Dermatopathology

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease.¹ The majority of BP cases are idiopathic and occur in patients older than 60 years. The disease is characterized by the development of circulating IgG autoantibodies reacting with the BP180 antigen of the basement membrane zone.¹ Psoriasis vulgaris (PV) is a common, chronic, immune-mediated disease affecting approximately 2% of the world’s population including children and adults.² Both entities may coexist with internal disorders such as hypertension, diabetes mellitus, coronary heart disease, congestive heart failure, hyperlipidemia, and cerebrovascular accident. It has been postulated that BP more often coexists with neurological disorders, such as stroke and Parkinson disease,³ whereas PV usually is associated with cardiovascular disorders and diabetes mellitus.² We report the case of a 35-year-old man with chronic PV and metabolic syndrome who developed BP that was successfully treated with methotrexate (MTX).

Case Report

A 35-year-old man with a 15-year history of PV, class 3 obesity (body mass index, 69.2), and thrombosis of the left leg was referred to the dermatology department due to a sudden extensive erythematous and bullous eruption located on the trunk, arms, and legs with involvement of the oral mucosa that had started 4 weeks prior. The skin lesions were accompanied by severe pruritus. On admission to the hospital, the patient presented with stable psoriatic plaques located on the trunk, arms, and proximal part of the lower legs with a psoriasis area severity index score of 11.8 (Figure 1A). He also had disseminated tense blisters and erosions partially arranged in an annular pattern located on the border of the psoriatic plaques as well as on an erythematous base or within unaffected skin (Figure 1B). Additionally, a few small erosions were present on the oral mucosa.

The patient’s father had a history of PV, but there was no family history of obesity or autoimmune blistering disorders. On physical examination, central obesity was noted with a waist circumference of 180 cm and a body mass index of 69.2; his blood pressure was 220/150 mm Hg. Laboratory tests revealed leukocytosis (20.06×10⁹/L [reference range, 4.5–11.0×10⁹/L]) with neutrophilia (16.2×10⁹/L [reference range, 1.6–7.6×10⁹/L]; 80.9% [reference range, 40.0%–70.0%]), eosinophilia (1.01×10⁹/L [reference range, 0–0.5×10⁹/L]), elevated C-reactive protein levels (49.4 mg/L [reference range, 0.0–9.0 mg/L]), elevated erythrocyte sedimentation rate (35 mm/h [reference range, 0–12 mm/h]), elevated γ-glutamyltransferase (66 U/L [reference range, 0–55 U/L]), decreased high-density lipoprotein levels (38 mg/dL [reference range, ≥40 mg/dL]), elevated fasting plasma glucose (116 mg/dL or 6.4 mmol/L [reference range, 70–99 mg/dL or 3.9–5.5 mmol/L]), elevated total IgE (1540 µg/L [reference range, 0–1000 µg/L]), elevated D-dimer (3.21 µg/mL [reference range, <0.5 µg/mL]), and low free triiodothyronine levels (130 pg/dL [reference range, 171–371 pg/dL]). The total protein level was 6.5 g/dL (reference range, 6.0–8.0 g/dL) and albumin level was 3.2 g/dL (reference range, 4.02–4.76 g/dL). A chest radiograph showed no abnormalities.

Based on the physical examination and laboratory testing, it was determined that the patient fulfilled 4 of 5 criteria for metabolic syndrome described by the International Diabetes Federation in 2006 (Table).⁴ Direct immunofluorescence performed on normal-appearing perilesional skin demonstrated linear IgG and C3 deposits along the basement membrane zone. Indirect immunofluorescence detected circulating IgG autoantibodies at a titer of 1:80. Serum studies using biochip mosaics⁵ revealed the reactivity of circulating IgG antibodies to the epidermal side of salt-split skin and with antigen dots of tetrameric BP180-NC16a, which prompted the diagnosis of BP (Figure 2).

Oral treatment with MTX 12.5 mg once weekly with clobetasol propionate cream applied to affected skin was initiated for 4 weeks. The PV resolved completely and blister formation stopped. A few weeks later BP reappeared, even though the patient was still taking MTX. The treatment failure may have been related to the patient’s class 3 obesity; therefore, the dose was increased to 20 mg once weekly for 8 weeks, which led to rapid healing of BP erosions. The patient was monitored for 2 months with no symptoms of recurrence.

Comment

Psoriasis Comorbidities

The correlation between PV and cardiovascular disorders such as myocardial infarction, cerebrovascular accident, and pulmonary embolism has been well established and is widely accepted.² It also has been documented that the risk for metabolic syndrome with components such as diabetes mellitus, hypertension, lipid abnormalities, obesity, and arteriosclerosis is notably increased in PV patients.⁶ Moreover, associated internal disorders are responsible for a 3- to 4-year reduction in life expectancy in patients with moderate to severe PV.⁷

Correlation of PV and BP

Psoriasis also may coexist with autoimmune disorders such as rheumatoid arthritis, lupus erythematosus, and blistering disorders.⁸ There are more than 60 known cases reporting PV in association with various types of subepidermal blistering diseases, including pemphigus vulgaris, epidermolysis bullosa acquisita, anti-p200 pemphigoid, and BP.^8,9 The pathogenetic relationship between BP and PV remains obscure. In most published cases, PV preceded BP by 5 to 30 years, possibly ascribable to patients being diagnosed with PV at a younger age.⁹ In general, patients with BP and PV are younger than patients with BP only, with a mean age of 62 years.⁹ Because our patient was in his mid-30s when he developed BP, in such cases physicians should take under consideration any triggering factors (eg, drugs). Physical examination and detailed laboratory findings allowed us to make the patient aware of the potential for development of metabolic syndrome. This condition in combination with PV could be a predisposing factor for BP development. According to more recent research, PV is considered a generalized inflammatory process rather than a disorder limited to the skin and joints.¹⁰ The chronic inflammatory process in psoriatic skin results in exposure of autoantigens, leading to an immune response and the production of BP antibodies. The neutrophil elastase enzyme present in psoriatic lesions also may take part in dermoepidermal junction degradation and blister formation of BP.¹¹ According to other observations, some antipsoriatic therapies (eg, psoralen plus UVA, UVB, dithranol, coal tar) could be associated with development of BP.¹² Moreover, it was shown that psoralen plus UVA therapy, which is widely used in PV treatment, alters the cytokine profile from helper T cells T_H1 to T_H2.¹² T_H2-dependent cytokines predominate the sera and erosions in BP patients and seem to be notably relevant to the pathophysiology of the disease.¹³ The history of our patient’s psoriatic treatment included only topical corticosteroids, keratolytic agents, and occasionally dithranol and coal tar; however, UV phototherapy or any other systemic therapies had never been utilized. Three previously reported cases of patients with PV and BP also revealed no history of UV phototherapy,^8,9 which suggests that mechanisms responsible for coexistence of PV and BP are more complex. It has been proven that proinflammatory cytokines secreted by T_H1 and T_H17 cells, in particular tumor necrosis factor α, IL-17, IL-22, and IL-23, play an important role in the development of psoriatic lesions.¹⁰ On the other hand, these cytokines are known to contribute to vascular inflammation, leading to development of arteriosclerosis, as well as to regulate adipogenesis and obesity.^14,15 Arakawa et al¹⁶ reported increased expression of IL-17 in lesional skin in BP. They concluded that IL-17 may contribute to the recruitment of eosinophils and neutrophils and tissue damage in BP. Therefore, it is highly likely that IL-17 might be a common factor underlying the coexistence of BP with PV and metabolic syndrome. More such reports are required for better understanding this association.

BP Treatment

Selecting a therapy for BP with coexistent PV is challenging, especially in patients with extreme obesity and metabolic syndrome. It is well established that obesity correlates with a higher incidence of PV and more severe disease. On the other hand, obesity also influences response to therapy. Systemic corticosteroids are contraindicated in psoriasis patients because of severe side effects, such as rebound phenomenon of psoriatic lesions and risk for development of generalized pustular PV. Although systemic corticosteroids are effective in BP, high-dose therapy may potentially be life-threatening, particularly in these obese patients with conditions such as hypertension and diabetes mellitus, among others,¹ as was observed in our case. Taking into consideration the above mentioned conditions and our experience on such cases, the current patient had received MTX (12.5 mg once weekly) and clobetasol propionate cream, which led to the rapid healing of the psoriatic plaques, whereas BP was more resistant to this therapy. This response may be explained by our patient’s class 3 obesity (body mass index, 69.2). Therefore, the dose of MTX was increased to 20 mg once weekly and was successful. The decision to use MTX was supported by evidence that this medicine may reduce the risk for arteriosclerosis and cardiovascular disorders.¹⁷

There are some alternative therapeutic options for patients with coexisting BP and PV, such as cyclosporine,¹⁸ combination low-dose cyclosporine and low-dose systemic corticosteroids,¹⁹ dapsone,²⁰ azathioprine,²¹ mycophenolate mofetil,²² and acitretin.²³ It also has been shown that biologics (eg, ustekinumab) may be a successful solution in patients with PV and antilaminin-γ1 pemphigoid.²⁴ However, these alternative therapeutic regimens could not be considered in our patient because of serious coexisting internal disorders.

Conclusion

We present a case of concomitant BP and PV in a patient with metabolic syndrome. Although the pathogenic role of this unique coexistence is not fully understood, MTX proved suitable and effective in this single case. Further studies should be performed to elucidate the pathogenic relationship and therapeutic solutions for cases with coexisting PV, BP, and metabolic syndrome.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease.¹ The majority of BP cases are idiopathic and occur in patients older than 60 years. The disease is characterized by the development of circulating IgG autoantibodies reacting with the BP180 antigen of the basement membrane zone.¹ Psoriasis vulgaris (PV) is a common, chronic, immune-mediated disease affecting approximately 2% of the world’s population including children and adults.² Both entities may coexist with internal disorders such as hypertension, diabetes mellitus, coronary heart disease, congestive heart failure, hyperlipidemia, and cerebrovascular accident. It has been postulated that BP more often coexists with neurological disorders, such as stroke and Parkinson disease,³ whereas PV usually is associated with cardiovascular disorders and diabetes mellitus.² We report the case of a 35-year-old man with chronic PV and metabolic syndrome who developed BP that was successfully treated with methotrexate (MTX).

Case Report

A 35-year-old man with a 15-year history of PV, class 3 obesity (body mass index, 69.2), and thrombosis of the left leg was referred to the dermatology department due to a sudden extensive erythematous and bullous eruption located on the trunk, arms, and legs with involvement of the oral mucosa that had started 4 weeks prior. The skin lesions were accompanied by severe pruritus. On admission to the hospital, the patient presented with stable psoriatic plaques located on the trunk, arms, and proximal part of the lower legs with a psoriasis area severity index score of 11.8 (Figure 1A). He also had disseminated tense blisters and erosions partially arranged in an annular pattern located on the border of the psoriatic plaques as well as on an erythematous base or within unaffected skin (Figure 1B). Additionally, a few small erosions were present on the oral mucosa.

The patient’s father had a history of PV, but there was no family history of obesity or autoimmune blistering disorders. On physical examination, central obesity was noted with a waist circumference of 180 cm and a body mass index of 69.2; his blood pressure was 220/150 mm Hg. Laboratory tests revealed leukocytosis (20.06×10⁹/L [reference range, 4.5–11.0×10⁹/L]) with neutrophilia (16.2×10⁹/L [reference range, 1.6–7.6×10⁹/L]; 80.9% [reference range, 40.0%–70.0%]), eosinophilia (1.01×10⁹/L [reference range, 0–0.5×10⁹/L]), elevated C-reactive protein levels (49.4 mg/L [reference range, 0.0–9.0 mg/L]), elevated erythrocyte sedimentation rate (35 mm/h [reference range, 0–12 mm/h]), elevated γ-glutamyltransferase (66 U/L [reference range, 0–55 U/L]), decreased high-density lipoprotein levels (38 mg/dL [reference range, ≥40 mg/dL]), elevated fasting plasma glucose (116 mg/dL or 6.4 mmol/L [reference range, 70–99 mg/dL or 3.9–5.5 mmol/L]), elevated total IgE (1540 µg/L [reference range, 0–1000 µg/L]), elevated D-dimer (3.21 µg/mL [reference range, <0.5 µg/mL]), and low free triiodothyronine levels (130 pg/dL [reference range, 171–371 pg/dL]). The total protein level was 6.5 g/dL (reference range, 6.0–8.0 g/dL) and albumin level was 3.2 g/dL (reference range, 4.02–4.76 g/dL). A chest radiograph showed no abnormalities.

Based on the physical examination and laboratory testing, it was determined that the patient fulfilled 4 of 5 criteria for metabolic syndrome described by the International Diabetes Federation in 2006 (Table).⁴ Direct immunofluorescence performed on normal-appearing perilesional skin demonstrated linear IgG and C3 deposits along the basement membrane zone. Indirect immunofluorescence detected circulating IgG autoantibodies at a titer of 1:80. Serum studies using biochip mosaics⁵ revealed the reactivity of circulating IgG antibodies to the epidermal side of salt-split skin and with antigen dots of tetrameric BP180-NC16a, which prompted the diagnosis of BP (Figure 2).

Oral treatment with MTX 12.5 mg once weekly with clobetasol propionate cream applied to affected skin was initiated for 4 weeks. The PV resolved completely and blister formation stopped. A few weeks later BP reappeared, even though the patient was still taking MTX. The treatment failure may have been related to the patient’s class 3 obesity; therefore, the dose was increased to 20 mg once weekly for 8 weeks, which led to rapid healing of BP erosions. The patient was monitored for 2 months with no symptoms of recurrence.

Comment

Psoriasis Comorbidities

The correlation between PV and cardiovascular disorders such as myocardial infarction, cerebrovascular accident, and pulmonary embolism has been well established and is widely accepted.² It also has been documented that the risk for metabolic syndrome with components such as diabetes mellitus, hypertension, lipid abnormalities, obesity, and arteriosclerosis is notably increased in PV patients.⁶ Moreover, associated internal disorders are responsible for a 3- to 4-year reduction in life expectancy in patients with moderate to severe PV.⁷

Correlation of PV and BP

Psoriasis also may coexist with autoimmune disorders such as rheumatoid arthritis, lupus erythematosus, and blistering disorders.⁸ There are more than 60 known cases reporting PV in association with various types of subepidermal blistering diseases, including pemphigus vulgaris, epidermolysis bullosa acquisita, anti-p200 pemphigoid, and BP.^8,9 The pathogenetic relationship between BP and PV remains obscure. In most published cases, PV preceded BP by 5 to 30 years, possibly ascribable to patients being diagnosed with PV at a younger age.⁹ In general, patients with BP and PV are younger than patients with BP only, with a mean age of 62 years.⁹ Because our patient was in his mid-30s when he developed BP, in such cases physicians should take under consideration any triggering factors (eg, drugs). Physical examination and detailed laboratory findings allowed us to make the patient aware of the potential for development of metabolic syndrome. This condition in combination with PV could be a predisposing factor for BP development. According to more recent research, PV is considered a generalized inflammatory process rather than a disorder limited to the skin and joints.¹⁰ The chronic inflammatory process in psoriatic skin results in exposure of autoantigens, leading to an immune response and the production of BP antibodies. The neutrophil elastase enzyme present in psoriatic lesions also may take part in dermoepidermal junction degradation and blister formation of BP.¹¹ According to other observations, some antipsoriatic therapies (eg, psoralen plus UVA, UVB, dithranol, coal tar) could be associated with development of BP.¹² Moreover, it was shown that psoralen plus UVA therapy, which is widely used in PV treatment, alters the cytokine profile from helper T cells T_H1 to T_H2.¹² T_H2-dependent cytokines predominate the sera and erosions in BP patients and seem to be notably relevant to the pathophysiology of the disease.¹³ The history of our patient’s psoriatic treatment included only topical corticosteroids, keratolytic agents, and occasionally dithranol and coal tar; however, UV phototherapy or any other systemic therapies had never been utilized. Three previously reported cases of patients with PV and BP also revealed no history of UV phototherapy,^8,9 which suggests that mechanisms responsible for coexistence of PV and BP are more complex. It has been proven that proinflammatory cytokines secreted by T_H1 and T_H17 cells, in particular tumor necrosis factor α, IL-17, IL-22, and IL-23, play an important role in the development of psoriatic lesions.¹⁰ On the other hand, these cytokines are known to contribute to vascular inflammation, leading to development of arteriosclerosis, as well as to regulate adipogenesis and obesity.^14,15 Arakawa et al¹⁶ reported increased expression of IL-17 in lesional skin in BP. They concluded that IL-17 may contribute to the recruitment of eosinophils and neutrophils and tissue damage in BP. Therefore, it is highly likely that IL-17 might be a common factor underlying the coexistence of BP with PV and metabolic syndrome. More such reports are required for better understanding this association.

BP Treatment

Selecting a therapy for BP with coexistent PV is challenging, especially in patients with extreme obesity and metabolic syndrome. It is well established that obesity correlates with a higher incidence of PV and more severe disease. On the other hand, obesity also influences response to therapy. Systemic corticosteroids are contraindicated in psoriasis patients because of severe side effects, such as rebound phenomenon of psoriatic lesions and risk for development of generalized pustular PV. Although systemic corticosteroids are effective in BP, high-dose therapy may potentially be life-threatening, particularly in these obese patients with conditions such as hypertension and diabetes mellitus, among others,¹ as was observed in our case. Taking into consideration the above mentioned conditions and our experience on such cases, the current patient had received MTX (12.5 mg once weekly) and clobetasol propionate cream, which led to the rapid healing of the psoriatic plaques, whereas BP was more resistant to this therapy. This response may be explained by our patient’s class 3 obesity (body mass index, 69.2). Therefore, the dose of MTX was increased to 20 mg once weekly and was successful. The decision to use MTX was supported by evidence that this medicine may reduce the risk for arteriosclerosis and cardiovascular disorders.¹⁷

There are some alternative therapeutic options for patients with coexisting BP and PV, such as cyclosporine,¹⁸ combination low-dose cyclosporine and low-dose systemic corticosteroids,¹⁹ dapsone,²⁰ azathioprine,²¹ mycophenolate mofetil,²² and acitretin.²³ It also has been shown that biologics (eg, ustekinumab) may be a successful solution in patients with PV and antilaminin-γ1 pemphigoid.²⁴ However, these alternative therapeutic regimens could not be considered in our patient because of serious coexisting internal disorders.

Conclusion

We present a case of concomitant BP and PV in a patient with metabolic syndrome. Although the pathogenic role of this unique coexistence is not fully understood, MTX proved suitable and effective in this single case. Further studies should be performed to elucidate the pathogenic relationship and therapeutic solutions for cases with coexisting PV, BP, and metabolic syndrome.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease.¹ The majority of BP cases are idiopathic and occur in patients older than 60 years. The disease is characterized by the development of circulating IgG autoantibodies reacting with the BP180 antigen of the basement membrane zone.¹ Psoriasis vulgaris (PV) is a common, chronic, immune-mediated disease affecting approximately 2% of the world’s population including children and adults.² Both entities may coexist with internal disorders such as hypertension, diabetes mellitus, coronary heart disease, congestive heart failure, hyperlipidemia, and cerebrovascular accident. It has been postulated that BP more often coexists with neurological disorders, such as stroke and Parkinson disease,³ whereas PV usually is associated with cardiovascular disorders and diabetes mellitus.² We report the case of a 35-year-old man with chronic PV and metabolic syndrome who developed BP that was successfully treated with methotrexate (MTX).

Case Report

A 35-year-old man with a 15-year history of PV, class 3 obesity (body mass index, 69.2), and thrombosis of the left leg was referred to the dermatology department due to a sudden extensive erythematous and bullous eruption located on the trunk, arms, and legs with involvement of the oral mucosa that had started 4 weeks prior. The skin lesions were accompanied by severe pruritus. On admission to the hospital, the patient presented with stable psoriatic plaques located on the trunk, arms, and proximal part of the lower legs with a psoriasis area severity index score of 11.8 (Figure 1A). He also had disseminated tense blisters and erosions partially arranged in an annular pattern located on the border of the psoriatic plaques as well as on an erythematous base or within unaffected skin (Figure 1B). Additionally, a few small erosions were present on the oral mucosa.

