Dermatopathology

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various medical conditions, including parasitic infections, nephrotic syndrome, and colorectal cancer,¹ before being withdrawn from the US market in 2000.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.

The Diagnosis: Irritated Seborrheic Keratosis

Biopsies of one of the protruding papules and the underlying plaque were performed. The specimen from the papule showed hyperkeratosis, acanthosis, papillomatosis, and a flattened dermoepidermal junction with demarcated horizontal margin, which demonstrated apparent upward growth of the epidermis. Moderate lymphocytic infiltration in the upper dermis also was observed (Figure, A). The histologic findings of the plaque showed acanthosis, several pseudohorn cysts, hyperpigmentation of the basal layer, and a horizontal demarcation of the dermoepidermal junction (Figure, B).

Seborrheic keratosis is the most common benign epidermal tumor of the skin with variable appearance.¹ It usually begins with well-circumscribed, dull, flat, tan or brown patches that then grow into waxy verrucous papules.¹ There are many clinicopathologic variants of SK such as common SK, stucco keratosis, and dermatosis papulosa nigra in clinical variation, as well as acanthotic, hyperkeratotic, clonal, reticulated, irritated, and melanoacanthoma subtypes based on histological variation.^2,3

Seborrheic keratosis is a tumor of keratinocytic origin. Although genetics, sun exposure,⁴ and human papillomavirus infection⁵ are thought to be causative factors, the precise etiology of SK is unknown.¹

The histology of SK shows monotonous basaloid tumor cells without atypia. It generally is comprised of focal acanthosis and papillomatosis with a sharp flat base. Intraepithelial horn pseudocysts are notable features of SK and increased melanin often is seen.^2,6

Irritated SK is a histologic variant of SK that has been mechanically or chemically irritated or is involved in immunologic responses. Histologically, the dermis underlying an SK lesion filled with a dense lymphocytic infiltration is characteristic.^1,2

For symptomatic or cosmetically undesirable lesions, complete removal of the lesion is the preferred treatment. Cryotherapy, electrodesiccation followed by curettage, curettage followed by desiccation, laser ablation, and surgical excision are effective treatments.¹

The Diagnosis: Irritated Seborrheic Keratosis

Biopsies of one of the protruding papules and the underlying plaque were performed. The specimen from the papule showed hyperkeratosis, acanthosis, papillomatosis, and a flattened dermoepidermal junction with demarcated horizontal margin, which demonstrated apparent upward growth of the epidermis. Moderate lymphocytic infiltration in the upper dermis also was observed (Figure, A). The histologic findings of the plaque showed acanthosis, several pseudohorn cysts, hyperpigmentation of the basal layer, and a horizontal demarcation of the dermoepidermal junction (Figure, B).

Seborrheic keratosis is the most common benign epidermal tumor of the skin with variable appearance.¹ It usually begins with well-circumscribed, dull, flat, tan or brown patches that then grow into waxy verrucous papules.¹ There are many clinicopathologic variants of SK such as common SK, stucco keratosis, and dermatosis papulosa nigra in clinical variation, as well as acanthotic, hyperkeratotic, clonal, reticulated, irritated, and melanoacanthoma subtypes based on histological variation.^2,3

Seborrheic keratosis is a tumor of keratinocytic origin. Although genetics, sun exposure,⁴ and human papillomavirus infection⁵ are thought to be causative factors, the precise etiology of SK is unknown.¹

The histology of SK shows monotonous basaloid tumor cells without atypia. It generally is comprised of focal acanthosis and papillomatosis with a sharp flat base. Intraepithelial horn pseudocysts are notable features of SK and increased melanin often is seen.^2,6

Irritated SK is a histologic variant of SK that has been mechanically or chemically irritated or is involved in immunologic responses. Histologically, the dermis underlying an SK lesion filled with a dense lymphocytic infiltration is characteristic.^1,2

For symptomatic or cosmetically undesirable lesions, complete removal of the lesion is the preferred treatment. Cryotherapy, electrodesiccation followed by curettage, curettage followed by desiccation, laser ablation, and surgical excision are effective treatments.¹

The Diagnosis: Irritated Seborrheic Keratosis

Biopsies of one of the protruding papules and the underlying plaque were performed. The specimen from the papule showed hyperkeratosis, acanthosis, papillomatosis, and a flattened dermoepidermal junction with demarcated horizontal margin, which demonstrated apparent upward growth of the epidermis. Moderate lymphocytic infiltration in the upper dermis also was observed (Figure, A). The histologic findings of the plaque showed acanthosis, several pseudohorn cysts, hyperpigmentation of the basal layer, and a horizontal demarcation of the dermoepidermal junction (Figure, B).

