganglion cells where it remains latent.¹ It is hypothesized that cell-mediated immunity suppresses viral activity and maintains viral latency. A decline in varicella zoster virus–specific cell-mediated immunity can result in reactivation of the latent virus.¹ The virus is then transported to the skin from the dorsal root ganglion via myelinated nerves, which terminate at the isthmus of hair follicles, and subsequent infection of the folliculosebaceous unit occurs.⁴

Laboratory tests that can assist in the diagnosis of herpes zoster, especially atypical cases, include Tzanck smear and viral culture of the vesicle fluid.¹ When vesicles are not present, biopsy of the lesion followed by immunohistochemical staining and polymerase chain reaction assay can aid in the diagnosis. The differential diagnosis for our patient included pseudolymphoma, herpes simplex virus, lymphomatoid papulosis, sarcoidosis, trigeminal trophic syndrome, and Sweet syndrome.

Vesicles were not present in our patient, but the dermatomal nature of the eruption and the pain she experienced made the clinical scenario suspicious for herpes zoster. A 4-mm punch biopsy of a single folliculosebaceous unit revealed herpetic, cytopathic features including prominent keratinocyte necrosis involving sebaceous, isthmic, and infundibular epithelium; ballooning of epithelial cells with steel gray nuclei; and multinucleation with nuclear molding (Figure 1). Strong nuclear and cytoplasmic staining was seen in the affected keratinocytes under anti–varicella zoster virus immunohistochemical analysis (Figure 2). Staining for herpes simplex virus types 1 and 2 was negative. Within days of starting valacyclovir 1000 mg (every 8 hours for 1 week), the patient’s symptoms resolved.
 

Atypical presentations of herpes zoster (eg, presentations that are not completely dermatomal) are becoming more common. Herpetic infections should always be in the differential diagnosis for cutaneous ulcerations. Misdiagnosis of herpes zoster due to atypical features is common and can delay prompt and adequate treatment.