The patient’s father had a history of PV, but there was no family history of obesity or autoimmune blistering disorders. On physical examination, central obesity was noted with a waist circumference of 180 cm and a body mass index of 69.2; his blood pressure was 220/150 mm Hg. Laboratory tests revealed leukocytosis (20.06×10⁹/L [reference range, 4.5–11.0×10⁹/L]) with neutrophilia (16.2×10⁹/L [reference range, 1.6–7.6×10⁹/L]; 80.9% [reference range, 40.0%–70.0%]), eosinophilia (1.01×10⁹/L [reference range, 0–0.5×10⁹/L]), elevated C-reactive protein levels (49.4 mg/L [reference range, 0.0–9.0 mg/L]), elevated erythrocyte sedimentation rate (35 mm/h [reference range, 0–12 mm/h]), elevated γ-glutamyltransferase (66 U/L [reference range, 0–55 U/L]), decreased high-density lipoprotein levels (38 mg/dL [reference range, ≥40 mg/dL]), elevated fasting plasma glucose (116 mg/dL or 6.4 mmol/L [reference range, 70–99 mg/dL or 3.9–5.5 mmol/L]), elevated total IgE (1540 µg/L [reference range, 0–1000 µg/L]), elevated D-dimer (3.21 µg/mL [reference range, <0.5 µg/mL]), and low free triiodothyronine levels (130 pg/dL [reference range, 171–371 pg/dL]). The total protein level was 6.5 g/dL (reference range, 6.0–8.0 g/dL) and albumin level was 3.2 g/dL (reference range, 4.02–4.76 g/dL). A chest radiograph showed no abnormalities.

Based on the physical examination and laboratory testing, it was determined that the patient fulfilled 4 of 5 criteria for metabolic syndrome described by the International Diabetes Federation in 2006 (Table).⁴ Direct immunofluorescence performed on normal-appearing perilesional skin demonstrated linear IgG and C3 deposits along the basement membrane zone. Indirect immunofluorescence detected circulating IgG autoantibodies at a titer of 1:80. Serum studies using biochip mosaics⁵ revealed the reactivity of circulating IgG antibodies to the epidermal side of salt-split skin and with antigen dots of tetrameric BP180-NC16a, which prompted the diagnosis of BP (Figure 2).

Oral treatment with MTX 12.5 mg once weekly with clobetasol propionate cream applied to affected skin was initiated for 4 weeks. The PV resolved completely and blister formation stopped. A few weeks later BP reappeared, even though the patient was still taking MTX. The treatment failure may have been related to the patient’s class 3 obesity; therefore, the dose was increased to 20 mg once weekly for 8 weeks, which led to rapid healing of BP erosions. The patient was monitored for 2 months with no symptoms of recurrence.

Comment

Psoriasis Comorbidities

The correlation between PV and cardiovascular disorders such as myocardial infarction, cerebrovascular accident, and pulmonary embolism has been well established and is widely accepted.² It also has been documented that the risk for metabolic syndrome with components such as diabetes mellitus, hypertension, lipid abnormalities, obesity, and arteriosclerosis is notably increased in PV patients.⁶ Moreover, associated internal disorders are responsible for a 3- to 4-year reduction in life expectancy in patients with moderate to severe PV.⁷

Correlation of PV and BP

Psoriasis also may coexist with autoimmune disorders such as rheumatoid arthritis, lupus erythematosus, and blistering disorders.⁸ There are more than 60 known cases reporting PV in association with various types of subepidermal blistering diseases, including pemphigus vulgaris, epidermolysis bullosa acquisita, anti-p200 pemphigoid, and BP.^8,9 The pathogenetic relationship between BP and PV remains obscure. In most published cases, PV preceded BP by 5 to 30 years, possibly ascribable to patients being diagnosed with PV at a younger age.⁹ In general, patients with BP and PV are younger than patients with BP only, with a mean age of 62 years.⁹ Because our patient was in his mid-30s when he developed BP, in such cases physicians should take under consideration any triggering factors (eg, drugs). Physical examination and detailed laboratory findings allowed us to make the patient aware of the potential for development of metabolic syndrome. This condition in combination with PV could be a predisposing factor for BP development. According to more recent research, PV is considered a generalized inflammatory process rather than a disorder limited to the skin and joints.¹⁰ The chronic inflammatory process in psoriatic skin results in exposure of autoantigens, leading to an immune response and the production of BP antibodies. The neutrophil elastase enzyme present in psoriatic lesions also may take part in dermoepidermal junction degradation and blister formation of BP.¹¹ According to other observations, some antipsoriatic therapies (eg, psoralen plus UVA, UVB, dithranol, coal tar) could be associated with development of BP.¹² Moreover, it was shown that psoralen plus UVA therapy, which is widely used in PV treatment, alters the cytokine profile from helper T cells T_H1 to T_H2.¹² T_H2-dependent cytokines predominate the sera and erosions in BP patients and seem to be notably relevant to the pathophysiology of the disease.¹³ The history of our patient’s psoriatic treatment included only topical corticosteroids, keratolytic agents, and occasionally dithranol and coal tar; however, UV phototherapy or any other systemic therapies had never been utilized. Three previously reported cases of patients with PV and BP also revealed no history of UV phototherapy,^8,9 which suggests that mechanisms responsible for coexistence of PV and BP are more complex. It has been proven that proinflammatory cytokines secreted by T_H1 and T_H17 cells, in particular tumor necrosis factor α, IL-17, IL-22, and IL-23, play an important role in the development of psoriatic lesions.¹⁰ On the other hand, these cytokines are known to contribute to vascular inflammation, leading to development of arteriosclerosis, as well as to regulate adipogenesis and obesity.^14,15 Arakawa et al¹⁶ reported increased expression of IL-17 in lesional skin in BP. They concluded that IL-17 may contribute to the recruitment of eosinophils and neutrophils and tissue damage in BP. Therefore, it is highly likely that IL-17 might be a common factor underlying the coexistence of BP with PV and metabolic syndrome. More such reports are required for better understanding this association.

BP Treatment

Selecting a therapy for BP with coexistent PV is challenging, especially in patients with extreme obesity and metabolic syndrome. It is well established that obesity correlates with a higher incidence of PV and more severe disease. On the other hand, obesity also influences response to therapy. Systemic corticosteroids are contraindicated in psoriasis patients because of severe side effects, such as rebound phenomenon of psoriatic lesions and risk for development of generalized pustular PV. Although systemic corticosteroids are effective in BP, high-dose therapy may potentially be life-threatening, particularly in these obese patients with conditions such as hypertension and diabetes mellitus, among others,¹ as was observed in our case. Taking into consideration the above mentioned conditions and our experience on such cases, the current patient had received MTX (12.5 mg once weekly) and clobetasol propionate cream, which led to the rapid healing of the psoriatic plaques, whereas BP was more resistant to this therapy. This response may be explained by our patient’s class 3 obesity (body mass index, 69.2). Therefore, the dose of MTX was increased to 20 mg once weekly and was successful. The decision to use MTX was supported by evidence that this medicine may reduce the risk for arteriosclerosis and cardiovascular disorders.¹⁷

There are some alternative therapeutic options for patients with coexisting BP and PV, such as cyclosporine,¹⁸ combination low-dose cyclosporine and low-dose systemic corticosteroids,¹⁹ dapsone,²⁰ azathioprine,²¹ mycophenolate mofetil,²² and acitretin.²³ It also has been shown that biologics (eg, ustekinumab) may be a successful solution in patients with PV and antilaminin-γ1 pemphigoid.²⁴ However, these alternative therapeutic regimens could not be considered in our patient because of serious coexisting internal disorders.

Conclusion

We present a case of concomitant BP and PV in a patient with metabolic syndrome. Although the pathogenic role of this unique coexistence is not fully understood, MTX proved suitable and effective in this single case. Further studies should be performed to elucidate the pathogenic relationship and therapeutic solutions for cases with coexisting PV, BP, and metabolic syndrome.

Metastatic Crohn disease (MCD) is defined by the presence of cutaneous noncaseating granulomatous lesions that are noncontiguous with the gastrointestinal (GI) tract or fistulae.¹ The clinical presentation of MCD is so variable that its diagnosis requires a high index of suspicion.^1,2 In particular, the presence of erythematous tender nodules on the legs is easily mistaken for erythema nodosum (EN). Skin biopsy has an important role in confirming the diagnosis, as histopathological examination would reveal a noncaseating granuloma similar to those in the involved GI tract.² Herein, we report a case of MCD on the right leg that was clinically reminiscent of unilateral EN.

Case Report

A 21-year-old woman presented to the dermatology department with 2 painful erythematous nodules on the lower right leg of 2 weeks’ duration. She also reported abdominal pain, diarrhea, and bloody stool. She had been diagnosed with Crohn disease (CD) 6 years prior that had been well controlled with systemic low-dose steroids (5–15 mg/d), metronidazole (750 mg/d), and intermittent mesalamine and antidiarrheal drugs. However, she had not taken her medication for several weeks on her own authority. Subsequently, the patient developed skin lesions, which were characterized by ill-defined erythematous nodules with tenderness on the right lower leg along with GI symptoms (Figure 1). Laboratory studies revealed anemia (hemoglobin, 9.9 g/dL [reference range, 12.0–16.0 g/dL]) and an elevated C-reactive protein level (4.3 mg/dL [reference range, 0–0.3 mg/dL]). Other routine laboratory findings were normal.

Histopathologically, a skin biopsy from the right ankle showed vague, ill-defined, noncaseating granulomas scattered in the deep dermis and lobules of the subcutis (Figure 2). The granulomas were composed of epithelioid cells and Langerhans-type giant cells. Lymphocytes and neutrophils also were present, but eosinophils were absent. Immunohistochemical staining revealed that the infiltrating cells were mostly CD4⁺ helper/inducer T cells intermixed with CD8⁺ suppressor/cytotoxic T cells. The CD4:CD8 ratio was approximately 2:1. Counts of CD20⁺ B cells were low. Epithelioid cells and giant cells were positive for CD68.

A colonoscopy was performed to evaluate the aggravation of CD. Multiple longitudinal ulcers were observed in the ileocecal valve area and from the transverse colon to the sigmoid colon (Figure 3A). Histopathologic findings from the colon showed mucosal ulceration and noncaseating granulomas with heavy infiltration of lymphocytes and plasma cells (Figure 3B). Staining for infectious microorganisms (eg, Ziehl-Neelsen, periodic acid–Schiff, Gram) was negative. A polymerase chain reaction performed on sections cut from the paraffin block of the skin biopsy was negative for Mycobacterium tuberculosis DNA.

Based on the clinical and histopathologic findings, the patient was diagnosed with MCD that was clinically reminiscent of unilateral EN. Four weeks after the initiation of therapy with systemic corticosteroids (25 mg/d), oral metronidazole (750 mg/d), and mesalamine (1200 mg/d) for CD, the skin lesions were completely resolved and the patient’s GI symptoms improved simultaneously.

Comment

Crohn disease is a chronic inflammatory granulomatous disease of the GI tract that often is associated with reactive cutaneous lesions including EN, pyoderma gangrenosum, necrotizing vasculitis, and epidermolysis bullosa acquisita. Of these, EN is the most common to appear in CD patients and has been reported to occur in 1% to 15% of patients.^3-5 In particular, skin lesions on the leg presenting as tender erythematous nodules and patches are often diagnosed as EN, which is relatively common. In our case, we initially suspected EN due to the rare presentation of MCD and lack of specific clinical features; however, the skin biopsy revealed noncaseating granulomas in the mid to deep dermis and subcutis consistent with MCD.

Metastatic Crohn disease is a rare disease entity and is characterized by the presence of noncaseating granulomas of the skin at sites separated from the GI tract by normal tissue.¹ Although its pathogenesis is unclear, it has been suggested that immune complexes deposited in the skin could be responsible for the granulomatous reactions.⁴ A T lymphocyte–mediated type IV hypersensitivity reaction also could be responsible.^6,7 Because antimicrobial therapy can be curative for infection-related MCD, special histologic stains and/or tissue cultures can help to exclude an infectious etiology.⁸

Clinical presentations of MCD vary greatly, with observations such as single or multiple erythematous swellings, papules, plaques, nodules, abscesses, and ulcers.^1,2 The relationship between these clinical presentations and the intestinal activity of CD still is unknown; in some cases, however, the metastatic granulomatous lesions and the bowel disease show comparable severity.^2,9,10 In a review of the literature, MCD was generally reported to present in the genital area in children. In adults, lesions most frequently present in the genital area, followed by ulcers on the arms and legs.^1,2 These variations in clinical features and location resemble benign or infectious disease and can lead to delays in diagnosis.

Histopathologically, MCD lesions usually are ill-defined noncaseating granulomas with numerous multinucleated giant cells and lymphomononuclear cells located mostly in the dermis and occasionally extending into the subcutis. The cutaneous granulomata are similar to those present in the affected GI tract. Lymphocytes and plasma cells also are commonly present and eosinophils can be prominent.^1,2,11 In some cases of MCD, granulomatous vasculitis of small- to medium-sized vessels can be found and is associated with dermal and subcutaneous granulomatous inflammation.^8,11,12 Misago and Narisawa¹³ suggested that granulomatous vasculitis and panniculitis associated with CD is considered to be a rare subtype of MCD. Few cases of MCD presenting as granulomatous panniculitis have been described in the literature.^14-16 Our patient presented with lesions that clinically resembled EN; however, the biopsy was more consistent with MCD. The Table summarizes the distinguishing clinical and histopathological features of MCD in our case and classic EN.

Although some authors believe that MCD is not related to CD activity, others assert that MCD lesions may parallel GI activity.^1,2 Our patient was treated with systemic corticosteroids, oral metronidazole, and mesalamine to control the GI symptoms associated with CD. Four weeks after treatment, the GI symptoms and skin lesions improved simultaneously without any additional dermatologic treatment. We believe that MCD has the potential to serve as an early marker of the recurrence of CD and can help with the early diagnosis of CD aggravation, though an association between MCD and CD activity has not been confirmed.

Conclusion

We reported a case of MCD that was clinically reminiscent of unilateral EN and associated with GI disease activity. Physicians should be aware of the possibility of skin manifestations in CD, especially when erythematous nodular lesions are present on the leg.

Metastatic Crohn disease (MCD) is defined by the presence of cutaneous noncaseating granulomatous lesions that are noncontiguous with the gastrointestinal (GI) tract or fistulae.¹ The clinical presentation of MCD is so variable that its diagnosis requires a high index of suspicion.^1,2 In particular, the presence of erythematous tender nodules on the legs is easily mistaken for erythema nodosum (EN). Skin biopsy has an important role in confirming the diagnosis, as histopathological examination would reveal a noncaseating granuloma similar to those in the involved GI tract.² Herein, we report a case of MCD on the right leg that was clinically reminiscent of unilateral EN.

Case Report

A 21-year-old woman presented to the dermatology department with 2 painful erythematous nodules on the lower right leg of 2 weeks’ duration. She also reported abdominal pain, diarrhea, and bloody stool. She had been diagnosed with Crohn disease (CD) 6 years prior that had been well controlled with systemic low-dose steroids (5–15 mg/d), metronidazole (750 mg/d), and intermittent mesalamine and antidiarrheal drugs. However, she had not taken her medication for several weeks on her own authority. Subsequently, the patient developed skin lesions, which were characterized by ill-defined erythematous nodules with tenderness on the right lower leg along with GI symptoms (Figure 1). Laboratory studies revealed anemia (hemoglobin, 9.9 g/dL [reference range, 12.0–16.0 g/dL]) and an elevated C-reactive protein level (4.3 mg/dL [reference range, 0–0.3 mg/dL]). Other routine laboratory findings were normal.

Histopathologically, a skin biopsy from the right ankle showed vague, ill-defined, noncaseating granulomas scattered in the deep dermis and lobules of the subcutis (Figure 2). The granulomas were composed of epithelioid cells and Langerhans-type giant cells. Lymphocytes and neutrophils also were present, but eosinophils were absent. Immunohistochemical staining revealed that the infiltrating cells were mostly CD4⁺ helper/inducer T cells intermixed with CD8⁺ suppressor/cytotoxic T cells. The CD4:CD8 ratio was approximately 2:1. Counts of CD20⁺ B cells were low. Epithelioid cells and giant cells were positive for CD68.

A colonoscopy was performed to evaluate the aggravation of CD. Multiple longitudinal ulcers were observed in the ileocecal valve area and from the transverse colon to the sigmoid colon (Figure 3A). Histopathologic findings from the colon showed mucosal ulceration and noncaseating granulomas with heavy infiltration of lymphocytes and plasma cells (Figure 3B). Staining for infectious microorganisms (eg, Ziehl-Neelsen, periodic acid–Schiff, Gram) was negative. A polymerase chain reaction performed on sections cut from the paraffin block of the skin biopsy was negative for Mycobacterium tuberculosis DNA.

Based on the clinical and histopathologic findings, the patient was diagnosed with MCD that was clinically reminiscent of unilateral EN. Four weeks after the initiation of therapy with systemic corticosteroids (25 mg/d), oral metronidazole (750 mg/d), and mesalamine (1200 mg/d) for CD, the skin lesions were completely resolved and the patient’s GI symptoms improved simultaneously.

Comment

Crohn disease is a chronic inflammatory granulomatous disease of the GI tract that often is associated with reactive cutaneous lesions including EN, pyoderma gangrenosum, necrotizing vasculitis, and epidermolysis bullosa acquisita. Of these, EN is the most common to appear in CD patients and has been reported to occur in 1% to 15% of patients.^3-5 In particular, skin lesions on the leg presenting as tender erythematous nodules and patches are often diagnosed as EN, which is relatively common. In our case, we initially suspected EN due to the rare presentation of MCD and lack of specific clinical features; however, the skin biopsy revealed noncaseating granulomas in the mid to deep dermis and subcutis consistent with MCD.

Metastatic Crohn disease is a rare disease entity and is characterized by the presence of noncaseating granulomas of the skin at sites separated from the GI tract by normal tissue.¹ Although its pathogenesis is unclear, it has been suggested that immune complexes deposited in the skin could be responsible for the granulomatous reactions.⁴ A T lymphocyte–mediated type IV hypersensitivity reaction also could be responsible.^6,7 Because antimicrobial therapy can be curative for infection-related MCD, special histologic stains and/or tissue cultures can help to exclude an infectious etiology.⁸

Clinical presentations of MCD vary greatly, with observations such as single or multiple erythematous swellings, papules, plaques, nodules, abscesses, and ulcers.^1,2 The relationship between these clinical presentations and the intestinal activity of CD still is unknown; in some cases, however, the metastatic granulomatous lesions and the bowel disease show comparable severity.^2,9,10 In a review of the literature, MCD was generally reported to present in the genital area in children. In adults, lesions most frequently present in the genital area, followed by ulcers on the arms and legs.^1,2 These variations in clinical features and location resemble benign or infectious disease and can lead to delays in diagnosis.

Histopathologically, MCD lesions usually are ill-defined noncaseating granulomas with numerous multinucleated giant cells and lymphomononuclear cells located mostly in the dermis and occasionally extending into the subcutis. The cutaneous granulomata are similar to those present in the affected GI tract. Lymphocytes and plasma cells also are commonly present and eosinophils can be prominent.^1,2,11 In some cases of MCD, granulomatous vasculitis of small- to medium-sized vessels can be found and is associated with dermal and subcutaneous granulomatous inflammation.^8,11,12 Misago and Narisawa¹³ suggested that granulomatous vasculitis and panniculitis associated with CD is considered to be a rare subtype of MCD. Few cases of MCD presenting as granulomatous panniculitis have been described in the literature.^14-16 Our patient presented with lesions that clinically resembled EN; however, the biopsy was more consistent with MCD. The Table summarizes the distinguishing clinical and histopathological features of MCD in our case and classic EN.

Although some authors believe that MCD is not related to CD activity, others assert that MCD lesions may parallel GI activity.^1,2 Our patient was treated with systemic corticosteroids, oral metronidazole, and mesalamine to control the GI symptoms associated with CD. Four weeks after treatment, the GI symptoms and skin lesions improved simultaneously without any additional dermatologic treatment. We believe that MCD has the potential to serve as an early marker of the recurrence of CD and can help with the early diagnosis of CD aggravation, though an association between MCD and CD activity has not been confirmed.

Conclusion

We reported a case of MCD that was clinically reminiscent of unilateral EN and associated with GI disease activity. Physicians should be aware of the possibility of skin manifestations in CD, especially when erythematous nodular lesions are present on the leg.

Metastatic Crohn disease (MCD) is defined by the presence of cutaneous noncaseating granulomatous lesions that are noncontiguous with the gastrointestinal (GI) tract or fistulae.¹ The clinical presentation of MCD is so variable that its diagnosis requires a high index of suspicion.^1,2 In particular, the presence of erythematous tender nodules on the legs is easily mistaken for erythema nodosum (EN). Skin biopsy has an important role in confirming the diagnosis, as histopathological examination would reveal a noncaseating granuloma similar to those in the involved GI tract.² Herein, we report a case of MCD on the right leg that was clinically reminiscent of unilateral EN.

Case Report

A 21-year-old woman presented to the dermatology department with 2 painful erythematous nodules on the lower right leg of 2 weeks’ duration. She also reported abdominal pain, diarrhea, and bloody stool. She had been diagnosed with Crohn disease (CD) 6 years prior that had been well controlled with systemic low-dose steroids (5–15 mg/d), metronidazole (750 mg/d), and intermittent mesalamine and antidiarrheal drugs. However, she had not taken her medication for several weeks on her own authority. Subsequently, the patient developed skin lesions, which were characterized by ill-defined erythematous nodules with tenderness on the right lower leg along with GI symptoms (Figure 1). Laboratory studies revealed anemia (hemoglobin, 9.9 g/dL [reference range, 12.0–16.0 g/dL]) and an elevated C-reactive protein level (4.3 mg/dL [reference range, 0–0.3 mg/dL]). Other routine laboratory findings were normal.