Seborrheic keratosis is the most common benign epidermal tumor of the skin with variable appearance.¹ It usually begins with well-circumscribed, dull, flat, tan or brown patches that then grow into waxy verrucous papules.¹ There are many clinicopathologic variants of SK such as common SK, stucco keratosis, and dermatosis papulosa nigra in clinical variation, as well as acanthotic, hyperkeratotic, clonal, reticulated, irritated, and melanoacanthoma subtypes based on histological variation.^2,3

Seborrheic keratosis is a tumor of keratinocytic origin. Although genetics, sun exposure,⁴ and human papillomavirus infection⁵ are thought to be causative factors, the precise etiology of SK is unknown.¹

The histology of SK shows monotonous basaloid tumor cells without atypia. It generally is comprised of focal acanthosis and papillomatosis with a sharp flat base. Intraepithelial horn pseudocysts are notable features of SK and increased melanin often is seen.^2,6

Irritated SK is a histologic variant of SK that has been mechanically or chemically irritated or is involved in immunologic responses. Histologically, the dermis underlying an SK lesion filled with a dense lymphocytic infiltration is characteristic.^1,2

For symptomatic or cosmetically undesirable lesions, complete removal of the lesion is the preferred treatment. Cryotherapy, electrodesiccation followed by curettage, curettage followed by desiccation, laser ablation, and surgical excision are effective treatments.¹

Case Report

A 25-year-old woman with a 5-month history of severe lichen planus (LP) on the arms, legs, and trunk presented to the emergency department with generalized blisters and erythema over the entire body, including the face and soles, of 2 days’ duration. She was evaluated for the LP 1 week prior in a referral dermatology clinic, and in addition to topical corticosteroids, she received 1 injection of 40 mg intramuscular triamcinolone acetonide. Hours following the injection she developed nausea, vomiting, and fever. The patient reported that her last menstrual period was 3 weeks prior to the current presentation.

Physical examination revealed numerous lichenified, flat-topped, pink-violaceous, hyperpigmented, scaly papules and plaques (Figure 1), as well as tense, yellow, fluid-filled vesicles and bullae of various sizes on the neck, arms (Figure 2), legs, trunk, and dorsal aspect of the feet. The vesicles occurred on both normal skin and the lichenified plaques with a negative Nikolsky sign. There also were urticarial erythematous papules and plaques on the arms, trunk, neck, and face, some of which had vesicles or a violaceous dusky central hue (Figure 3). Vesicles were noted within both nostrils (nasal mucosa), and there were extremely tender erythematous patches and thick sheets of scales on the soles.

An elevated β human chorionic gonadotropin level and transvaginal ultrasonography confirmed an intrauterine pregnancy of 12 weeks’ gestation despite the patient’s report of the last menstrual period.

Histologic examination of a vesicle on the right arm revealed hyperkeratosis with hypergranulosis, vacuolar alteration of the basal layer with a paucicellular subepidermal vesicle, and melanophages in the superficial dermis consistent with vesicular LP (Figure 4). Histologic examination of an erythematous edematous plaque on the right upper leg revealed edema in the upper dermis with a perivascular and interstitial lymphocytic infiltrate with eosinophils. A third biopsy of a lichenoid flat-topped papule on the left arm revealed a mild bandlike infiltrate of lymphocytes and scattered eosinophils, eosinophilic colloid bodies and edema in the papillary dermis, and subepidermal vesicles and vacuolar alteration of the basal layer consistent with a vesicular lichenoid dermatitis (Figure 5). Direct immunofluorescence (DIF) of perilesional skin showed linear deposition of C3 and IgM along the basement membrane zone (BMZ) in addition to a shaggy pattern with cytoid bodies (Figure 6). There also was a faint linear deposit of IgA along the BMZ with cytoid bodies but negative for IgG. These results were interpreted as consistent with LP pemphigoides (LPP). Neither an enzyme-linked immunosorbent assay nor an immunoblot analysis was performed.