Histopathologically, a skin biopsy from the right ankle showed vague, ill-defined, noncaseating granulomas scattered in the deep dermis and lobules of the subcutis (Figure 2). The granulomas were composed of epithelioid cells and Langerhans-type giant cells. Lymphocytes and neutrophils also were present, but eosinophils were absent. Immunohistochemical staining revealed that the infiltrating cells were mostly CD4⁺ helper/inducer T cells intermixed with CD8⁺ suppressor/cytotoxic T cells. The CD4:CD8 ratio was approximately 2:1. Counts of CD20⁺ B cells were low. Epithelioid cells and giant cells were positive for CD68.

A colonoscopy was performed to evaluate the aggravation of CD. Multiple longitudinal ulcers were observed in the ileocecal valve area and from the transverse colon to the sigmoid colon (Figure 3A). Histopathologic findings from the colon showed mucosal ulceration and noncaseating granulomas with heavy infiltration of lymphocytes and plasma cells (Figure 3B). Staining for infectious microorganisms (eg, Ziehl-Neelsen, periodic acid–Schiff, Gram) was negative. A polymerase chain reaction performed on sections cut from the paraffin block of the skin biopsy was negative for Mycobacterium tuberculosis DNA.

Based on the clinical and histopathologic findings, the patient was diagnosed with MCD that was clinically reminiscent of unilateral EN. Four weeks after the initiation of therapy with systemic corticosteroids (25 mg/d), oral metronidazole (750 mg/d), and mesalamine (1200 mg/d) for CD, the skin lesions were completely resolved and the patient’s GI symptoms improved simultaneously.

Comment

Crohn disease is a chronic inflammatory granulomatous disease of the GI tract that often is associated with reactive cutaneous lesions including EN, pyoderma gangrenosum, necrotizing vasculitis, and epidermolysis bullosa acquisita. Of these, EN is the most common to appear in CD patients and has been reported to occur in 1% to 15% of patients.^3-5 In particular, skin lesions on the leg presenting as tender erythematous nodules and patches are often diagnosed as EN, which is relatively common. In our case, we initially suspected EN due to the rare presentation of MCD and lack of specific clinical features; however, the skin biopsy revealed noncaseating granulomas in the mid to deep dermis and subcutis consistent with MCD.

Metastatic Crohn disease is a rare disease entity and is characterized by the presence of noncaseating granulomas of the skin at sites separated from the GI tract by normal tissue.¹ Although its pathogenesis is unclear, it has been suggested that immune complexes deposited in the skin could be responsible for the granulomatous reactions.⁴ A T lymphocyte–mediated type IV hypersensitivity reaction also could be responsible.^6,7 Because antimicrobial therapy can be curative for infection-related MCD, special histologic stains and/or tissue cultures can help to exclude an infectious etiology.⁸

Clinical presentations of MCD vary greatly, with observations such as single or multiple erythematous swellings, papules, plaques, nodules, abscesses, and ulcers.^1,2 The relationship between these clinical presentations and the intestinal activity of CD still is unknown; in some cases, however, the metastatic granulomatous lesions and the bowel disease show comparable severity.^2,9,10 In a review of the literature, MCD was generally reported to present in the genital area in children. In adults, lesions most frequently present in the genital area, followed by ulcers on the arms and legs.^1,2 These variations in clinical features and location resemble benign or infectious disease and can lead to delays in diagnosis.

Histopathologically, MCD lesions usually are ill-defined noncaseating granulomas with numerous multinucleated giant cells and lymphomononuclear cells located mostly in the dermis and occasionally extending into the subcutis. The cutaneous granulomata are similar to those present in the affected GI tract. Lymphocytes and plasma cells also are commonly present and eosinophils can be prominent.^1,2,11 In some cases of MCD, granulomatous vasculitis of small- to medium-sized vessels can be found and is associated with dermal and subcutaneous granulomatous inflammation.^8,11,12 Misago and Narisawa¹³ suggested that granulomatous vasculitis and panniculitis associated with CD is considered to be a rare subtype of MCD. Few cases of MCD presenting as granulomatous panniculitis have been described in the literature.^14-16 Our patient presented with lesions that clinically resembled EN; however, the biopsy was more consistent with MCD. The Table summarizes the distinguishing clinical and histopathological features of MCD in our case and classic EN.

Although some authors believe that MCD is not related to CD activity, others assert that MCD lesions may parallel GI activity.^1,2 Our patient was treated with systemic corticosteroids, oral metronidazole, and mesalamine to control the GI symptoms associated with CD. Four weeks after treatment, the GI symptoms and skin lesions improved simultaneously without any additional dermatologic treatment. We believe that MCD has the potential to serve as an early marker of the recurrence of CD and can help with the early diagnosis of CD aggravation, though an association between MCD and CD activity has not been confirmed.

Conclusion

We reported a case of MCD that was clinically reminiscent of unilateral EN and associated with GI disease activity. Physicians should be aware of the possibility of skin manifestations in CD, especially when erythematous nodular lesions are present on the leg.

To the Editor:

We report 2 cases of desmoplastic hairless hypopigmented nevi (DHHN), which are giant congenital melanocytic nevi (GCMN) that show sclerosis with progressive loss of pigment and hair. These changes in GCMN could be considered signs of regression.

A 6-year-old boy presented in the dermatology department with an asymptomatic skin lesion on the right buttock since birth. The parents claimed that the lesion was darkly pigmented at birth and gradually increased in size, with progressive reduction in color in the last 2 years. Physical examination revealed a 10×6-cm, well-defined, raised plaque on the upper medial side of the right buttock (Figure 1). The plaque was firm with a shiny smooth surface and was devoid of hair. The surface was flesh colored with scattered pigmented spots. A punch biopsy of the lesion showed increased melanin content in the basal cell layer. The upper dermis showed small nests of epithelioid nevus cells, most of them containing melanin pigment (Figure 2). In the lower two-thirds of the dermis, nevus cells were both epithelioid and spindle shaped and were arranged in between thick sclerotic collagen bundles with an increased number of fibroblasts. There was a marked reduction in the number of hair follicles. Immunohistochemical staining results were S-100 positive and CD34 negative.

A 5-year-old boy presented in the dermatology department with a large hairy GCMN covering most of the trunk since birth. In the last 1.5 years the parents noted gradual fading of color, decreased hair density, and increased induration of the nevus. Physical examination revealed a large plaque covering the anterior aspect of the trunk (Figure 3) and the back extending down to the buttocks. The lesion formed large skin folds that were more pronounced on the back. The nevus was darkly pigmented with large areas of lighter color that were indurated, devoid of hair, and showed small spots of dark pigmentation. A punch biopsy from the lesion showed small nests of nevus cells in the upper part of the reticular dermis. In the lower part of the dermis, nevus cells were arranged in single units in between thick collagen bundles.

In 2003, Ruiz-Maldonado et al¹ described 4 cases of GCMN that showed progressive loss of pigmentation, sclerosis, and hair loss. They proposed the term desmoplastic hairless hypopigmented nevus for their cases and considered it as a variant of GCMN.¹ Prior to these reported cases, 2 similar cases were described. The first was a report by Hogan et al² in 1988 of a 7-month-old girl with a GCMN involving the occipital area and the upper back that became indurated and ulcerated with progressive involution that led to complete disappearance of the nevus. The second was a report by Pattee et al³ in 2001 of a newborn with a GCMN located on the trunk with progressive sclerodermiform reaction. After surgical excision of the nevus, the sclerotic margin disappeared.³

Following the report by Ruiz-Maldonaldo et al,¹ 5 more cases of DHHN were described.^4-8 All cases of DHHN share the same clinical and histopathological features. The clinical features include a GCMN present since birth with progressive sclerosis over time and loss of both pigmentation and hair. Histologically, DHHN shows the typical changes of a congenital melanocytic nevus with decreased numbers of nevus cells, thick sclerotic collagen bundles of the reticular dermis, increased number of fibroblasts, and decreased number of hair follicles. The progressive reduction in the number of nevus cells in melanocytic nevi is considered a sign of regression. Spontaneous regression was rarely described in GCMN, and all the reported cases of regression were associated with desmoplasia.⁴ Desmoplasia is thought to be induced by either melanocytes that function as adaptive fibroblasts or by fibroblasts themselves, as fibroblasts can show multifunctional differentiation capabilities.⁹ The direct correlation between the increased induration of DHHN and pigment depletion supports the former hypothesis. The absence of inflammatory cells within the sections of DHHN lesions is against the possibility of an immune-mediated reaction as a cause for the clinical and histological changes seen in this rare form of GCMN. The progressive hair loss in DHHN may be explained by the progressive fibrotic changes in the reticular dermis that affect the blood supply to follicles, leading to atrophy or even absence of the follicles. The progressive reduction in the number of nevus cells in DHHN reduces the potential for malignant transformation and hence following a watchful waiting strategy is a reasonable way to manage these nevi.

We present 2 patients with DHHN, which is a rare form of GCMN that shows signs of regression. The cause of these changes is still unclear.

To the Editor:

We report 2 cases of desmoplastic hairless hypopigmented nevi (DHHN), which are giant congenital melanocytic nevi (GCMN) that show sclerosis with progressive loss of pigment and hair. These changes in GCMN could be considered signs of regression.

A 6-year-old boy presented in the dermatology department with an asymptomatic skin lesion on the right buttock since birth. The parents claimed that the lesion was darkly pigmented at birth and gradually increased in size, with progressive reduction in color in the last 2 years. Physical examination revealed a 10×6-cm, well-defined, raised plaque on the upper medial side of the right buttock (Figure 1). The plaque was firm with a shiny smooth surface and was devoid of hair. The surface was flesh colored with scattered pigmented spots. A punch biopsy of the lesion showed increased melanin content in the basal cell layer. The upper dermis showed small nests of epithelioid nevus cells, most of them containing melanin pigment (Figure 2). In the lower two-thirds of the dermis, nevus cells were both epithelioid and spindle shaped and were arranged in between thick sclerotic collagen bundles with an increased number of fibroblasts. There was a marked reduction in the number of hair follicles. Immunohistochemical staining results were S-100 positive and CD34 negative.

A 5-year-old boy presented in the dermatology department with a large hairy GCMN covering most of the trunk since birth. In the last 1.5 years the parents noted gradual fading of color, decreased hair density, and increased induration of the nevus. Physical examination revealed a large plaque covering the anterior aspect of the trunk (Figure 3) and the back extending down to the buttocks. The lesion formed large skin folds that were more pronounced on the back. The nevus was darkly pigmented with large areas of lighter color that were indurated, devoid of hair, and showed small spots of dark pigmentation. A punch biopsy from the lesion showed small nests of nevus cells in the upper part of the reticular dermis. In the lower part of the dermis, nevus cells were arranged in single units in between thick collagen bundles.

In 2003, Ruiz-Maldonado et al¹ described 4 cases of GCMN that showed progressive loss of pigmentation, sclerosis, and hair loss. They proposed the term desmoplastic hairless hypopigmented nevus for their cases and considered it as a variant of GCMN.¹ Prior to these reported cases, 2 similar cases were described. The first was a report by Hogan et al² in 1988 of a 7-month-old girl with a GCMN involving the occipital area and the upper back that became indurated and ulcerated with progressive involution that led to complete disappearance of the nevus. The second was a report by Pattee et al³ in 2001 of a newborn with a GCMN located on the trunk with progressive sclerodermiform reaction. After surgical excision of the nevus, the sclerotic margin disappeared.³

Following the report by Ruiz-Maldonaldo et al,¹ 5 more cases of DHHN were described.^4-8 All cases of DHHN share the same clinical and histopathological features. The clinical features include a GCMN present since birth with progressive sclerosis over time and loss of both pigmentation and hair. Histologically, DHHN shows the typical changes of a congenital melanocytic nevus with decreased numbers of nevus cells, thick sclerotic collagen bundles of the reticular dermis, increased number of fibroblasts, and decreased number of hair follicles. The progressive reduction in the number of nevus cells in melanocytic nevi is considered a sign of regression. Spontaneous regression was rarely described in GCMN, and all the reported cases of regression were associated with desmoplasia.⁴ Desmoplasia is thought to be induced by either melanocytes that function as adaptive fibroblasts or by fibroblasts themselves, as fibroblasts can show multifunctional differentiation capabilities.⁹ The direct correlation between the increased induration of DHHN and pigment depletion supports the former hypothesis. The absence of inflammatory cells within the sections of DHHN lesions is against the possibility of an immune-mediated reaction as a cause for the clinical and histological changes seen in this rare form of GCMN. The progressive hair loss in DHHN may be explained by the progressive fibrotic changes in the reticular dermis that affect the blood supply to follicles, leading to atrophy or even absence of the follicles. The progressive reduction in the number of nevus cells in DHHN reduces the potential for malignant transformation and hence following a watchful waiting strategy is a reasonable way to manage these nevi.

We present 2 patients with DHHN, which is a rare form of GCMN that shows signs of regression. The cause of these changes is still unclear.

To the Editor:

We report 2 cases of desmoplastic hairless hypopigmented nevi (DHHN), which are giant congenital melanocytic nevi (GCMN) that show sclerosis with progressive loss of pigment and hair. These changes in GCMN could be considered signs of regression.

A 6-year-old boy presented in the dermatology department with an asymptomatic skin lesion on the right buttock since birth. The parents claimed that the lesion was darkly pigmented at birth and gradually increased in size, with progressive reduction in color in the last 2 years. Physical examination revealed a 10×6-cm, well-defined, raised plaque on the upper medial side of the right buttock (Figure 1). The plaque was firm with a shiny smooth surface and was devoid of hair. The surface was flesh colored with scattered pigmented spots. A punch biopsy of the lesion showed increased melanin content in the basal cell layer. The upper dermis showed small nests of epithelioid nevus cells, most of them containing melanin pigment (Figure 2). In the lower two-thirds of the dermis, nevus cells were both epithelioid and spindle shaped and were arranged in between thick sclerotic collagen bundles with an increased number of fibroblasts. There was a marked reduction in the number of hair follicles. Immunohistochemical staining results were S-100 positive and CD34 negative.

A 5-year-old boy presented in the dermatology department with a large hairy GCMN covering most of the trunk since birth. In the last 1.5 years the parents noted gradual fading of color, decreased hair density, and increased induration of the nevus. Physical examination revealed a large plaque covering the anterior aspect of the trunk (Figure 3) and the back extending down to the buttocks. The lesion formed large skin folds that were more pronounced on the back. The nevus was darkly pigmented with large areas of lighter color that were indurated, devoid of hair, and showed small spots of dark pigmentation. A punch biopsy from the lesion showed small nests of nevus cells in the upper part of the reticular dermis. In the lower part of the dermis, nevus cells were arranged in single units in between thick collagen bundles.

In 2003, Ruiz-Maldonado et al¹ described 4 cases of GCMN that showed progressive loss of pigmentation, sclerosis, and hair loss. They proposed the term desmoplastic hairless hypopigmented nevus for their cases and considered it as a variant of GCMN.¹ Prior to these reported cases, 2 similar cases were described. The first was a report by Hogan et al² in 1988 of a 7-month-old girl with a GCMN involving the occipital area and the upper back that became indurated and ulcerated with progressive involution that led to complete disappearance of the nevus. The second was a report by Pattee et al³ in 2001 of a newborn with a GCMN located on the trunk with progressive sclerodermiform reaction. After surgical excision of the nevus, the sclerotic margin disappeared.³

Following the report by Ruiz-Maldonaldo et al,¹ 5 more cases of DHHN were described.^4-8 All cases of DHHN share the same clinical and histopathological features. The clinical features include a GCMN present since birth with progressive sclerosis over time and loss of both pigmentation and hair. Histologically, DHHN shows the typical changes of a congenital melanocytic nevus with decreased numbers of nevus cells, thick sclerotic collagen bundles of the reticular dermis, increased number of fibroblasts, and decreased number of hair follicles. The progressive reduction in the number of nevus cells in melanocytic nevi is considered a sign of regression. Spontaneous regression was rarely described in GCMN, and all the reported cases of regression were associated with desmoplasia.⁴ Desmoplasia is thought to be induced by either melanocytes that function as adaptive fibroblasts or by fibroblasts themselves, as fibroblasts can show multifunctional differentiation capabilities.⁹ The direct correlation between the increased induration of DHHN and pigment depletion supports the former hypothesis. The absence of inflammatory cells within the sections of DHHN lesions is against the possibility of an immune-mediated reaction as a cause for the clinical and histological changes seen in this rare form of GCMN. The progressive hair loss in DHHN may be explained by the progressive fibrotic changes in the reticular dermis that affect the blood supply to follicles, leading to atrophy or even absence of the follicles. The progressive reduction in the number of nevus cells in DHHN reduces the potential for malignant transformation and hence following a watchful waiting strategy is a reasonable way to manage these nevi.

We present 2 patients with DHHN, which is a rare form of GCMN that shows signs of regression. The cause of these changes is still unclear.

The Diagnosis: Livedoid Vasculopathy

Livedoid vasculopathy (LV) is a rare cutaneous disorder that most commonly affects the lower legs. It has an estimated incidence of 1 case per 100,000 per year and predominantly affects women.¹ The disease pathogenesis is not fully understood but is thought to involve thrombosis and occlusion of dermal vessels resulting in tissue hypoxia.² Both inherited and acquired thrombophilic conditions frequently are seen in patients with LV.^3,4 Livedoid vasculopathy also has been described as idiopathic⁵ and is associated with immune complex deposition.⁶ However, the number of cases of idiopathic LV may be overestimated; as technological advancements to detect coagulation abnormalities improve, it is hypothesized that this entity will be identified less often.^2,4

Livedoid vasculopathy has been described in the literature using the term PPURPLE (painful purpuric ulcers with reticular pattern of lower extremities).⁷ The triad of livedo racemosa, recurrent painful ulcerations, and residual healing with atrophie blanche characterizes the clinical manifestations of LV; however, all 3 characteristics do not need to appear simultaneously for a diagnosis to be made. The condition has a chronic course with spontaneous remissions and exacerbations. Episodic ulcerations occur, especially in the summertime, and heal slowly, leaving behind atrophic, porcelain white, stellate-shaped scars called atrophie blanche. Livedo racemosa also may be seen in Sneddon syndrome; however, these patients experience neurologic symptoms secondary to cerebrovascular occlusion. In contrast to livedo racemosa, acquired livedo reticularis represents a physiologic hypoperfusion pattern that occurs in response to cold exposure.⁸ A localized sharp pain, known as angina cutis, typically precedes the clinical symptom of painful ulcerations.⁹ Atrophie blanche once was thought to be specific to LV but has been seen in other diseases such as systemic lupus erythematosus and chronic venous insufficiency.²

The diagnosis of LV is based on identification of characteristic clinical features and skin biopsy. In almost all biopsy specimens, histopathology reveals fibrinoid occlusion of vessels in the superficial and mid dermis.⁴ Other findings may include epidermal necrosis and vessel wall hyalinization and infarction² (Figure). Because LV is commonly misdiagnosed as vasculitis, the absence of hallmark features of vasculitis such as neutrophilic infiltrate of blood vessel walls and fibrinoid necrosis suggest the diagnosis. Extensive laboratory evaluation for inherited and acquired coagulation abnormalities should be performed.

Treatment of LV is difficult, as there is currently no consensus on optimal therapy. The mainstay of therapy is to reduce pain, prevent infection, and reduce ulceration and development of atrophie blanche. Underlying causes should be identified and appropriately treated. Because the primary pathogenesis of LV is considered to be a hypercoagulable state, first-line treatment often includes therapies to enhance blood flow and prevent thrombosis such as smoking cessation, antiplatelet therapy, and pentoxifylline. Vasodilating agents, anti-inflammatory agents, anticoagulation, and fibrinolytic therapy also have been used with varying degrees of success.⁷

The Diagnosis: Livedoid Vasculopathy

Livedoid vasculopathy (LV) is a rare cutaneous disorder that most commonly affects the lower legs. It has an estimated incidence of 1 case per 100,000 per year and predominantly affects women.¹ The disease pathogenesis is not fully understood but is thought to involve thrombosis and occlusion of dermal vessels resulting in tissue hypoxia.² Both inherited and acquired thrombophilic conditions frequently are seen in patients with LV.^3,4 Livedoid vasculopathy also has been described as idiopathic⁵ and is associated with immune complex deposition.⁶ However, the number of cases of idiopathic LV may be overestimated; as technological advancements to detect coagulation abnormalities improve, it is hypothesized that this entity will be identified less often.^2,4

Livedoid vasculopathy has been described in the literature using the term PPURPLE (painful purpuric ulcers with reticular pattern of lower extremities).⁷ The triad of livedo racemosa, recurrent painful ulcerations, and residual healing with atrophie blanche characterizes the clinical manifestations of LV; however, all 3 characteristics do not need to appear simultaneously for a diagnosis to be made. The condition has a chronic course with spontaneous remissions and exacerbations. Episodic ulcerations occur, especially in the summertime, and heal slowly, leaving behind atrophic, porcelain white, stellate-shaped scars called atrophie blanche. Livedo racemosa also may be seen in Sneddon syndrome; however, these patients experience neurologic symptoms secondary to cerebrovascular occlusion. In contrast to livedo racemosa, acquired livedo reticularis represents a physiologic hypoperfusion pattern that occurs in response to cold exposure.⁸ A localized sharp pain, known as angina cutis, typically precedes the clinical symptom of painful ulcerations.⁹ Atrophie blanche once was thought to be specific to LV but has been seen in other diseases such as systemic lupus erythematosus and chronic venous insufficiency.²

The diagnosis of LV is based on identification of characteristic clinical features and skin biopsy. In almost all biopsy specimens, histopathology reveals fibrinoid occlusion of vessels in the superficial and mid dermis.⁴ Other findings may include epidermal necrosis and vessel wall hyalinization and infarction² (Figure). Because LV is commonly misdiagnosed as vasculitis, the absence of hallmark features of vasculitis such as neutrophilic infiltrate of blood vessel walls and fibrinoid necrosis suggest the diagnosis. Extensive laboratory evaluation for inherited and acquired coagulation abnormalities should be performed.

Treatment of LV is difficult, as there is currently no consensus on optimal therapy. The mainstay of therapy is to reduce pain, prevent infection, and reduce ulceration and development of atrophie blanche. Underlying causes should be identified and appropriately treated. Because the primary pathogenesis of LV is considered to be a hypercoagulable state, first-line treatment often includes therapies to enhance blood flow and prevent thrombosis such as smoking cessation, antiplatelet therapy, and pentoxifylline. Vasodilating agents, anti-inflammatory agents, anticoagulation, and fibrinolytic therapy also have been used with varying degrees of success.⁷

The Diagnosis: Livedoid Vasculopathy

Livedoid vasculopathy (LV) is a rare cutaneous disorder that most commonly affects the lower legs. It has an estimated incidence of 1 case per 100,000 per year and predominantly affects women.¹ The disease pathogenesis is not fully understood but is thought to involve thrombosis and occlusion of dermal vessels resulting in tissue hypoxia.² Both inherited and acquired thrombophilic conditions frequently are seen in patients with LV.^3,4 Livedoid vasculopathy also has been described as idiopathic⁵ and is associated with immune complex deposition.⁶ However, the number of cases of idiopathic LV may be overestimated; as technological advancements to detect coagulation abnormalities improve, it is hypothesized that this entity will be identified less often.^2,4

Livedoid vasculopathy has been described in the literature using the term PPURPLE (painful purpuric ulcers with reticular pattern of lower extremities).⁷ The triad of livedo racemosa, recurrent painful ulcerations, and residual healing with atrophie blanche characterizes the clinical manifestations of LV; however, all 3 characteristics do not need to appear simultaneously for a diagnosis to be made. The condition has a chronic course with spontaneous remissions and exacerbations. Episodic ulcerations occur, especially in the summertime, and heal slowly, leaving behind atrophic, porcelain white, stellate-shaped scars called atrophie blanche. Livedo racemosa also may be seen in Sneddon syndrome; however, these patients experience neurologic symptoms secondary to cerebrovascular occlusion. In contrast to livedo racemosa, acquired livedo reticularis represents a physiologic hypoperfusion pattern that occurs in response to cold exposure.⁸ A localized sharp pain, known as angina cutis, typically precedes the clinical symptom of painful ulcerations.⁹ Atrophie blanche once was thought to be specific to LV but has been seen in other diseases such as systemic lupus erythematosus and chronic venous insufficiency.²

The diagnosis of LV is based on identification of characteristic clinical features and skin biopsy. In almost all biopsy specimens, histopathology reveals fibrinoid occlusion of vessels in the superficial and mid dermis.⁴ Other findings may include epidermal necrosis and vessel wall hyalinization and infarction² (Figure). Because LV is commonly misdiagnosed as vasculitis, the absence of hallmark features of vasculitis such as neutrophilic infiltrate of blood vessel walls and fibrinoid necrosis suggest the diagnosis. Extensive laboratory evaluation for inherited and acquired coagulation abnormalities should be performed.

Treatment of LV is difficult, as there is currently no consensus on optimal therapy. The mainstay of therapy is to reduce pain, prevent infection, and reduce ulceration and development of atrophie blanche. Underlying causes should be identified and appropriately treated. Because the primary pathogenesis of LV is considered to be a hypercoagulable state, first-line treatment often includes therapies to enhance blood flow and prevent thrombosis such as smoking cessation, antiplatelet therapy, and pentoxifylline. Vasodilating agents, anti-inflammatory agents, anticoagulation, and fibrinolytic therapy also have been used with varying degrees of success.⁷

The Diagnosis: Radiation-Associated Angiosarcoma

At the time of presentation, a 4-mm lesional punch biopsy was obtained (Figure), which revealed an epithelioid neoplasm within the dermis expressing CD31 and CD34, and staining negatively for S-100, CD45, and estrogen and progesterone receptors. The histologic and immunophenotypic findings were compatible with the diagnosis of angiosarcoma. Given the patient’s history of radiation for breast carcinoma several years ago, this tumor was consistent with radiation-associated angiosarcoma (RAAS).

Development of secondary angiosarcoma has been linked to both prior radiation (RAAS) and chronic lymphedema (Stewart-Treves syndrome).¹ Radiation-associated angiosarcoma is defined as a “pathologically confirmed breast or chest wall angiosarcoma arising within a previously irradiated field.”² The incidence of RAAS is estimated to be 0.9 per 1000 individuals following radiation treatment of breast cancer over the subsequent 15 years and a mean time from radiation to development of 7 years.¹ Incidence is expected to increase in the future due to improved likelihood of surviving early-stage breast carcinoma and the increased use of external beam radiation therapy for management of breast cancer.

Differentiating between primary and secondary angiosarcoma of the breast is important. Although primary breast angiosarcoma usually arises in women aged 30 to 40 years, RAAS tends to arise in older women (mean age, 68 years) and is seen only in those women with prior radiation.² Additionally, high-level amplification of MYC, a known photo-oncogene, on chromosome 8 is a key genetic alteration of RAAS that helps to distinguish it from primary angiosarcoma, though this variance may be present in only half of RAAS cases.³ Immunohistochemical analysis of tumor cells for MYC expression correlates well with this amplification and also is helpful in distinguishing atypical vascular lesions from RAAS.⁴ Atypical vascular lesions, similar to RAAS, occur years after radiation exposure and may have a similar clinical presentation. Atypical vascular lesions do not progress to angiosarcoma in reported cases, but clinical and histologic overlap with RAAS make the diagnosis difficult.⁵ In these cases, analysis with fluorescence in situ hybridization or immunohistochemistry for the MYC amplification is important to differentiate these tumors.⁶

At the time of presentation, the majority of patients with RAAS of the breast have localized disease, often with a variable presentation. In all known cases, there have been skin changes present, emphasizing the importance of both patient and clinician vigilance on a regular basis in at-risk individuals. In one study, the most common presentation was breast ecchymosis, which was observed in 55% of patients.⁷ These lesions involve the dermis and are commonly mistaken for benign conditions such as infection or hemorrhage.² In 2 other studies, RAAS most often manifested as a skin nodule or apparent tumor, closely followed by either a rash or bruiselike presentation.^1,2

The overall recommendation for management of patients with ecchymotic skin lesions in previously irradiated regions is to obtain a biopsy specimen for tissue diagnosis. Although there is no standard of care for the management of RAAS, a multidisciplinary approach involving specialists from oncology, surgical oncology, and radiation oncology is recommended. Most often, radical surgery encompassing both the breast parenchyma and the at-risk radiated skin is performed. Extensive surgery has demonstrated the best survival benefits compared to mastectomy alone.⁷ Chemotherapeutics also may be used as adjuncts to surgery, which have been determined to decrease local recurrence rates but have no proven survival benefits.² Adverse prognostic factors for survival are tumor size greater than 10 cm and development of local and/or distant metastases.² Following the diagnosis of RAAS, our patient underwent radical mastectomy with adjuvant chemotherapy and remained disease free 6 months after surgery.

In summary, RAAS is a well-known, albeit relatively uncommon, consequence of radiation therapy. Dermatologists, oncologists, and primary care providers play an important role in recognizing this entity when evaluating patients with ecchymotic lesions as well as nodules or tumors within an irradiated field. Biopsy should be obtained promptly to prevent delay in diagnosis and to expedite referral to appropriate specialists for further evaluation and treatment.

The Diagnosis: Radiation-Associated Angiosarcoma

At the time of presentation, a 4-mm lesional punch biopsy was obtained (Figure), which revealed an epithelioid neoplasm within the dermis expressing CD31 and CD34, and staining negatively for S-100, CD45, and estrogen and progesterone receptors. The histologic and immunophenotypic findings were compatible with the diagnosis of angiosarcoma. Given the patient’s history of radiation for breast carcinoma several years ago, this tumor was consistent with radiation-associated angiosarcoma (RAAS).

Development of secondary angiosarcoma has been linked to both prior radiation (RAAS) and chronic lymphedema (Stewart-Treves syndrome).¹ Radiation-associated angiosarcoma is defined as a “pathologically confirmed breast or chest wall angiosarcoma arising within a previously irradiated field.”² The incidence of RAAS is estimated to be 0.9 per 1000 individuals following radiation treatment of breast cancer over the subsequent 15 years and a mean time from radiation to development of 7 years.¹ Incidence is expected to increase in the future due to improved likelihood of surviving early-stage breast carcinoma and the increased use of external beam radiation therapy for management of breast cancer.

Differentiating between primary and secondary angiosarcoma of the breast is important. Although primary breast angiosarcoma usually arises in women aged 30 to 40 years, RAAS tends to arise in older women (mean age, 68 years) and is seen only in those women with prior radiation.² Additionally, high-level amplification of MYC, a known photo-oncogene, on chromosome 8 is a key genetic alteration of RAAS that helps to distinguish it from primary angiosarcoma, though this variance may be present in only half of RAAS cases.³ Immunohistochemical analysis of tumor cells for MYC expression correlates well with this amplification and also is helpful in distinguishing atypical vascular lesions from RAAS.⁴ Atypical vascular lesions, similar to RAAS, occur years after radiation exposure and may have a similar clinical presentation. Atypical vascular lesions do not progress to angiosarcoma in reported cases, but clinical and histologic overlap with RAAS make the diagnosis difficult.⁵ In these cases, analysis with fluorescence in situ hybridization or immunohistochemistry for the MYC amplification is important to differentiate these tumors.⁶

At the time of presentation, the majority of patients with RAAS of the breast have localized disease, often with a variable presentation. In all known cases, there have been skin changes present, emphasizing the importance of both patient and clinician vigilance on a regular basis in at-risk individuals. In one study, the most common presentation was breast ecchymosis, which was observed in 55% of patients.⁷ These lesions involve the dermis and are commonly mistaken for benign conditions such as infection or hemorrhage.² In 2 other studies, RAAS most often manifested as a skin nodule or apparent tumor, closely followed by either a rash or bruiselike presentation.^1,2

The overall recommendation for management of patients with ecchymotic skin lesions in previously irradiated regions is to obtain a biopsy specimen for tissue diagnosis. Although there is no standard of care for the management of RAAS, a multidisciplinary approach involving specialists from oncology, surgical oncology, and radiation oncology is recommended. Most often, radical surgery encompassing both the breast parenchyma and the at-risk radiated skin is performed. Extensive surgery has demonstrated the best survival benefits compared to mastectomy alone.⁷ Chemotherapeutics also may be used as adjuncts to surgery, which have been determined to decrease local recurrence rates but have no proven survival benefits.² Adverse prognostic factors for survival are tumor size greater than 10 cm and development of local and/or distant metastases.² Following the diagnosis of RAAS, our patient underwent radical mastectomy with adjuvant chemotherapy and remained disease free 6 months after surgery.

In summary, RAAS is a well-known, albeit relatively uncommon, consequence of radiation therapy. Dermatologists, oncologists, and primary care providers play an important role in recognizing this entity when evaluating patients with ecchymotic lesions as well as nodules or tumors within an irradiated field. Biopsy should be obtained promptly to prevent delay in diagnosis and to expedite referral to appropriate specialists for further evaluation and treatment.

The Diagnosis: Radiation-Associated Angiosarcoma

At the time of presentation, a 4-mm lesional punch biopsy was obtained (Figure), which revealed an epithelioid neoplasm within the dermis expressing CD31 and CD34, and staining negatively for S-100, CD45, and estrogen and progesterone receptors. The histologic and immunophenotypic findings were compatible with the diagnosis of angiosarcoma. Given the patient’s history of radiation for breast carcinoma several years ago, this tumor was consistent with radiation-associated angiosarcoma (RAAS).

Development of secondary angiosarcoma has been linked to both prior radiation (RAAS) and chronic lymphedema (Stewart-Treves syndrome).¹ Radiation-associated angiosarcoma is defined as a “pathologically confirmed breast or chest wall angiosarcoma arising within a previously irradiated field.”² The incidence of RAAS is estimated to be 0.9 per 1000 individuals following radiation treatment of breast cancer over the subsequent 15 years and a mean time from radiation to development of 7 years.¹ Incidence is expected to increase in the future due to improved likelihood of surviving early-stage breast carcinoma and the increased use of external beam radiation therapy for management of breast cancer.

Differentiating between primary and secondary angiosarcoma of the breast is important. Although primary breast angiosarcoma usually arises in women aged 30 to 40 years, RAAS tends to arise in older women (mean age, 68 years) and is seen only in those women with prior radiation.² Additionally, high-level amplification of MYC, a known photo-oncogene, on chromosome 8 is a key genetic alteration of RAAS that helps to distinguish it from primary angiosarcoma, though this variance may be present in only half of RAAS cases.³ Immunohistochemical analysis of tumor cells for MYC expression correlates well with this amplification and also is helpful in distinguishing atypical vascular lesions from RAAS.⁴ Atypical vascular lesions, similar to RAAS, occur years after radiation exposure and may have a similar clinical presentation. Atypical vascular lesions do not progress to angiosarcoma in reported cases, but clinical and histologic overlap with RAAS make the diagnosis difficult.⁵ In these cases, analysis with fluorescence in situ hybridization or immunohistochemistry for the MYC amplification is important to differentiate these tumors.⁶

At the time of presentation, the majority of patients with RAAS of the breast have localized disease, often with a variable presentation. In all known cases, there have been skin changes present, emphasizing the importance of both patient and clinician vigilance on a regular basis in at-risk individuals. In one study, the most common presentation was breast ecchymosis, which was observed in 55% of patients.⁷ These lesions involve the dermis and are commonly mistaken for benign conditions such as infection or hemorrhage.² In 2 other studies, RAAS most often manifested as a skin nodule or apparent tumor, closely followed by either a rash or bruiselike presentation.^1,2

The overall recommendation for management of patients with ecchymotic skin lesions in previously irradiated regions is to obtain a biopsy specimen for tissue diagnosis. Although there is no standard of care for the management of RAAS, a multidisciplinary approach involving specialists from oncology, surgical oncology, and radiation oncology is recommended. Most often, radical surgery encompassing both the breast parenchyma and the at-risk radiated skin is performed. Extensive surgery has demonstrated the best survival benefits compared to mastectomy alone.⁷ Chemotherapeutics also may be used as adjuncts to surgery, which have been determined to decrease local recurrence rates but have no proven survival benefits.² Adverse prognostic factors for survival are tumor size greater than 10 cm and development of local and/or distant metastases.² Following the diagnosis of RAAS, our patient underwent radical mastectomy with adjuvant chemotherapy and remained disease free 6 months after surgery.

In summary, RAAS is a well-known, albeit relatively uncommon, consequence of radiation therapy. Dermatologists, oncologists, and primary care providers play an important role in recognizing this entity when evaluating patients with ecchymotic lesions as well as nodules or tumors within an irradiated field. Biopsy should be obtained promptly to prevent delay in diagnosis and to expedite referral to appropriate specialists for further evaluation and treatment.

Levamisole is an immunomodulatory drug that had been used to treat various medical conditions, including parasitic infections, nephrotic syndrome, and colorectal cancer,¹ before being withdrawn from the US market in 2000.The most common reasons for levamisole discontinuation were leukopenia and rashes (1%–2%),¹ many of which included leg ulcers and necrotizing purpura of the ears.^1,2 The drug is currently available only as a deworming agent in veterinary medicine.

Since 2007, increasing amounts of levamisole have been used as an adulterant in cocaine. In 2007, less than 10% of cocaine was contaminated with levamisole, with an increase to 77% by 2010.³ In addition, 78% of 249 urine toxicology screens that were positive for cocaine in an inner city hospital also tested positive for levamisole.⁴ Levamisole-cut cocaine has become a concern because it is associated with a life-threatening syndrome involving a necrotizing purpuric rash, autoantibody production, and leukopenia.⁵

Levamisole-induced vasculitis is an independent entity from cocaine-induced vasculitis, which is associated with skin findings ranging from palpable purpura and chronic ulcers to digital infarction secondary to its vasospastic activity.^6-8 Cocaine-induced vasculopathy has been related to cytoplasmic antineutrophil cytoplasmic antibody positivity and often resembles Wegener granulomatosis.⁶ Although both cocaine and levamisole have reportedly caused acrally distributed purpura and vasculopathy, levamisole is specifically associated with retiform purpura, ear involvement, and leukopenia.^6,9 In addition, levamisole-induced skin reactions have been linked to specific antibodies, including antinuclear, antiphospholipid, and perinuclear antineutrophil cytoplasmic antibody (p-ANCA).^2,5-7,9-14

We present a case of refractory levamisole-induced vasculitis and review its clinical presentation, diagnostic approach, laboratory findings, histology, and management. Furthermore, we discuss the possibility of a new treatment option for levamisole-induced vasculitis for patients with refractory disease or for patients who continue to use levamisole.

Case Report

A 49-year-old man with a history of polysubstance abuse presented with intermittent fevers and painful swollen ears as well as joint pain of 3 weeks’ duration. One week after the lesions developed on the ears, similar lesions were seen on the legs, arms, and trunk. He admitted to cocaine use 3 weeks prior to presentation when the symptoms began.

On physical examination, violaceous patches with necrotic bleeding edges and overlying black eschars were noted on the helices, antihelices, and ear lobules bilaterally (Figure 1). Retiform, purpuric to dark brown patches, some with signs of epidermal necrosis, were scattered on the arms, legs, and chest (Figure 2).

Laboratory examination revealed renal failure, anemia of chronic disease, and thrombocytosis (Table). The patient also screened positive for lupus anticoagulant and antinuclear antibodies and had elevated p-ANCA and anti–double-stranded DNA (Table). He also had an elevated sedimentation rate (109 mm/h [reference range, 0–20 mm/h]) and C-reactive protein level (11.3 mg/dL [reference range, 0–1.0 mg/dL])(Table). Urine toxicology was positive for cocaine.

A punch biopsy of the left thigh was performed on the edge of a retiform purpuric patch. Histopathologic examination revealed epidermal necrosis with subjacent intraluminal vascular thrombi along with extravasated red blood cells and neutrophilic debris (leukocytoclasis) and fibrin in and around vessel walls, consistent with vasculitis (Figure 3).

The patient was admitted to the hospital for pain management and wound care. Despite cocaine cessation and oral prednisone taper, the lesions on the legs worsened over the next several weeks. His condition was further complicated by wound infections, nonhealing ulcers, and subjective fevers and chills requiring frequent hospitalization. The patient was managed by the dermatology department as an outpatient and in clinic between hospital visits. He was treated with antibiotics, ulcer debridement, compression wraps, and aspirin (81 mg once daily) with moderate improvement.

Ten weeks after the first visit, the patient returned with worsening and recurrent leg and ear lesions. He denied any cocaine use since the initial hospital admission; however, a toxicology screen was never obtained. It was decided that the patient would need additional treatment along with traditional trigger (cocaine) avoidance and wound care. Combined treatment with aspirin (81 mg once daily), oral prednisone (40 mg once daily), and vardenafil hydrochloride (20 mg twice weekly) was initiated. At the end of week 1, the patient began to exhibit signs of improvement, which continued over the next 4 weeks. He was then lost to follow-up.