Because the patient was pregnant and had failed to respond to topical and intramuscular corticosteroids, she was started on intravenous methylprednisolone in the emergency department until new lesions stopped appearing. She was then discharged home on oral prednisone 50 mg (0.5 mg/kg/d), with close observation by her obstetrician. She also used clobetasol propionate ointment 0.05% for more severe lesions and triamcinolone acetonide cream 0.1% for less severe lesions until lesions resolved.

During treatment, the patient developed cellulitis on the leg that presented as pustules and erythema at a site of an eroded bulla, inframammary and axillary cutaneous candidiasis, and hyperglycemia at 19 weeks’ gestation. The cutaneous infections resolved with oral clindamycin 300 mg 3 times daily for 10 days. Topical mupirocin was used to treat the cellulitis and a mixture of zinc oxide, econazole cream, and desonide cream twice daily treated the candidiasis. Her obstetrician managed the hyperglycemia.

The bullous lesions and LP completely resolved after 2 months of treatment with oral prednisone 50 mg daily. The patient tolerated a corticosteroid taper (dose decreased by 5 mg every 2 weeks) until arriving at 10 mg, which was then decreased to 7.5 mg until delivery. A cesarean delivery was performed due to a large-for-gestational-age fetus, and an internist was consulted for the necessary precautions to increase the steroid dose during delivery due to the stress of the surgery and the risk for a hypothalamic crisis. There were no peripartum complications, and the baby was born without cutaneous lesions and remains healthy 1 year later. The patient remained disease free over 2 months postpartum, until new LP lesions developed without vesicles or bullae, which were then controlled with topical therapy. She was subsequently lost to follow-up.

Comment

Kaposi first described LPP in 1892 and used the term lichen ruber pemphigoides to describe a case of typical LP together with a widespread bullous eruption. Lichen planus pemphigoides is characterized by tense blisters that arise on lesions of LP as well as on skin unaffected by LP. In contrast, bullous LP blisters are confined to LP lesions only and occur from intense lichenoid inflammation and extensive liquefactive degeneration of basal keratinocytes. The vesicle formation in LPP is a result of autoantibodies to the bullous pemphigoid (BP) antigen BPAg2, which can be explained by the epitope spreading epiphenomenon whereby epidermotropic cytotoxic T cells damage the basal keratinocytes in LP by targeting unknown epidermal antigens, resulting in the exposure of BP180 and therefore instigating the autoimmune response.¹ The process of epitope spreading takes months to develop; the mean duration of LP before LPP is 8 weeks in children and 12 weeks in adults,² which is comparable to the current case.

Pathogenesis

Lichen planus pemphigoides usually is idiopathic; however, there have been cases reported in association with various medications including calcium channel blockers such as diltiazem, Chinese herbs,³ simvastatin,⁴ ramipril,^5,6 captopril,⁷ psoralen plus UVA phototherapy,⁸ and cinnarizine.⁹ In addition, in a case-controlled study, the use of neuroleptics or diuretics was found to be a risk factor for LPP development.¹⁰

This case is unique because it shows an association of LPP with an intrauterine pregnancy. Despite the fact that we did not perform the required studies to determine the exact cause, there probably exists an association between LPP and the pregnancy, as the patient presented with a 5-month history of severe LP prior to vesicle formation. The patient only developed the vesicular lesions during pregnancy, which were later controlled with systemic steroids and then recurred postpartum only as LP lesions, suggesting that the patient’s pregnancy may have contributed in the pathogenesis as an inducing factor. We suspect that the LP was aggravated by the pregnancy and continued to worsen, so much as to cause epitope spreading and lead to the bullous eruption at the end of the first trimester.²