Comment

Our patient presented with severe necrotizing cutaneous vasculitis, likely secondary to levamisole exposure. Some of our patient’s cutaneous findings may be explained exclusively on the basis of cocaine exposure, but the characteristic lesion distribution and histopathologic findings along with the evidence of autoantibody positivity and concurrent arthralgias make the combination of levamisole and cocaine a more likely cause. Similar skin lesions were first described in children treated with levamisole for nephrotic syndrome.² The most common site of clinical involvement in these children was the ears, as seen in our patient. Our patient tested positive for p-ANCA, which is the most commonly reported autoantibody associated with this patient population. Sixty-one percent (20/33) of patients with levamisole-induced vasculitis from 2 separate reviews showed p-ANCA positivity.^7,10

On histopathology, our patient’s skin biopsy findings were consistent with those of prior reports of levamisole-induced vasculitis, which describe patterns of thrombotic vasculitis, leukocytoclasis, and fibrin deposition or occlusive disease.^2,6,7,9-14 Mixed histologic findings of vasculitis and thrombosis, usually with varying ages of thrombi, are characteristic of levamisole-induced purpura. In addition, the disease can present nonspecifically with pure microvascular thrombosis without vasculitis, especially later in the course.⁹

The recommended management of levamisole-induced vasculitis currently involves the withdrawal of the culprit adulterated cocaine along with supportive treatment. Spontaneous and complete clinical resolution of lesions has been reported within 2 to 3 weeks and serology normalization within 2 to 14 months of levamisole cessation.^2,6 A 2011 review of patients with levamisole-induced vasculitis reported 66% (19/29) of cases with either full cutaneous resolution after levamisole withdrawal or recurrence with resumed use, supporting a causal relationship.⁷ Walsh et al⁹ described 2 patients with recurrent and exacerbated retiform purpura following cocaine binges. Both of these patients had urine samples that tested positive for levamisole.⁹ In more severe cases, medications shown to be effective include colchicine, polidocanol, antibiotics, methotrexate, anticoagulants, and most commonly systemic corticosteroids.^7,10,11,15 Nonsteroidal anti-inflammatory drugs were successful in treating lesions in 2 patients with concurrent arthralgia.⁷ Rarely, patients have required surgical debridement or skin grafting due to advanced disease at initial presentation.^9,12-14 One of the most severe cases of levamisole-induced vasculitis reported in the literature involved 52% of the patient’s total body surface area with skin, soft tissue, and bony necrosis requiring nasal amputation, upper lip excision, skin grafting, and extremity amputation.¹⁴ Another severe case with widespread skin involvement was recently reported.¹⁶

For unclear reasons, our patient continued to develop cutaneous lesions despite self-reported cocaine cessation. Complete resolution required the combination of vardenafil, prednisone, and aspirin, along with debridement and wound care. Vardenafil, a selective phosphodiesterase 5 inhibitor, enhances the effect of nitrous oxide by increasing levels of cyclic guanosine monophosphate,¹⁷ which results in smooth muscle relaxation and vasodilatation. The primary indication for vardenafil is the treatment of erectile dysfunction, but it often is used off label in diseases that may benefit from vasodilatation. Because of its mechanism of action, it is understandable that a vasodilator such as vardenafil could be therapeutic in a condition associated with thrombosis. Moreover, the autoinflammatory nature of levamisole-induced vasculitis makes corticosteroid treatment effective. Given the 10-week delay in improvement, we suspect that it was the combination of treatment or an individual agent that led to our patient’s eventual recovery.

There are few reports in the literature focusing on optimal treatment of levamisole-induced vasculitis and none that mention alternative management for patients who continue to develop new lesions despite cocaine avoidance. Although the discontinuation of levamisole seems to be imperative for resolution of cutaneous lesions, it may not always be enough. It is possible that there is a subpopulation of patients that may not respond to the simple withdrawal of cocaine. It also should be mentioned that there was no urine toxicology screen obtained to support our patient’s reported cocaine cessation. Therefore, it is possible that his worsening condition was secondary to continued cocaine use. However, the patient successfully responded to the combination of vardenafil and prednisone, regardless of whether his condition persisted due to continued use of cocaine or not. This case suggests the possibility of a new treatment option for levamisole-induced vasculitis for patients who continue to use levamisole despite instruction for cessation or for patients with refractory disease.

Conclusion

A trial of prednisone and vardenafil should be considered for patients with refractory levamisole-induced vasculitis. Further studies and discussions of disease course are needed to identify the best treatment of this skin condition, especially for patients with refractory lesions.

Levamisole is an immunomodulatory drug that had been used to treat various medical conditions, including parasitic infections, nephrotic syndrome, and colorectal cancer,¹ before being withdrawn from the US market in 2000.The most common reasons for levamisole discontinuation were leukopenia and rashes (1%–2%),¹ many of which included leg ulcers and necrotizing purpura of the ears.^1,2 The drug is currently available only as a deworming agent in veterinary medicine.

Since 2007, increasing amounts of levamisole have been used as an adulterant in cocaine. In 2007, less than 10% of cocaine was contaminated with levamisole, with an increase to 77% by 2010.³ In addition, 78% of 249 urine toxicology screens that were positive for cocaine in an inner city hospital also tested positive for levamisole.⁴ Levamisole-cut cocaine has become a concern because it is associated with a life-threatening syndrome involving a necrotizing purpuric rash, autoantibody production, and leukopenia.⁵

Levamisole-induced vasculitis is an independent entity from cocaine-induced vasculitis, which is associated with skin findings ranging from palpable purpura and chronic ulcers to digital infarction secondary to its vasospastic activity.^6-8 Cocaine-induced vasculopathy has been related to cytoplasmic antineutrophil cytoplasmic antibody positivity and often resembles Wegener granulomatosis.⁶ Although both cocaine and levamisole have reportedly caused acrally distributed purpura and vasculopathy, levamisole is specifically associated with retiform purpura, ear involvement, and leukopenia.^6,9 In addition, levamisole-induced skin reactions have been linked to specific antibodies, including antinuclear, antiphospholipid, and perinuclear antineutrophil cytoplasmic antibody (p-ANCA).^2,5-7,9-14

We present a case of refractory levamisole-induced vasculitis and review its clinical presentation, diagnostic approach, laboratory findings, histology, and management. Furthermore, we discuss the possibility of a new treatment option for levamisole-induced vasculitis for patients with refractory disease or for patients who continue to use levamisole.

Case Report

A 49-year-old man with a history of polysubstance abuse presented with intermittent fevers and painful swollen ears as well as joint pain of 3 weeks’ duration. One week after the lesions developed on the ears, similar lesions were seen on the legs, arms, and trunk. He admitted to cocaine use 3 weeks prior to presentation when the symptoms began.

On physical examination, violaceous patches with necrotic bleeding edges and overlying black eschars were noted on the helices, antihelices, and ear lobules bilaterally (Figure 1). Retiform, purpuric to dark brown patches, some with signs of epidermal necrosis, were scattered on the arms, legs, and chest (Figure 2).

Laboratory examination revealed renal failure, anemia of chronic disease, and thrombocytosis (Table). The patient also screened positive for lupus anticoagulant and antinuclear antibodies and had elevated p-ANCA and anti–double-stranded DNA (Table). He also had an elevated sedimentation rate (109 mm/h [reference range, 0–20 mm/h]) and C-reactive protein level (11.3 mg/dL [reference range, 0–1.0 mg/dL])(Table). Urine toxicology was positive for cocaine.

A punch biopsy of the left thigh was performed on the edge of a retiform purpuric patch. Histopathologic examination revealed epidermal necrosis with subjacent intraluminal vascular thrombi along with extravasated red blood cells and neutrophilic debris (leukocytoclasis) and fibrin in and around vessel walls, consistent with vasculitis (Figure 3).

The patient was admitted to the hospital for pain management and wound care. Despite cocaine cessation and oral prednisone taper, the lesions on the legs worsened over the next several weeks. His condition was further complicated by wound infections, nonhealing ulcers, and subjective fevers and chills requiring frequent hospitalization. The patient was managed by the dermatology department as an outpatient and in clinic between hospital visits. He was treated with antibiotics, ulcer debridement, compression wraps, and aspirin (81 mg once daily) with moderate improvement.

Ten weeks after the first visit, the patient returned with worsening and recurrent leg and ear lesions. He denied any cocaine use since the initial hospital admission; however, a toxicology screen was never obtained. It was decided that the patient would need additional treatment along with traditional trigger (cocaine) avoidance and wound care. Combined treatment with aspirin (81 mg once daily), oral prednisone (40 mg once daily), and vardenafil hydrochloride (20 mg twice weekly) was initiated. At the end of week 1, the patient began to exhibit signs of improvement, which continued over the next 4 weeks. He was then lost to follow-up.

Comment

Our patient presented with severe necrotizing cutaneous vasculitis, likely secondary to levamisole exposure. Some of our patient’s cutaneous findings may be explained exclusively on the basis of cocaine exposure, but the characteristic lesion distribution and histopathologic findings along with the evidence of autoantibody positivity and concurrent arthralgias make the combination of levamisole and cocaine a more likely cause. Similar skin lesions were first described in children treated with levamisole for nephrotic syndrome.² The most common site of clinical involvement in these children was the ears, as seen in our patient. Our patient tested positive for p-ANCA, which is the most commonly reported autoantibody associated with this patient population. Sixty-one percent (20/33) of patients with levamisole-induced vasculitis from 2 separate reviews showed p-ANCA positivity.^7,10

On histopathology, our patient’s skin biopsy findings were consistent with those of prior reports of levamisole-induced vasculitis, which describe patterns of thrombotic vasculitis, leukocytoclasis, and fibrin deposition or occlusive disease.^2,6,7,9-14 Mixed histologic findings of vasculitis and thrombosis, usually with varying ages of thrombi, are characteristic of levamisole-induced purpura. In addition, the disease can present nonspecifically with pure microvascular thrombosis without vasculitis, especially later in the course.⁹

The recommended management of levamisole-induced vasculitis currently involves the withdrawal of the culprit adulterated cocaine along with supportive treatment. Spontaneous and complete clinical resolution of lesions has been reported within 2 to 3 weeks and serology normalization within 2 to 14 months of levamisole cessation.^2,6 A 2011 review of patients with levamisole-induced vasculitis reported 66% (19/29) of cases with either full cutaneous resolution after levamisole withdrawal or recurrence with resumed use, supporting a causal relationship.⁷ Walsh et al⁹ described 2 patients with recurrent and exacerbated retiform purpura following cocaine binges. Both of these patients had urine samples that tested positive for levamisole.⁹ In more severe cases, medications shown to be effective include colchicine, polidocanol, antibiotics, methotrexate, anticoagulants, and most commonly systemic corticosteroids.^7,10,11,15 Nonsteroidal anti-inflammatory drugs were successful in treating lesions in 2 patients with concurrent arthralgia.⁷ Rarely, patients have required surgical debridement or skin grafting due to advanced disease at initial presentation.^9,12-14 One of the most severe cases of levamisole-induced vasculitis reported in the literature involved 52% of the patient’s total body surface area with skin, soft tissue, and bony necrosis requiring nasal amputation, upper lip excision, skin grafting, and extremity amputation.¹⁴ Another severe case with widespread skin involvement was recently reported.¹⁶

For unclear reasons, our patient continued to develop cutaneous lesions despite self-reported cocaine cessation. Complete resolution required the combination of vardenafil, prednisone, and aspirin, along with debridement and wound care. Vardenafil, a selective phosphodiesterase 5 inhibitor, enhances the effect of nitrous oxide by increasing levels of cyclic guanosine monophosphate,¹⁷ which results in smooth muscle relaxation and vasodilatation. The primary indication for vardenafil is the treatment of erectile dysfunction, but it often is used off label in diseases that may benefit from vasodilatation. Because of its mechanism of action, it is understandable that a vasodilator such as vardenafil could be therapeutic in a condition associated with thrombosis. Moreover, the autoinflammatory nature of levamisole-induced vasculitis makes corticosteroid treatment effective. Given the 10-week delay in improvement, we suspect that it was the combination of treatment or an individual agent that led to our patient’s eventual recovery.

There are few reports in the literature focusing on optimal treatment of levamisole-induced vasculitis and none that mention alternative management for patients who continue to develop new lesions despite cocaine avoidance. Although the discontinuation of levamisole seems to be imperative for resolution of cutaneous lesions, it may not always be enough. It is possible that there is a subpopulation of patients that may not respond to the simple withdrawal of cocaine. It also should be mentioned that there was no urine toxicology screen obtained to support our patient’s reported cocaine cessation. Therefore, it is possible that his worsening condition was secondary to continued cocaine use. However, the patient successfully responded to the combination of vardenafil and prednisone, regardless of whether his condition persisted due to continued use of cocaine or not. This case suggests the possibility of a new treatment option for levamisole-induced vasculitis for patients who continue to use levamisole despite instruction for cessation or for patients with refractory disease.

Conclusion

A trial of prednisone and vardenafil should be considered for patients with refractory levamisole-induced vasculitis. Further studies and discussions of disease course are needed to identify the best treatment of this skin condition, especially for patients with refractory lesions.

Levamisole is an immunomodulatory drug that had been used to treat various medical conditions, including parasitic infections, nephrotic syndrome, and colorectal cancer,¹ before being withdrawn from the US market in 2000.The most common reasons for levamisole discontinuation were leukopenia and rashes (1%–2%),¹ many of which included leg ulcers and necrotizing purpura of the ears.^1,2 The drug is currently available only as a deworming agent in veterinary medicine.

Since 2007, increasing amounts of levamisole have been used as an adulterant in cocaine. In 2007, less than 10% of cocaine was contaminated with levamisole, with an increase to 77% by 2010.³ In addition, 78% of 249 urine toxicology screens that were positive for cocaine in an inner city hospital also tested positive for levamisole.⁴ Levamisole-cut cocaine has become a concern because it is associated with a life-threatening syndrome involving a necrotizing purpuric rash, autoantibody production, and leukopenia.⁵

Levamisole-induced vasculitis is an independent entity from cocaine-induced vasculitis, which is associated with skin findings ranging from palpable purpura and chronic ulcers to digital infarction secondary to its vasospastic activity.^6-8 Cocaine-induced vasculopathy has been related to cytoplasmic antineutrophil cytoplasmic antibody positivity and often resembles Wegener granulomatosis.⁶ Although both cocaine and levamisole have reportedly caused acrally distributed purpura and vasculopathy, levamisole is specifically associated with retiform purpura, ear involvement, and leukopenia.^6,9 In addition, levamisole-induced skin reactions have been linked to specific antibodies, including antinuclear, antiphospholipid, and perinuclear antineutrophil cytoplasmic antibody (p-ANCA).^2,5-7,9-14

We present a case of refractory levamisole-induced vasculitis and review its clinical presentation, diagnostic approach, laboratory findings, histology, and management. Furthermore, we discuss the possibility of a new treatment option for levamisole-induced vasculitis for patients with refractory disease or for patients who continue to use levamisole.

Case Report

A 49-year-old man with a history of polysubstance abuse presented with intermittent fevers and painful swollen ears as well as joint pain of 3 weeks’ duration. One week after the lesions developed on the ears, similar lesions were seen on the legs, arms, and trunk. He admitted to cocaine use 3 weeks prior to presentation when the symptoms began.

On physical examination, violaceous patches with necrotic bleeding edges and overlying black eschars were noted on the helices, antihelices, and ear lobules bilaterally (Figure 1). Retiform, purpuric to dark brown patches, some with signs of epidermal necrosis, were scattered on the arms, legs, and chest (Figure 2).

Laboratory examination revealed renal failure, anemia of chronic disease, and thrombocytosis (Table). The patient also screened positive for lupus anticoagulant and antinuclear antibodies and had elevated p-ANCA and anti–double-stranded DNA (Table). He also had an elevated sedimentation rate (109 mm/h [reference range, 0–20 mm/h]) and C-reactive protein level (11.3 mg/dL [reference range, 0–1.0 mg/dL])(Table). Urine toxicology was positive for cocaine.

A punch biopsy of the left thigh was performed on the edge of a retiform purpuric patch. Histopathologic examination revealed epidermal necrosis with subjacent intraluminal vascular thrombi along with extravasated red blood cells and neutrophilic debris (leukocytoclasis) and fibrin in and around vessel walls, consistent with vasculitis (Figure 3).

The patient was admitted to the hospital for pain management and wound care. Despite cocaine cessation and oral prednisone taper, the lesions on the legs worsened over the next several weeks. His condition was further complicated by wound infections, nonhealing ulcers, and subjective fevers and chills requiring frequent hospitalization. The patient was managed by the dermatology department as an outpatient and in clinic between hospital visits. He was treated with antibiotics, ulcer debridement, compression wraps, and aspirin (81 mg once daily) with moderate improvement.

Ten weeks after the first visit, the patient returned with worsening and recurrent leg and ear lesions. He denied any cocaine use since the initial hospital admission; however, a toxicology screen was never obtained. It was decided that the patient would need additional treatment along with traditional trigger (cocaine) avoidance and wound care. Combined treatment with aspirin (81 mg once daily), oral prednisone (40 mg once daily), and vardenafil hydrochloride (20 mg twice weekly) was initiated. At the end of week 1, the patient began to exhibit signs of improvement, which continued over the next 4 weeks. He was then lost to follow-up.

Comment

Our patient presented with severe necrotizing cutaneous vasculitis, likely secondary to levamisole exposure. Some of our patient’s cutaneous findings may be explained exclusively on the basis of cocaine exposure, but the characteristic lesion distribution and histopathologic findings along with the evidence of autoantibody positivity and concurrent arthralgias make the combination of levamisole and cocaine a more likely cause. Similar skin lesions were first described in children treated with levamisole for nephrotic syndrome.² The most common site of clinical involvement in these children was the ears, as seen in our patient. Our patient tested positive for p-ANCA, which is the most commonly reported autoantibody associated with this patient population. Sixty-one percent (20/33) of patients with levamisole-induced vasculitis from 2 separate reviews showed p-ANCA positivity.^7,10

On histopathology, our patient’s skin biopsy findings were consistent with those of prior reports of levamisole-induced vasculitis, which describe patterns of thrombotic vasculitis, leukocytoclasis, and fibrin deposition or occlusive disease.^2,6,7,9-14 Mixed histologic findings of vasculitis and thrombosis, usually with varying ages of thrombi, are characteristic of levamisole-induced purpura. In addition, the disease can present nonspecifically with pure microvascular thrombosis without vasculitis, especially later in the course.⁹

The recommended management of levamisole-induced vasculitis currently involves the withdrawal of the culprit adulterated cocaine along with supportive treatment. Spontaneous and complete clinical resolution of lesions has been reported within 2 to 3 weeks and serology normalization within 2 to 14 months of levamisole cessation.^2,6 A 2011 review of patients with levamisole-induced vasculitis reported 66% (19/29) of cases with either full cutaneous resolution after levamisole withdrawal or recurrence with resumed use, supporting a causal relationship.⁷ Walsh et al⁹ described 2 patients with recurrent and exacerbated retiform purpura following cocaine binges. Both of these patients had urine samples that tested positive for levamisole.⁹ In more severe cases, medications shown to be effective include colchicine, polidocanol, antibiotics, methotrexate, anticoagulants, and most commonly systemic corticosteroids.^7,10,11,15 Nonsteroidal anti-inflammatory drugs were successful in treating lesions in 2 patients with concurrent arthralgia.⁷ Rarely, patients have required surgical debridement or skin grafting due to advanced disease at initial presentation.^9,12-14 One of the most severe cases of levamisole-induced vasculitis reported in the literature involved 52% of the patient’s total body surface area with skin, soft tissue, and bony necrosis requiring nasal amputation, upper lip excision, skin grafting, and extremity amputation.¹⁴ Another severe case with widespread skin involvement was recently reported.¹⁶

For unclear reasons, our patient continued to develop cutaneous lesions despite self-reported cocaine cessation. Complete resolution required the combination of vardenafil, prednisone, and aspirin, along with debridement and wound care. Vardenafil, a selective phosphodiesterase 5 inhibitor, enhances the effect of nitrous oxide by increasing levels of cyclic guanosine monophosphate,¹⁷ which results in smooth muscle relaxation and vasodilatation. The primary indication for vardenafil is the treatment of erectile dysfunction, but it often is used off label in diseases that may benefit from vasodilatation. Because of its mechanism of action, it is understandable that a vasodilator such as vardenafil could be therapeutic in a condition associated with thrombosis. Moreover, the autoinflammatory nature of levamisole-induced vasculitis makes corticosteroid treatment effective. Given the 10-week delay in improvement, we suspect that it was the combination of treatment or an individual agent that led to our patient’s eventual recovery.

There are few reports in the literature focusing on optimal treatment of levamisole-induced vasculitis and none that mention alternative management for patients who continue to develop new lesions despite cocaine avoidance. Although the discontinuation of levamisole seems to be imperative for resolution of cutaneous lesions, it may not always be enough. It is possible that there is a subpopulation of patients that may not respond to the simple withdrawal of cocaine. It also should be mentioned that there was no urine toxicology screen obtained to support our patient’s reported cocaine cessation. Therefore, it is possible that his worsening condition was secondary to continued cocaine use. However, the patient successfully responded to the combination of vardenafil and prednisone, regardless of whether his condition persisted due to continued use of cocaine or not. This case suggests the possibility of a new treatment option for levamisole-induced vasculitis for patients who continue to use levamisole despite instruction for cessation or for patients with refractory disease.

Conclusion

A trial of prednisone and vardenafil should be considered for patients with refractory levamisole-induced vasculitis. Further studies and discussions of disease course are needed to identify the best treatment of this skin condition, especially for patients with refractory lesions.

The Diagnosis: Atypical Mycobacterial Infection

Punch biopsy specimens demonstrated necrotizing granulomatous inflammation in the dermis and subcutis (Figure). Special staining for microorganisms was negative. Tissue culture grew Mycobacterium avium-intracellulare (MAI). The patient began treatment with azithromycin, ethambutol, and rifabutin. Tissue susceptibilities later showed resistance to rifabutin and sensitivity to clarithromycin, moxifloxacin, and clofazimine. She subsequently was switched to azithromycin, clofazimine, and moxifloxacin with good response.

Mycobacterium avium-intracellulare is a slow-growing, nonchromogenic, atypical mycobacteria. Although ubiquitous, it tends to only cause serious infection in the setting of immunosuppression. Transmission usually is through the respiratory or gastrointestinal tract.¹ Skin infections with MAI are uncommon and usually are secondary to seeding from disseminated infection or from direct inoculation.²

The clinical presentations of primary cutaneous MAI are myriad, including an isolated red nodule, multiple ulcers, abscesses, draining sinuses, facial nodules, granulomatous plaques, and panniculitis.^2,3 Of 3 reported cases of primary cutaneous MAI in the form of sporotrichoid lesions, 2 involved patients with AIDS² and 1 involved a cardiac transplant recipient.⁴

Cutaneous MAI is typically diagnosed with skin biopsy and tissue culture. Tissue culture is critical for determining the specific mycobacterial species and antibiotic susceptibilities. Polymerase chain reaction has been utilized to rapidly diagnose cutaneous MAI infection from an acid-fast bacilli–positive tissue sample in which the tissue culture was negative.⁵

Recommended treatment protocols for MAI involve multidrug regimens because of the intrinsic resistance of MAI and the concern for development of resistance with monotherapy.² No definitive guidelines exist for treatment of primary cutaneous MAI infections. However, regimens for the treatment of pulmonary infection that also have been successfully utilized for cutaneous infection include a macrolide, ethambutol, and a rifamycin.⁶ Clinicians should be aware of MAI as a cause of primary cutaneous infections presenting as lymphocutaneous suppurative nodules and ulcerations.

The Diagnosis: Atypical Mycobacterial Infection

Punch biopsy specimens demonstrated necrotizing granulomatous inflammation in the dermis and subcutis (Figure). Special staining for microorganisms was negative. Tissue culture grew Mycobacterium avium-intracellulare (MAI). The patient began treatment with azithromycin, ethambutol, and rifabutin. Tissue susceptibilities later showed resistance to rifabutin and sensitivity to clarithromycin, moxifloxacin, and clofazimine. She subsequently was switched to azithromycin, clofazimine, and moxifloxacin with good response.

Mycobacterium avium-intracellulare is a slow-growing, nonchromogenic, atypical mycobacteria. Although ubiquitous, it tends to only cause serious infection in the setting of immunosuppression. Transmission usually is through the respiratory or gastrointestinal tract.¹ Skin infections with MAI are uncommon and usually are secondary to seeding from disseminated infection or from direct inoculation.²

The clinical presentations of primary cutaneous MAI are myriad, including an isolated red nodule, multiple ulcers, abscesses, draining sinuses, facial nodules, granulomatous plaques, and panniculitis.^2,3 Of 3 reported cases of primary cutaneous MAI in the form of sporotrichoid lesions, 2 involved patients with AIDS² and 1 involved a cardiac transplant recipient.⁴

Cutaneous MAI is typically diagnosed with skin biopsy and tissue culture. Tissue culture is critical for determining the specific mycobacterial species and antibiotic susceptibilities. Polymerase chain reaction has been utilized to rapidly diagnose cutaneous MAI infection from an acid-fast bacilli–positive tissue sample in which the tissue culture was negative.⁵

Recommended treatment protocols for MAI involve multidrug regimens because of the intrinsic resistance of MAI and the concern for development of resistance with monotherapy.² No definitive guidelines exist for treatment of primary cutaneous MAI infections. However, regimens for the treatment of pulmonary infection that also have been successfully utilized for cutaneous infection include a macrolide, ethambutol, and a rifamycin.⁶ Clinicians should be aware of MAI as a cause of primary cutaneous infections presenting as lymphocutaneous suppurative nodules and ulcerations.

The Diagnosis: Atypical Mycobacterial Infection

Punch biopsy specimens demonstrated necrotizing granulomatous inflammation in the dermis and subcutis (Figure). Special staining for microorganisms was negative. Tissue culture grew Mycobacterium avium-intracellulare (MAI). The patient began treatment with azithromycin, ethambutol, and rifabutin. Tissue susceptibilities later showed resistance to rifabutin and sensitivity to clarithromycin, moxifloxacin, and clofazimine. She subsequently was switched to azithromycin, clofazimine, and moxifloxacin with good response.

Mycobacterium avium-intracellulare is a slow-growing, nonchromogenic, atypical mycobacteria. Although ubiquitous, it tends to only cause serious infection in the setting of immunosuppression. Transmission usually is through the respiratory or gastrointestinal tract.¹ Skin infections with MAI are uncommon and usually are secondary to seeding from disseminated infection or from direct inoculation.²

The clinical presentations of primary cutaneous MAI are myriad, including an isolated red nodule, multiple ulcers, abscesses, draining sinuses, facial nodules, granulomatous plaques, and panniculitis.^2,3 Of 3 reported cases of primary cutaneous MAI in the form of sporotrichoid lesions, 2 involved patients with AIDS² and 1 involved a cardiac transplant recipient.⁴

Cutaneous MAI is typically diagnosed with skin biopsy and tissue culture. Tissue culture is critical for determining the specific mycobacterial species and antibiotic susceptibilities. Polymerase chain reaction has been utilized to rapidly diagnose cutaneous MAI infection from an acid-fast bacilli–positive tissue sample in which the tissue culture was negative.⁵

Recommended treatment protocols for MAI involve multidrug regimens because of the intrinsic resistance of MAI and the concern for development of resistance with monotherapy.² No definitive guidelines exist for treatment of primary cutaneous MAI infections. However, regimens for the treatment of pulmonary infection that also have been successfully utilized for cutaneous infection include a macrolide, ethambutol, and a rifamycin.⁶ Clinicians should be aware of MAI as a cause of primary cutaneous infections presenting as lymphocutaneous suppurative nodules and ulcerations.

Case Report

A 23-year-old woman presented with a horizontal split along the midline of the right great toenail associated with some tenderness of 2 to 3 months’ duration. Approximately 5 years prior, she noticed a bluish-colored area under the nail that had been steadily increasing in size. She denied a history of trauma, drainage, or bleeding. There was no history of other nail abnormalities. Her medications and personal, family, and social history were noncontributory.

Physical examination of the right great toenail revealed a horizontal split of the nail plate with a bluish hue visible under the nail plate (Figure 1A). The remaining toenails and fingernails were normal. A punch biopsy of the nail bed was performed with a presumptive clinical diagnosis of subungual melanoma versus melanocytic nevus versus cyst (Figure 1B). Nail plate avulsion revealed a blackened nail bed dotted with areas of bluish color and a red friable nodule present focally. Upon further inspection, extension was apparent into the distal matrix.

Histopathologic examination revealed a cystic structure with an epithelial lining mostly reminiscent of an isthmus catagen cyst admixed with the presence of both an intermittent focal granular layer and an eosinophilic cuticle surrounding pink laminated keratin, most consistent with a diagnosis of subungual onycholemmal cyst (SOC)(Figure 2). A reexcision was performed with removal of half of the nail bed, including a portion of the distal matrix extending inferiorly to the bone. Variably sized, epithelium-lined, keratin-filled cystic structures emanated from the nail bed epithelium. There were foci of hemorrhage and granulation tissue secondary to cyst rupture (Figure 3). The defect healed by secondary intention. No clinical evidence of recurrence was seen at 6-month follow-up.

Subungual onycholemmal cysts, also known as subungual epidermoid cysts or subungual epidermoid inclusions, are rare and distinctive nail abnormalities occurring in the dermis of the nail bed. We present a case of an SOC in a toenail mimicking subungual malignant melanoma.

Originally described by Samman¹ in 1959, SOCs were attributed to trauma to the nail with resultant implantation of the epidermis into the deeper tissue. Lewin^2,3 examined 90 postmortem fingernail and nail bed samples and found 8 subungual epidermoid cysts associated with clubbing of the fingernails. He postulated that the early pathogenesis of clubbing involved dermal fibroblast proliferation in the nail bed, leading to sequestration of nail bed epithelium into the dermis with resultant cyst formation. Microscopic subungual cysts also were identified in normal-appearing nails without evidence of trauma, thought to have arisen from the tips of the nail bed rete ridges by a process of bulbous proliferation rather than sequestration. These findings in normal nails suggest that SOCs may represent a more common entity than previously recognized.

It is imperative to recognize the presence of nail unit tumors early because of the risk for permanent nail plate dystrophy and the possibility of a malignant tumor.^4,5 Subungual onycholemmal cysts may present with a wide spectrum of clinical findings including marked subungual hyperkeratosis, onychodystrophy, ridging, nail bed pigmentation, clubbing, thickening, or less often a normal-appearing nail. Based on reported cases, several trends are evident. Although nail dystrophy is most often asymptomatic, pain is not uncommon.^5,6 It most commonly involves single digits, predominantly thumbs and great toenails.^7,8 This predilection suggests that trauma or other local factors may be involved in its pathogenesis. Of note, trauma to the nail may occur years before the development of the lesions or it may not be recalled at all.

Diagnosis requires a degree of clinical suspicion and a nail bed biopsy with partial or total nail plate avulsion to visualize the pathologic portion of the nail bed. Because surgical intervention may lead to the implantation of epithelium, recurrences after nail biopsy or excision may occur.

In contrast to epidermal inclusion cysts arising in the skin, most SOCs do not have a granular layer.⁹ Hair and nails represent analogous differentiation products of the ectoderm. The nail matrix is homologous to portions of the hair matrix, while the nail bed epithelium is comparable to the outer root sheath of the hair follicle.⁷ Subungual onycholemmal cysts originate from the nail bed epithelium, which keratinizes in the absence of a granular layer, similar to the follicular isthmus outer root sheath. Thus, SOCs are comparable to the outer root sheath–derived isthmus-catagen cysts because of their abrupt central keratinization.⁸

Subungual onycholemmal cysts also must be distinguished from slowly growing malignant tumors of the nail bed epithelium, referred to as onycholemmal carcinomas by Alessi et al.¹⁰ This entity characteristically presents in elderly patients as a slowly growing, circumscribed, subungual discoloration that may ulcerate, destroying the nail apparatus and penetrating the phalangeal bone. On histopathology, it is characterized by small cysts filled with eosinophilic keratin devoid of a granular layer and lined by atypical squamous epithelium accompanied by solid nests and strands of atypical keratinocytes within the dermis.¹¹ When a cystic component and clear cells predominate, the designation of malignant proliferating onycholemmal cyst has been applied. Its infiltrative growth pattern with destruction of the underlying bone makes it an important entity to exclude when considering the differential diagnosis of tumors of the nail bed.

Subungual melanomas comprise only 1% to 3% of malignant melanomas and 85% are initially misdiagnosed due to their rarity and nonspecific variable presentation. Aside from clinical evidence of Hutchinson sign in the early stages in almost all cases, accurate diagnosis of subungual melanoma and differentiation from SOCs relies on histopathology. A biopsy is necessary to make the diagnosis, but even microscopic findings may be nonspecific during the early stages.

Conclusion

We report a case of a 23-year-old woman with horizontal ridging and tenderness of the right great toenail associated with pigmentation of 5 years’ duration due to an SOC. The etiology of these subungual cysts, with or without nail abnormalities, still remains unclear. Its predilection for the thumbs and great toenails suggests that trauma or other local factors may be involved in its pathogenesis. Because of the rarity of this entity, there are no guidelines for surgical treatment. Subungual onycholemmal cysts may be an underrecognized and more common entity that must be considered when discussing tumors of the nail unit.

Case Report

A 23-year-old woman presented with a horizontal split along the midline of the right great toenail associated with some tenderness of 2 to 3 months’ duration. Approximately 5 years prior, she noticed a bluish-colored area under the nail that had been steadily increasing in size. She denied a history of trauma, drainage, or bleeding. There was no history of other nail abnormalities. Her medications and personal, family, and social history were noncontributory.

Physical examination of the right great toenail revealed a horizontal split of the nail plate with a bluish hue visible under the nail plate (Figure 1A). The remaining toenails and fingernails were normal. A punch biopsy of the nail bed was performed with a presumptive clinical diagnosis of subungual melanoma versus melanocytic nevus versus cyst (Figure 1B). Nail plate avulsion revealed a blackened nail bed dotted with areas of bluish color and a red friable nodule present focally. Upon further inspection, extension was apparent into the distal matrix.

Histopathologic examination revealed a cystic structure with an epithelial lining mostly reminiscent of an isthmus catagen cyst admixed with the presence of both an intermittent focal granular layer and an eosinophilic cuticle surrounding pink laminated keratin, most consistent with a diagnosis of subungual onycholemmal cyst (SOC)(Figure 2). A reexcision was performed with removal of half of the nail bed, including a portion of the distal matrix extending inferiorly to the bone. Variably sized, epithelium-lined, keratin-filled cystic structures emanated from the nail bed epithelium. There were foci of hemorrhage and granulation tissue secondary to cyst rupture (Figure 3). The defect healed by secondary intention. No clinical evidence of recurrence was seen at 6-month follow-up.

Subungual onycholemmal cysts, also known as subungual epidermoid cysts or subungual epidermoid inclusions, are rare and distinctive nail abnormalities occurring in the dermis of the nail bed. We present a case of an SOC in a toenail mimicking subungual malignant melanoma.

Originally described by Samman¹ in 1959, SOCs were attributed to trauma to the nail with resultant implantation of the epidermis into the deeper tissue. Lewin^2,3 examined 90 postmortem fingernail and nail bed samples and found 8 subungual epidermoid cysts associated with clubbing of the fingernails. He postulated that the early pathogenesis of clubbing involved dermal fibroblast proliferation in the nail bed, leading to sequestration of nail bed epithelium into the dermis with resultant cyst formation. Microscopic subungual cysts also were identified in normal-appearing nails without evidence of trauma, thought to have arisen from the tips of the nail bed rete ridges by a process of bulbous proliferation rather than sequestration. These findings in normal nails suggest that SOCs may represent a more common entity than previously recognized.

It is imperative to recognize the presence of nail unit tumors early because of the risk for permanent nail plate dystrophy and the possibility of a malignant tumor.^4,5 Subungual onycholemmal cysts may present with a wide spectrum of clinical findings including marked subungual hyperkeratosis, onychodystrophy, ridging, nail bed pigmentation, clubbing, thickening, or less often a normal-appearing nail. Based on reported cases, several trends are evident. Although nail dystrophy is most often asymptomatic, pain is not uncommon.^5,6 It most commonly involves single digits, predominantly thumbs and great toenails.^7,8 This predilection suggests that trauma or other local factors may be involved in its pathogenesis. Of note, trauma to the nail may occur years before the development of the lesions or it may not be recalled at all.

Diagnosis requires a degree of clinical suspicion and a nail bed biopsy with partial or total nail plate avulsion to visualize the pathologic portion of the nail bed. Because surgical intervention may lead to the implantation of epithelium, recurrences after nail biopsy or excision may occur.

In contrast to epidermal inclusion cysts arising in the skin, most SOCs do not have a granular layer.⁹ Hair and nails represent analogous differentiation products of the ectoderm. The nail matrix is homologous to portions of the hair matrix, while the nail bed epithelium is comparable to the outer root sheath of the hair follicle.⁷ Subungual onycholemmal cysts originate from the nail bed epithelium, which keratinizes in the absence of a granular layer, similar to the follicular isthmus outer root sheath. Thus, SOCs are comparable to the outer root sheath–derived isthmus-catagen cysts because of their abrupt central keratinization.⁸

Subungual onycholemmal cysts also must be distinguished from slowly growing malignant tumors of the nail bed epithelium, referred to as onycholemmal carcinomas by Alessi et al.¹⁰ This entity characteristically presents in elderly patients as a slowly growing, circumscribed, subungual discoloration that may ulcerate, destroying the nail apparatus and penetrating the phalangeal bone. On histopathology, it is characterized by small cysts filled with eosinophilic keratin devoid of a granular layer and lined by atypical squamous epithelium accompanied by solid nests and strands of atypical keratinocytes within the dermis.¹¹ When a cystic component and clear cells predominate, the designation of malignant proliferating onycholemmal cyst has been applied. Its infiltrative growth pattern with destruction of the underlying bone makes it an important entity to exclude when considering the differential diagnosis of tumors of the nail bed.

Subungual melanomas comprise only 1% to 3% of malignant melanomas and 85% are initially misdiagnosed due to their rarity and nonspecific variable presentation. Aside from clinical evidence of Hutchinson sign in the early stages in almost all cases, accurate diagnosis of subungual melanoma and differentiation from SOCs relies on histopathology. A biopsy is necessary to make the diagnosis, but even microscopic findings may be nonspecific during the early stages.

Conclusion

We report a case of a 23-year-old woman with horizontal ridging and tenderness of the right great toenail associated with pigmentation of 5 years’ duration due to an SOC. The etiology of these subungual cysts, with or without nail abnormalities, still remains unclear. Its predilection for the thumbs and great toenails suggests that trauma or other local factors may be involved in its pathogenesis. Because of the rarity of this entity, there are no guidelines for surgical treatment. Subungual onycholemmal cysts may be an underrecognized and more common entity that must be considered when discussing tumors of the nail unit.

Case Report

A 23-year-old woman presented with a horizontal split along the midline of the right great toenail associated with some tenderness of 2 to 3 months’ duration. Approximately 5 years prior, she noticed a bluish-colored area under the nail that had been steadily increasing in size. She denied a history of trauma, drainage, or bleeding. There was no history of other nail abnormalities. Her medications and personal, family, and social history were noncontributory.

Physical examination of the right great toenail revealed a horizontal split of the nail plate with a bluish hue visible under the nail plate (Figure 1A). The remaining toenails and fingernails were normal. A punch biopsy of the nail bed was performed with a presumptive clinical diagnosis of subungual melanoma versus melanocytic nevus versus cyst (Figure 1B). Nail plate avulsion revealed a blackened nail bed dotted with areas of bluish color and a red friable nodule present focally. Upon further inspection, extension was apparent into the distal matrix.

Histopathologic examination revealed a cystic structure with an epithelial lining mostly reminiscent of an isthmus catagen cyst admixed with the presence of both an intermittent focal granular layer and an eosinophilic cuticle surrounding pink laminated keratin, most consistent with a diagnosis of subungual onycholemmal cyst (SOC)(Figure 2). A reexcision was performed with removal of half of the nail bed, including a portion of the distal matrix extending inferiorly to the bone. Variably sized, epithelium-lined, keratin-filled cystic structures emanated from the nail bed epithelium. There were foci of hemorrhage and granulation tissue secondary to cyst rupture (Figure 3). The defect healed by secondary intention. No clinical evidence of recurrence was seen at 6-month follow-up.

Subungual onycholemmal cysts, also known as subungual epidermoid cysts or subungual epidermoid inclusions, are rare and distinctive nail abnormalities occurring in the dermis of the nail bed. We present a case of an SOC in a toenail mimicking subungual malignant melanoma.

Originally described by Samman¹ in 1959, SOCs were attributed to trauma to the nail with resultant implantation of the epidermis into the deeper tissue. Lewin^2,3 examined 90 postmortem fingernail and nail bed samples and found 8 subungual epidermoid cysts associated with clubbing of the fingernails. He postulated that the early pathogenesis of clubbing involved dermal fibroblast proliferation in the nail bed, leading to sequestration of nail bed epithelium into the dermis with resultant cyst formation. Microscopic subungual cysts also were identified in normal-appearing nails without evidence of trauma, thought to have arisen from the tips of the nail bed rete ridges by a process of bulbous proliferation rather than sequestration. These findings in normal nails suggest that SOCs may represent a more common entity than previously recognized.

It is imperative to recognize the presence of nail unit tumors early because of the risk for permanent nail plate dystrophy and the possibility of a malignant tumor.^4,5 Subungual onycholemmal cysts may present with a wide spectrum of clinical findings including marked subungual hyperkeratosis, onychodystrophy, ridging, nail bed pigmentation, clubbing, thickening, or less often a normal-appearing nail. Based on reported cases, several trends are evident. Although nail dystrophy is most often asymptomatic, pain is not uncommon.^5,6 It most commonly involves single digits, predominantly thumbs and great toenails.^7,8 This predilection suggests that trauma or other local factors may be involved in its pathogenesis. Of note, trauma to the nail may occur years before the development of the lesions or it may not be recalled at all.

Diagnosis requires a degree of clinical suspicion and a nail bed biopsy with partial or total nail plate avulsion to visualize the pathologic portion of the nail bed. Because surgical intervention may lead to the implantation of epithelium, recurrences after nail biopsy or excision may occur.

In contrast to epidermal inclusion cysts arising in the skin, most SOCs do not have a granular layer.⁹ Hair and nails represent analogous differentiation products of the ectoderm. The nail matrix is homologous to portions of the hair matrix, while the nail bed epithelium is comparable to the outer root sheath of the hair follicle.⁷ Subungual onycholemmal cysts originate from the nail bed epithelium, which keratinizes in the absence of a granular layer, similar to the follicular isthmus outer root sheath. Thus, SOCs are comparable to the outer root sheath–derived isthmus-catagen cysts because of their abrupt central keratinization.⁸

Subungual onycholemmal cysts also must be distinguished from slowly growing malignant tumors of the nail bed epithelium, referred to as onycholemmal carcinomas by Alessi et al.¹⁰ This entity characteristically presents in elderly patients as a slowly growing, circumscribed, subungual discoloration that may ulcerate, destroying the nail apparatus and penetrating the phalangeal bone. On histopathology, it is characterized by small cysts filled with eosinophilic keratin devoid of a granular layer and lined by atypical squamous epithelium accompanied by solid nests and strands of atypical keratinocytes within the dermis.¹¹ When a cystic component and clear cells predominate, the designation of malignant proliferating onycholemmal cyst has been applied. Its infiltrative growth pattern with destruction of the underlying bone makes it an important entity to exclude when considering the differential diagnosis of tumors of the nail bed.

Subungual melanomas comprise only 1% to 3% of malignant melanomas and 85% are initially misdiagnosed due to their rarity and nonspecific variable presentation. Aside from clinical evidence of Hutchinson sign in the early stages in almost all cases, accurate diagnosis of subungual melanoma and differentiation from SOCs relies on histopathology. A biopsy is necessary to make the diagnosis, but even microscopic findings may be nonspecific during the early stages.

Conclusion

We report a case of a 23-year-old woman with horizontal ridging and tenderness of the right great toenail associated with pigmentation of 5 years’ duration due to an SOC. The etiology of these subungual cysts, with or without nail abnormalities, still remains unclear. Its predilection for the thumbs and great toenails suggests that trauma or other local factors may be involved in its pathogenesis. Because of the rarity of this entity, there are no guidelines for surgical treatment. Subungual onycholemmal cysts may be an underrecognized and more common entity that must be considered when discussing tumors of the nail unit.

The Diagnosis: Subcutaneous Phaeohyphomycosis

Subcutaneous phaeohyphomycosis (SP), also called mycotic cyst, is characterized by a painless, nodular lesion that develops in response to traumatic implantation of dematiaceous, pigment-forming fungi.¹ Similar to other fungal infections, SP can arise opportunistically in immunocompromised patients.^2,3 More than 60 genera (and more than 100 species) are known etiologic agents of phaeohyphomycosis; the 2 main causes of infection are Bipolaris spicifera and Exophiala jeanselmei.^4,5 Given this variety, phaeohyphomycosis can present superficially as black piedra or tinea nigra, cutaneously as scytalidiosis, subcutaneously as SP, or disseminated as sinusitis or systemic phaeohyphomycosis.

Coined in 1974 by Ajello et al,⁶ the term phaeohyphomycosis translates to “condition of dark hyphal fungus,” a term used to designate mycoses caused by fungi with melanized hyphae. Histologically, SP demonstrates a circumscribed chronic cyst or abscess with a dense fibrous wall (quiz image A). At high power, the wall is composed of chronic granulomatous inflammation with foamy macrophages, and the cystic cavity contains necrotic debris admixed with neutrophils. Pigmented filamentous hyphae and yeastlike entities can be seen in the cyst wall, in multinucleated giant cells, in the necrotic debris, or directly attached to the implanted foreign material (quiz image B).⁷ The first-line treatment of SP is wide local excision and oral itraconazole. It often requires adjustments to dosage or change to antifungal due to recurrence and etiologic variation.⁸ Furthermore, if SP is not definitively treated, immunocompromised patients are at an increased risk for developing potentially fatal systemic phaeohyphomycosis.³

Chromoblastomycosis (CBM), also caused by dematiaceous fungi, is characterized by an initially indolent clinical presentation. Typically found on the legs and lower thighs of agricultural workers, the lesion begins as a slow-growing, nodular papule with subsequent transformation into an edematous verrucous plaque with peripheral erythema.⁹ Lesions can be annular with central clearing, and lymphedema with elephantiasis may be present.¹⁰ Histologically, CBM shows pseudoepitheliomatous hyperplasia and intraepidermal pustules as the host rids the infection via transepithelial elimination. Dematiaceous fungi often are seen in the dermis, either freestanding or attached to foreign plant material. Medlar bodies, also called copper penny spores or sclerotic bodies, are the most defining histologic finding and are characterized by groups of brown, thick-walled cells found in giant cells or neutrophil abscesses (Figure 1). Hyphae are not typically found in this type of infection.¹¹

Granulomatous foreign body reactions occur in response to the inoculation of nonhuman material and are characterized by dermal or subcutaneous nodules. Tissue macrophages phagocytize material not removed shortly after implantation, which initiates an inflammatory response that attempts to isolate the material from the uninvolved surrounding tissue. Vegetative foreign bodies will cause the most severe inflammatory reactions.¹² Histologically, foreign body granulomas are noncaseating with epithelioid histiocytes surrounding a central foreign body (Figure 2). Occasionally, foreign bodies may be difficult to detect; some are birefringent to polarized light.¹³ Additionally, inoculation injuries can predispose patients to SP, CBM, and other fungal infections.

Tattoos are characterized by exogenous pigment deposition into the dermis.¹⁴ Histologically, tattoos display exogenous pigment deposited throughout the reticular dermis, attached to collagen bundles, within macrophages, or adjacent to adnexal structures (eg, pilosebaceous units or eccrine glands). Although all tattoo pigments can cause adverse reactions, hypersensitivity reactions occur most commonly in response to red pigment, resulting in discrete areas of spongiosis and granulomatous or lichenoid inflammation. Occasionally, hypersensitivity reactions can induce necrobiotic granulomatous reactions characterized by collagen alteration surrounded by palisaded histiocytes and lymphocytes (Figure 3).^15,16 There also may be focally dense areas of superficial and deep perivascular lymphohistiocytic infiltrate. Clinical context is important, as brown tattoo pigment (Figure 3) can be easily confused with the pigmented hyphae of phaeohyphomycosis, melanin, or hemosiderin.

Subcutaneous hyalohyphomycosis is a nondemat-iaceous (nonpigmented) infection that is caused by hyaline septate hyphal cells.¹⁷ Hyalohyphomycosis skin lesions can present as painful erythematous nodules that evolve into excoriated pustules.¹⁸ Hyalohyphomycosis most often arises in immunocompromised patients. Causative organisms are ubiquitous soil saprophytes and plant pathogens, most often Aspergillus and Fusarium species, with a predilection for affecting severely immunocompromised hosts, particularly children.¹⁹ These species tend to be vasculotropic, which can result in tissue necrosis and systemic dissemination. Histologically, fungi are dispersed within tissue. They have a bright, bubbly, mildly basophilic cytoplasm and are nonpigmented, branching, and septate (Figure 4).¹¹

The Diagnosis: Subcutaneous Phaeohyphomycosis

Subcutaneous phaeohyphomycosis (SP), also called mycotic cyst, is characterized by a painless, nodular lesion that develops in response to traumatic implantation of dematiaceous, pigment-forming fungi.¹ Similar to other fungal infections, SP can arise opportunistically in immunocompromised patients.^2,3 More than 60 genera (and more than 100 species) are known etiologic agents of phaeohyphomycosis; the 2 main causes of infection are Bipolaris spicifera and Exophiala jeanselmei.^4,5 Given this variety, phaeohyphomycosis can present superficially as black piedra or tinea nigra, cutaneously as scytalidiosis, subcutaneously as SP, or disseminated as sinusitis or systemic phaeohyphomycosis.

Coined in 1974 by Ajello et al,⁶ the term phaeohyphomycosis translates to “condition of dark hyphal fungus,” a term used to designate mycoses caused by fungi with melanized hyphae. Histologically, SP demonstrates a circumscribed chronic cyst or abscess with a dense fibrous wall (quiz image A). At high power, the wall is composed of chronic granulomatous inflammation with foamy macrophages, and the cystic cavity contains necrotic debris admixed with neutrophils. Pigmented filamentous hyphae and yeastlike entities can be seen in the cyst wall, in multinucleated giant cells, in the necrotic debris, or directly attached to the implanted foreign material (quiz image B).⁷ The first-line treatment of SP is wide local excision and oral itraconazole. It often requires adjustments to dosage or change to antifungal due to recurrence and etiologic variation.⁸ Furthermore, if SP is not definitively treated, immunocompromised patients are at an increased risk for developing potentially fatal systemic phaeohyphomycosis.³

Chromoblastomycosis (CBM), also caused by dematiaceous fungi, is characterized by an initially indolent clinical presentation. Typically found on the legs and lower thighs of agricultural workers, the lesion begins as a slow-growing, nodular papule with subsequent transformation into an edematous verrucous plaque with peripheral erythema.⁹ Lesions can be annular with central clearing, and lymphedema with elephantiasis may be present.¹⁰ Histologically, CBM shows pseudoepitheliomatous hyperplasia and intraepidermal pustules as the host rids the infection via transepithelial elimination. Dematiaceous fungi often are seen in the dermis, either freestanding or attached to foreign plant material. Medlar bodies, also called copper penny spores or sclerotic bodies, are the most defining histologic finding and are characterized by groups of brown, thick-walled cells found in giant cells or neutrophil abscesses (Figure 1). Hyphae are not typically found in this type of infection.¹¹

Granulomatous foreign body reactions occur in response to the inoculation of nonhuman material and are characterized by dermal or subcutaneous nodules. Tissue macrophages phagocytize material not removed shortly after implantation, which initiates an inflammatory response that attempts to isolate the material from the uninvolved surrounding tissue. Vegetative foreign bodies will cause the most severe inflammatory reactions.¹² Histologically, foreign body granulomas are noncaseating with epithelioid histiocytes surrounding a central foreign body (Figure 2). Occasionally, foreign bodies may be difficult to detect; some are birefringent to polarized light.¹³ Additionally, inoculation injuries can predispose patients to SP, CBM, and other fungal infections.

Tattoos are characterized by exogenous pigment deposition into the dermis.¹⁴ Histologically, tattoos display exogenous pigment deposited throughout the reticular dermis, attached to collagen bundles, within macrophages, or adjacent to adnexal structures (eg, pilosebaceous units or eccrine glands). Although all tattoo pigments can cause adverse reactions, hypersensitivity reactions occur most commonly in response to red pigment, resulting in discrete areas of spongiosis and granulomatous or lichenoid inflammation. Occasionally, hypersensitivity reactions can induce necrobiotic granulomatous reactions characterized by collagen alteration surrounded by palisaded histiocytes and lymphocytes (Figure 3).^15,16 There also may be focally dense areas of superficial and deep perivascular lymphohistiocytic infiltrate. Clinical context is important, as brown tattoo pigment (Figure 3) can be easily confused with the pigmented hyphae of phaeohyphomycosis, melanin, or hemosiderin.

Subcutaneous hyalohyphomycosis is a nondemat-iaceous (nonpigmented) infection that is caused by hyaline septate hyphal cells.¹⁷ Hyalohyphomycosis skin lesions can present as painful erythematous nodules that evolve into excoriated pustules.¹⁸ Hyalohyphomycosis most often arises in immunocompromised patients. Causative organisms are ubiquitous soil saprophytes and plant pathogens, most often Aspergillus and Fusarium species, with a predilection for affecting severely immunocompromised hosts, particularly children.¹⁹ These species tend to be vasculotropic, which can result in tissue necrosis and systemic dissemination. Histologically, fungi are dispersed within tissue. They have a bright, bubbly, mildly basophilic cytoplasm and are nonpigmented, branching, and septate (Figure 4).¹¹

The Diagnosis: Subcutaneous Phaeohyphomycosis

Subcutaneous phaeohyphomycosis (SP), also called mycotic cyst, is characterized by a painless, nodular lesion that develops in response to traumatic implantation of dematiaceous, pigment-forming fungi.¹ Similar to other fungal infections, SP can arise opportunistically in immunocompromised patients.^2,3 More than 60 genera (and more than 100 species) are known etiologic agents of phaeohyphomycosis; the 2 main causes of infection are Bipolaris spicifera and Exophiala jeanselmei.^4,5 Given this variety, phaeohyphomycosis can present superficially as black piedra or tinea nigra, cutaneously as scytalidiosis, subcutaneously as SP, or disseminated as sinusitis or systemic phaeohyphomycosis.

Coined in 1974 by Ajello et al,⁶ the term phaeohyphomycosis translates to “condition of dark hyphal fungus,” a term used to designate mycoses caused by fungi with melanized hyphae. Histologically, SP demonstrates a circumscribed chronic cyst or abscess with a dense fibrous wall (quiz image A). At high power, the wall is composed of chronic granulomatous inflammation with foamy macrophages, and the cystic cavity contains necrotic debris admixed with neutrophils. Pigmented filamentous hyphae and yeastlike entities can be seen in the cyst wall, in multinucleated giant cells, in the necrotic debris, or directly attached to the implanted foreign material (quiz image B).⁷ The first-line treatment of SP is wide local excision and oral itraconazole. It often requires adjustments to dosage or change to antifungal due to recurrence and etiologic variation.⁸ Furthermore, if SP is not definitively treated, immunocompromised patients are at an increased risk for developing potentially fatal systemic phaeohyphomycosis.³

Chromoblastomycosis (CBM), also caused by dematiaceous fungi, is characterized by an initially indolent clinical presentation. Typically found on the legs and lower thighs of agricultural workers, the lesion begins as a slow-growing, nodular papule with subsequent transformation into an edematous verrucous plaque with peripheral erythema.⁹ Lesions can be annular with central clearing, and lymphedema with elephantiasis may be present.¹⁰ Histologically, CBM shows pseudoepitheliomatous hyperplasia and intraepidermal pustules as the host rids the infection via transepithelial elimination. Dematiaceous fungi often are seen in the dermis, either freestanding or attached to foreign plant material. Medlar bodies, also called copper penny spores or sclerotic bodies, are the most defining histologic finding and are characterized by groups of brown, thick-walled cells found in giant cells or neutrophil abscesses (Figure 1). Hyphae are not typically found in this type of infection.¹¹

Granulomatous foreign body reactions occur in response to the inoculation of nonhuman material and are characterized by dermal or subcutaneous nodules. Tissue macrophages phagocytize material not removed shortly after implantation, which initiates an inflammatory response that attempts to isolate the material from the uninvolved surrounding tissue. Vegetative foreign bodies will cause the most severe inflammatory reactions.¹² Histologically, foreign body granulomas are noncaseating with epithelioid histiocytes surrounding a central foreign body (Figure 2). Occasionally, foreign bodies may be difficult to detect; some are birefringent to polarized light.¹³ Additionally, inoculation injuries can predispose patients to SP, CBM, and other fungal infections.

Tattoos are characterized by exogenous pigment deposition into the dermis.¹⁴ Histologically, tattoos display exogenous pigment deposited throughout the reticular dermis, attached to collagen bundles, within macrophages, or adjacent to adnexal structures (eg, pilosebaceous units or eccrine glands). Although all tattoo pigments can cause adverse reactions, hypersensitivity reactions occur most commonly in response to red pigment, resulting in discrete areas of spongiosis and granulomatous or lichenoid inflammation. Occasionally, hypersensitivity reactions can induce necrobiotic granulomatous reactions characterized by collagen alteration surrounded by palisaded histiocytes and lymphocytes (Figure 3).^15,16 There also may be focally dense areas of superficial and deep perivascular lymphohistiocytic infiltrate. Clinical context is important, as brown tattoo pigment (Figure 3) can be easily confused with the pigmented hyphae of phaeohyphomycosis, melanin, or hemosiderin.

Subcutaneous hyalohyphomycosis is a nondemat-iaceous (nonpigmented) infection that is caused by hyaline septate hyphal cells.¹⁷ Hyalohyphomycosis skin lesions can present as painful erythematous nodules that evolve into excoriated pustules.¹⁸ Hyalohyphomycosis most often arises in immunocompromised patients. Causative organisms are ubiquitous soil saprophytes and plant pathogens, most often Aspergillus and Fusarium species, with a predilection for affecting severely immunocompromised hosts, particularly children.¹⁹ These species tend to be vasculotropic, which can result in tissue necrosis and systemic dissemination. Histologically, fungi are dispersed within tissue. They have a bright, bubbly, mildly basophilic cytoplasm and are nonpigmented, branching, and septate (Figure 4).¹¹

Mucin is an amorphous gelatinous substance that is found in a large variety of tissues. There are 2 types of cutaneous mucin: dermal and epithelial. Both types appear as basophilic shreds and granules with hematoxylin and eosin stain.1 Epithelial mucin (sialomucin) is found mainly in the gastrointestinal tract and lungs. In the skin, it is present in the cytoplasm of the dark cells of the eccrine glands and in the apocrine secretory cells. Epithelial mucin contains both neutral and acid glycosaminoglycans, stains positive with Alcian blue (pH 2.5) and periodic acid–Schiff, is resistant to hyaluronidase, and does not stain metachromatically with toluidine blue. Dermal mucin is composed of acid glycosaminoglycans (eg, dermatan sulfate, chondroitin 6-sulfate, chondroitin 4-sulfate, hyaluronic acid) and normally is produced by dermal fibroblasts. Dermal mucin stains positive with Alcian blue (pH 2.5); is periodic acid–Schiff negative and sensitive to hyaluronidase; and shows metachromasia with toluidine blue, methylene blue, and thionine.

Cutaneous mucinosis comprises a heterogeneous group of skin disorders characterized by the deposition of mucin in the interstices of the dermis. These diseases may be classified as primary mucinosis with the mucin deposition as the main histologic feature resulting in clinically distinctive lesions and secondary mucinosis with the mucin deposition as an additional histologic finding within the context of an independent skin disease or lesion (eg, basal cell carcinoma) with deposits of mucin in the stroma. Primary cutaneous mucinosis may be subclassified into 2 groups: degenerative-inflammatory mucinoses and neoplastic-hamartomatous mucinoses. According to the histologic features, the degenerative-inflammatory mucinoses are better divided into dermal and follicular mucinoses.² We describe a case of primary cutaneous dermal mucinosis on herpes zoster (HZ) scars as an isotopic response.

Case Report

A 33-year-old man presented to the dermatology department with slightly pruritic lesions on the left side of the chest and back that had appeared progressively at the site of HZ scars that had healed without treatment 9 months prior. Dermatologic examination revealed sharply defined whitish papules (Figure 1) measuring 2 to 4 mm in diameter with a smooth surface and linear distribution over the area of the left T8 and T9 dermatomes. The patient reported no postherpetic neuralgia and was otherwise healthy. Laboratory tests including a complete blood cell count, biochemistry, urinalysis, and determination of free thyroid hormones were within reference range. Serologic tests for human immunodeficiency virus, hepatitis B and C viruses, and syphilis were negative. Antinuclear antibodies also were negative.

Histopathology demonstrated abundant bluish granular material between collagen bundles of the papillary dermis (Figure 2). No cytopathologic signs of active herpetic infection were seen. The Alcian blue stain at pH 2.5 was strongly positive for mucin, which confirmed the diagnosis of primary cutaneous dermal mucinosis.

Topical corticosteroids were applied for 2 months with no notable improvement. The lesions gradually improved without any other therapy during the subsequent 6 months.

Comment

The occurrence of a new skin disease at the exact site of a prior unrelated cutaneous disorder that had already resolved was first reported by Wyburn-Mason³ in 1955. Forty years later, the term isotopic response was coined by Wolf et al⁴ to describe this phenomenon. Diverse types of skin diseases such as herpes simplex virus,⁵ varicella-zoster infections,⁴ and thrombophlebitis⁴ have been implicated in cases of isotopic response, but the most frequently associated primary disorder by far is cutaneous HZ.

Several benign and malignant disorders may occur at sites of resolved HZ lesions, including granulomatous dermatitis,⁶ granuloma annulare,⁷ fungal granuloma,⁸ fungal folliculitis,⁹ psoriasis,¹⁰ morphea,¹¹ lichen sclerosus,¹² Kaposi sarcoma,¹³ the lichenoid variant of chronic graft-versus-host disease,¹⁴ cutaneous sarcoidosis,¹⁵ granulomatous folliculitis,¹⁶ comedones,¹⁷ furuncles,¹⁸ erythema annulare centrifugum,¹⁹ eosinophilic dermatosis,²⁰ cutaneous pseudolymphoma,²¹ granulomatous vasculitis,²² Rosai-Dorfman disease,¹² xanthomatous changes,²³ tuberculoid granulomas,²⁴ acneform eruption,²⁵ lichen planus,²⁶ acquired reactive perforating collagenosis,²⁷ lymphoma,²⁸ leukemia,²⁹ angiosarcoma,³⁰ basal cell carcinoma,³¹ squamous cell carcinoma, and cutaneous metastasis from internal carcinoma.³² The interval between the acute HZ episode and presentation of the second disease is quite variable, ranging from days to several months. Postzoster isotopic response has been described in individuals with varying degrees of immune response, affecting both immunocompetent¹² and immunocompromised patients.¹⁴ There is no predilection for age, sex, or race. It also seems that antiviral treatment during the active episode does not prevent the development of secondary reactions.Kim et al³³ reported a 59-year-old woman who developed flesh-colored or erythematous papules on HZ scars over the area of the left T1 and T2 dermatomes 1 week after the active viral process. Histopathologic study demonstrated deposition of mucin between collagen bundles in the dermis. The authors established the diagnosis of secondary cutaneous mucinosis as an isotopic response.³³ Nevertheless, we believe that based on the aforementioned classification of cutaneous mucinosis,² both this case and our case are better considered as primary cutaneous dermal mucinosis, as the mucin deposition in the dermis was the main histologic finding resulting in a distinctive cutaneous disorder. In the case reported by Kim et al,³³ a possible relationship between cutaneous mucinosis and postherpetic neuralgia was suggested based on the slow regression of skin lesions in accordance with the improvement of the neuralgic pain; however, our patient did not have postherpetic neuralgia and the lesions persisted unchanged several months after the acute HZ episode. In the literature, there are reports of primary cutaneous dermal mucinosis associated with altered thyroid function³⁴; autoimmune connective tissue diseases, mostly lupus erythematosus³⁵; monoclonal gammopathy³⁶; and human immunodeficiency virus infection,³⁷ but these possibilities were ruled out in our patient by pertinent laboratory studies.

The pathogenesis of the postherpetic isotopic response remains unknown, but several mechanisms have been proposed. Some authors have suggested that postzoster dermatoses may represent isomorphic response of Köbner phenomenon.^13,15 Although isomorphic and isotopic responses share some similarities, these terms describe 2 different phenomena: the first refers to the appearance of the same cutaneous disorder at a different site favored by trauma, while the second manifests a new and unrelated disease at the same location.³⁸ Local anatomic changes such as altered microcirculation, collagen rearrangement, and an imperfect skin barrier may promote a prolonged local inflammatory response. Moreover, the destruction of nerve fibers by the varicella-zoster virus may indirectly influence the local immune system through the release of specific neuropeptides in the skin.³⁹ It has been speculated that some secondary reactions may be the result of type III and type IV hypersensitivity reactions⁴⁰ to viral antigens or to tissue antigens modified by the virus, inducing either immune hypersensitivity or local immune suppression.⁴¹ Some authors have documented the presence of varicella-zoster DNA within early postzoster lesions^6,7 by using polymerase chain reaction in early lesions but not in late-stage and residual lesions.^12,22 Nikkels et al⁴² studied early granulomatous lesions by immunohistochemistry and in situ hybridization techniques and concluded that major viral envelope glycoproteins (glycoproteins I and II) rather than complete viral particles could be responsible for delayed-type hypersensitivity reactions. All these findings suggest that secondary reactions presenting on HZ scars are mainly the result of atypical immune reactions to local antigenic stimuli.

The pathogenesis of our case is unknown. From a theoretical point of view, it is possible that varicella-zoster virus may induce fibroblastic proliferation and mucin production on HZ scars; however, if HZ is a frequent process and the virus may induce mucin production, then focal dermal mucinosis in an HZ scar should be a common finding. In our patient, there was no associated disease favoring the development of the cutaneous mucinosis. These localized variants of primary cutaneous mucinosis usually do not require therapy, and a wait-and-see approach is recommended. Topical applications of corticosteroids, pimecrolimus, or tacrolimus, as well as oral isotretinoin, may have some benefit,⁴³ but spontaneous resolution may occur.⁴⁴ In our patient, topical corticosteroids were applied 2 months following initial presentation without any benefit and the cutaneous lesions gradually improved without any therapy during the subsequent 6 months. Focal dermal mucinosis should be added to the list of cutaneous reactions that may develop in HZ scars.

Mucin is an amorphous gelatinous substance that is found in a large variety of tissues. There are 2 types of cutaneous mucin: dermal and epithelial. Both types appear as basophilic shreds and granules with hematoxylin and eosin stain.1 Epithelial mucin (sialomucin) is found mainly in the gastrointestinal tract and lungs. In the skin, it is present in the cytoplasm of the dark cells of the eccrine glands and in the apocrine secretory cells. Epithelial mucin contains both neutral and acid glycosaminoglycans, stains positive with Alcian blue (pH 2.5) and periodic acid–Schiff, is resistant to hyaluronidase, and does not stain metachromatically with toluidine blue. Dermal mucin is composed of acid glycosaminoglycans (eg, dermatan sulfate, chondroitin 6-sulfate, chondroitin 4-sulfate, hyaluronic acid) and normally is produced by dermal fibroblasts. Dermal mucin stains positive with Alcian blue (pH 2.5); is periodic acid–Schiff negative and sensitive to hyaluronidase; and shows metachromasia with toluidine blue, methylene blue, and thionine.

Cutaneous mucinosis comprises a heterogeneous group of skin disorders characterized by the deposition of mucin in the interstices of the dermis. These diseases may be classified as primary mucinosis with the mucin deposition as the main histologic feature resulting in clinically distinctive lesions and secondary mucinosis with the mucin deposition as an additional histologic finding within the context of an independent skin disease or lesion (eg, basal cell carcinoma) with deposits of mucin in the stroma. Primary cutaneous mucinosis may be subclassified into 2 groups: degenerative-inflammatory mucinoses and neoplastic-hamartomatous mucinoses. According to the histologic features, the degenerative-inflammatory mucinoses are better divided into dermal and follicular mucinoses.² We describe a case of primary cutaneous dermal mucinosis on herpes zoster (HZ) scars as an isotopic response.

Case Report

A 33-year-old man presented to the dermatology department with slightly pruritic lesions on the left side of the chest and back that had appeared progressively at the site of HZ scars that had healed without treatment 9 months prior. Dermatologic examination revealed sharply defined whitish papules (Figure 1) measuring 2 to 4 mm in diameter with a smooth surface and linear distribution over the area of the left T8 and T9 dermatomes. The patient reported no postherpetic neuralgia and was otherwise healthy. Laboratory tests including a complete blood cell count, biochemistry, urinalysis, and determination of free thyroid hormones were within reference range. Serologic tests for human immunodeficiency virus, hepatitis B and C viruses, and syphilis were negative. Antinuclear antibodies also were negative.

Histopathology demonstrated abundant bluish granular material between collagen bundles of the papillary dermis (Figure 2). No cytopathologic signs of active herpetic infection were seen. The Alcian blue stain at pH 2.5 was strongly positive for mucin, which confirmed the diagnosis of primary cutaneous dermal mucinosis.

Topical corticosteroids were applied for 2 months with no notable improvement. The lesions gradually improved without any other therapy during the subsequent 6 months.

Comment

The occurrence of a new skin disease at the exact site of a prior unrelated cutaneous disorder that had already resolved was first reported by Wyburn-Mason³ in 1955. Forty years later, the term isotopic response was coined by Wolf et al⁴ to describe this phenomenon. Diverse types of skin diseases such as herpes simplex virus,⁵ varicella-zoster infections,⁴ and thrombophlebitis⁴ have been implicated in cases of isotopic response, but the most frequently associated primary disorder by far is cutaneous HZ.

Several benign and malignant disorders may occur at sites of resolved HZ lesions, including granulomatous dermatitis,⁶ granuloma annulare,⁷ fungal granuloma,⁸ fungal folliculitis,⁹ psoriasis,¹⁰ morphea,¹¹ lichen sclerosus,¹² Kaposi sarcoma,¹³ the lichenoid variant of chronic graft-versus-host disease,¹⁴ cutaneous sarcoidosis,¹⁵ granulomatous folliculitis,¹⁶ comedones,¹⁷ furuncles,¹⁸ erythema annulare centrifugum,¹⁹ eosinophilic dermatosis,²⁰ cutaneous pseudolymphoma,²¹ granulomatous vasculitis,²² Rosai-Dorfman disease,¹² xanthomatous changes,²³ tuberculoid granulomas,²⁴ acneform eruption,²⁵ lichen planus,²⁶ acquired reactive perforating collagenosis,²⁷ lymphoma,²⁸ leukemia,²⁹ angiosarcoma,³⁰ basal cell carcinoma,³¹ squamous cell carcinoma, and cutaneous metastasis from internal carcinoma.³² The interval between the acute HZ episode and presentation of the second disease is quite variable, ranging from days to several months. Postzoster isotopic response has been described in individuals with varying degrees of immune response, affecting both immunocompetent¹² and immunocompromised patients.¹⁴ There is no predilection for age, sex, or race. It also seems that antiviral treatment during the active episode does not prevent the development of secondary reactions.Kim et al³³ reported a 59-year-old woman who developed flesh-colored or erythematous papules on HZ scars over the area of the left T1 and T2 dermatomes 1 week after the active viral process. Histopathologic study demonstrated deposition of mucin between collagen bundles in the dermis. The authors established the diagnosis of secondary cutaneous mucinosis as an isotopic response.³³ Nevertheless, we believe that based on the aforementioned classification of cutaneous mucinosis,² both this case and our case are better considered as primary cutaneous dermal mucinosis, as the mucin deposition in the dermis was the main histologic finding resulting in a distinctive cutaneous disorder. In the case reported by Kim et al,³³ a possible relationship between cutaneous mucinosis and postherpetic neuralgia was suggested based on the slow regression of skin lesions in accordance with the improvement of the neuralgic pain; however, our patient did not have postherpetic neuralgia and the lesions persisted unchanged several months after the acute HZ episode. In the literature, there are reports of primary cutaneous dermal mucinosis associated with altered thyroid function³⁴; autoimmune connective tissue diseases, mostly lupus erythematosus³⁵; monoclonal gammopathy³⁶; and human immunodeficiency virus infection,³⁷ but these possibilities were ruled out in our patient by pertinent laboratory studies.

The pathogenesis of the postherpetic isotopic response remains unknown, but several mechanisms have been proposed. Some authors have suggested that postzoster dermatoses may represent isomorphic response of Köbner phenomenon.^13,15 Although isomorphic and isotopic responses share some similarities, these terms describe 2 different phenomena: the first refers to the appearance of the same cutaneous disorder at a different site favored by trauma, while the second manifests a new and unrelated disease at the same location.³⁸ Local anatomic changes such as altered microcirculation, collagen rearrangement, and an imperfect skin barrier may promote a prolonged local inflammatory response. Moreover, the destruction of nerve fibers by the varicella-zoster virus may indirectly influence the local immune system through the release of specific neuropeptides in the skin.³⁹ It has been speculated that some secondary reactions may be the result of type III and type IV hypersensitivity reactions⁴⁰ to viral antigens or to tissue antigens modified by the virus, inducing either immune hypersensitivity or local immune suppression.⁴¹ Some authors have documented the presence of varicella-zoster DNA within early postzoster lesions^6,7 by using polymerase chain reaction in early lesions but not in late-stage and residual lesions.^12,22 Nikkels et al⁴² studied early granulomatous lesions by immunohistochemistry and in situ hybridization techniques and concluded that major viral envelope glycoproteins (glycoproteins I and II) rather than complete viral particles could be responsible for delayed-type hypersensitivity reactions. All these findings suggest that secondary reactions presenting on HZ scars are mainly the result of atypical immune reactions to local antigenic stimuli.

The pathogenesis of our case is unknown. From a theoretical point of view, it is possible that varicella-zoster virus may induce fibroblastic proliferation and mucin production on HZ scars; however, if HZ is a frequent process and the virus may induce mucin production, then focal dermal mucinosis in an HZ scar should be a common finding. In our patient, there was no associated disease favoring the development of the cutaneous mucinosis. These localized variants of primary cutaneous mucinosis usually do not require therapy, and a wait-and-see approach is recommended. Topical applications of corticosteroids, pimecrolimus, or tacrolimus, as well as oral isotretinoin, may have some benefit,⁴³ but spontaneous resolution may occur.⁴⁴ In our patient, topical corticosteroids were applied 2 months following initial presentation without any benefit and the cutaneous lesions gradually improved without any therapy during the subsequent 6 months. Focal dermal mucinosis should be added to the list of cutaneous reactions that may develop in HZ scars.

Mucin is an amorphous gelatinous substance that is found in a large variety of tissues. There are 2 types of cutaneous mucin: dermal and epithelial. Both types appear as basophilic shreds and granules with hematoxylin and eosin stain.1 Epithelial mucin (sialomucin) is found mainly in the gastrointestinal tract and lungs. In the skin, it is present in the cytoplasm of the dark cells of the eccrine glands and in the apocrine secretory cells. Epithelial mucin contains both neutral and acid glycosaminoglycans, stains positive with Alcian blue (pH 2.5) and periodic acid–Schiff, is resistant to hyaluronidase, and does not stain metachromatically with toluidine blue. Dermal mucin is composed of acid glycosaminoglycans (eg, dermatan sulfate, chondroitin 6-sulfate, chondroitin 4-sulfate, hyaluronic acid) and normally is produced by dermal fibroblasts. Dermal mucin stains positive with Alcian blue (pH 2.5); is periodic acid–Schiff negative and sensitive to hyaluronidase; and shows metachromasia with toluidine blue, methylene blue, and thionine.

Cutaneous mucinosis comprises a heterogeneous group of skin disorders characterized by the deposition of mucin in the interstices of the dermis. These diseases may be classified as primary mucinosis with the mucin deposition as the main histologic feature resulting in clinically distinctive lesions and secondary mucinosis with the mucin deposition as an additional histologic finding within the context of an independent skin disease or lesion (eg, basal cell carcinoma) with deposits of mucin in the stroma. Primary cutaneous mucinosis may be subclassified into 2 groups: degenerative-inflammatory mucinoses and neoplastic-hamartomatous mucinoses. According to the histologic features, the degenerative-inflammatory mucinoses are better divided into dermal and follicular mucinoses.² We describe a case of primary cutaneous dermal mucinosis on herpes zoster (HZ) scars as an isotopic response.

Case Report

A 33-year-old man presented to the dermatology department with slightly pruritic lesions on the left side of the chest and back that had appeared progressively at the site of HZ scars that had healed without treatment 9 months prior. Dermatologic examination revealed sharply defined whitish papules (Figure 1) measuring 2 to 4 mm in diameter with a smooth surface and linear distribution over the area of the left T8 and T9 dermatomes. The patient reported no postherpetic neuralgia and was otherwise healthy. Laboratory tests including a complete blood cell count, biochemistry, urinalysis, and determination of free thyroid hormones were within reference range. Serologic tests for human immunodeficiency virus, hepatitis B and C viruses, and syphilis were negative. Antinuclear antibodies also were negative.

Histopathology demonstrated abundant bluish granular material between collagen bundles of the papillary dermis (Figure 2). No cytopathologic signs of active herpetic infection were seen. The Alcian blue stain at pH 2.5 was strongly positive for mucin, which confirmed the diagnosis of primary cutaneous dermal mucinosis.

Topical corticosteroids were applied for 2 months with no notable improvement. The lesions gradually improved without any other therapy during the subsequent 6 months.

Comment

The occurrence of a new skin disease at the exact site of a prior unrelated cutaneous disorder that had already resolved was first reported by Wyburn-Mason³ in 1955. Forty years later, the term isotopic response was coined by Wolf et al⁴ to describe this phenomenon. Diverse types of skin diseases such as herpes simplex virus,⁵ varicella-zoster infections,⁴ and thrombophlebitis⁴ have been implicated in cases of isotopic response, but the most frequently associated primary disorder by far is cutaneous HZ.

Several benign and malignant disorders may occur at sites of resolved HZ lesions, including granulomatous dermatitis,⁶ granuloma annulare,⁷ fungal granuloma,⁸ fungal folliculitis,⁹ psoriasis,¹⁰ morphea,¹¹ lichen sclerosus,¹² Kaposi sarcoma,¹³ the lichenoid variant of chronic graft-versus-host disease,¹⁴ cutaneous sarcoidosis,¹⁵ granulomatous folliculitis,¹⁶ comedones,¹⁷ furuncles,¹⁸ erythema annulare centrifugum,¹⁹ eosinophilic dermatosis,²⁰ cutaneous pseudolymphoma,²¹ granulomatous vasculitis,²² Rosai-Dorfman disease,¹² xanthomatous changes,²³ tuberculoid granulomas,²⁴ acneform eruption,²⁵ lichen planus,²⁶ acquired reactive perforating collagenosis,²⁷ lymphoma,²⁸ leukemia,²⁹ angiosarcoma,³⁰ basal cell carcinoma,³¹ squamous cell carcinoma, and cutaneous metastasis from internal carcinoma.³² The interval between the acute HZ episode and presentation of the second disease is quite variable, ranging from days to several months. Postzoster isotopic response has been described in individuals with varying degrees of immune response, affecting both immunocompetent¹² and immunocompromised patients.¹⁴ There is no predilection for age, sex, or race. It also seems that antiviral treatment during the active episode does not prevent the development of secondary reactions.Kim et al³³ reported a 59-year-old woman who developed flesh-colored or erythematous papules on HZ scars over the area of the left T1 and T2 dermatomes 1 week after the active viral process. Histopathologic study demonstrated deposition of mucin between collagen bundles in the dermis. The authors established the diagnosis of secondary cutaneous mucinosis as an isotopic response.³³ Nevertheless, we believe that based on the aforementioned classification of cutaneous mucinosis,² both this case and our case are better considered as primary cutaneous dermal mucinosis, as the mucin deposition in the dermis was the main histologic finding resulting in a distinctive cutaneous disorder. In the case reported by Kim et al,³³ a possible relationship between cutaneous mucinosis and postherpetic neuralgia was suggested based on the slow regression of skin lesions in accordance with the improvement of the neuralgic pain; however, our patient did not have postherpetic neuralgia and the lesions persisted unchanged several months after the acute HZ episode. In the literature, there are reports of primary cutaneous dermal mucinosis associated with altered thyroid function³⁴; autoimmune connective tissue diseases, mostly lupus erythematosus³⁵; monoclonal gammopathy³⁶; and human immunodeficiency virus infection,³⁷ but these possibilities were ruled out in our patient by pertinent laboratory studies.

The pathogenesis of the postherpetic isotopic response remains unknown, but several mechanisms have been proposed. Some authors have suggested that postzoster dermatoses may represent isomorphic response of Köbner phenomenon.^13,15 Although isomorphic and isotopic responses share some similarities, these terms describe 2 different phenomena: the first refers to the appearance of the same cutaneous disorder at a different site favored by trauma, while the second manifests a new and unrelated disease at the same location.³⁸ Local anatomic changes such as altered microcirculation, collagen rearrangement, and an imperfect skin barrier may promote a prolonged local inflammatory response. Moreover, the destruction of nerve fibers by the varicella-zoster virus may indirectly influence the local immune system through the release of specific neuropeptides in the skin.³⁹ It has been speculated that some secondary reactions may be the result of type III and type IV hypersensitivity reactions⁴⁰ to viral antigens or to tissue antigens modified by the virus, inducing either immune hypersensitivity or local immune suppression.⁴¹ Some authors have documented the presence of varicella-zoster DNA within early postzoster lesions^6,7 by using polymerase chain reaction in early lesions but not in late-stage and residual lesions.^12,22 Nikkels et al⁴² studied early granulomatous lesions by immunohistochemistry and in situ hybridization techniques and concluded that major viral envelope glycoproteins (glycoproteins I and II) rather than complete viral particles could be responsible for delayed-type hypersensitivity reactions. All these findings suggest that secondary reactions presenting on HZ scars are mainly the result of atypical immune reactions to local antigenic stimuli.

The pathogenesis of our case is unknown. From a theoretical point of view, it is possible that varicella-zoster virus may induce fibroblastic proliferation and mucin production on HZ scars; however, if HZ is a frequent process and the virus may induce mucin production, then focal dermal mucinosis in an HZ scar should be a common finding. In our patient, there was no associated disease favoring the development of the cutaneous mucinosis. These localized variants of primary cutaneous mucinosis usually do not require therapy, and a wait-and-see approach is recommended. Topical applications of corticosteroids, pimecrolimus, or tacrolimus, as well as oral isotretinoin, may have some benefit,⁴³ but spontaneous resolution may occur.⁴⁴ In our patient, topical corticosteroids were applied 2 months following initial presentation without any benefit and the cutaneous lesions gradually improved without any therapy during the subsequent 6 months. Focal dermal mucinosis should be added to the list of cutaneous reactions that may develop in HZ scars.