Differential Diagnosis

Initially, we suspected a diagnosis of pemphigoid gestationis (PG), previously known as herpes gestationis. The classic presentation of PG starts with an intense pruritus followed by the emergence of pruritic urticarial papules and plaques in the umbilical or periumbilical areas. The lesions may become targetlike or polycyclic and may spread to other areas of the trunk, arms, and legs, often including the palms and soles.^11-15 Just as in our case, vesicles and bullous lesions appear at both the site of the urticarial plaques as well as on normal skin.16 The clinical features noted in our patient that were not typical of PG included the multiple lesions on the face and inside the nostrils. Only 20% of PG cases are associated with mucosal involvement,^11,12,15 and there are no documented reports of PG occurring in a patient with LP, according to a PubMed search of articles indexed for MEDLINE using the search terms pemphigoid gestationis, herpes gestationis, and lichen planus.

Lichen planus pemphigoides can be easily differentiated from BP. Lichen planus pemphigoides occurs in younger patients, with a mean age of 35 years, unlike BP, which commonly affects elderly men.¹⁷ Lichen planus pemphigoides also is less severe and has a better response to treatment than BP. It also affects the palms and soles, which are rarely affected in BP. There are no reports in the literature of BP developing during pregnancy, according to a PubMed search using the terms bullous pemphigoid and pregnancy. However, LPP and BP share a common antibody, the BP180 antigen, and differences exist in the epitope where the antibody binds in each condition.^18,19

Diagnosing LPP

In LPP, DIF typically shows linear deposits of IgG, IgM, IgA, fibrinogen, and C3 along the BMZ, of which IgG and C3 are most commonly seen.³ Our patient had linear deposition of C3, IgM, and IgA along the BMZ, which excluded bullous LP from the differential diagnosis. Bullous LP is not an autoimmune condition but rather is on the severe spectrum of LP where Max Joseph spaces become so large so as to lead to vesicle and bullae formation. In addition to the linear deposit at the BMZ, LPP typically reveals immunoglobulin (mainly IgM but also IgA), C3, and fibrinogen staining of colloid bodies in the papillary dermis on DIF; however, some cases of LPP only present with a linear deposition of C3 along the BMZ, which is why, similar to PG, these diagnoses by DIF are similar. Direct immunofluorescence of PG reveals linear IgG1 and IgG3 along the BMZ. IgG1 and IgG3 immunoglobulins are known to fix complement better than other immunoglobulins, thus linear C3 along the BMZ is the most consistently positive immunoreactant. Less common positive immunoreactivity with the same pattern has been seen with IgA, IgM, C1, and C4 (Table).^14,15,18 The lack of linear IgG and the presence of IgM is more suggestive of LPP.

The differential diagnosis of the subepidermal autoimmune blistering diseases associated with antibodies against BP180, including BP, LPP, and PG, often is challenging.¹⁵ However, LPP can now be distinguished by immunological studies including immunoblot analysis of the immunodominant region of NC16A of the BP180 antigen and the immunoglobulin subclass that reacts to 180-, 200-,²⁰ and 230-kDa antigens within the BMZ (Table).^15,18-20 The Table summarizes the different autoantibodies, antigens, and epitopes to distinguish subepidermal autoimmune blistering diseases.

Despite not performing these studies in our patient, we concluded that the clinical, histological, and DIF findings of this case are more consistent with LPP than with the other subepidermal blistering diseases. However, we cannot exclude the possibility of the patient having a new entity with a unique antibody from epitope spreading.

Conclusion

We present a case of lichenoid papules and plaques consistent with LP, with the development of vesicles and bullae after the first trimester of pregnancy. The clinical, pathologic, and DIF findings were highly suggestive of LPP. Although the exact pathogenic mechanism is not fully known, we suspect that pregnancy may have contributed to the origin of the disease. Further evaluation of pregnant patients with lichenoid lesions who develop blisters are needed for the elucidation of the mechanism, which may be secondary to epitope spreading that led to new autoantibody formation.

Case Report

A 25-year-old woman with a 5-month history of severe lichen planus (LP) on the arms, legs, and trunk presented to the emergency department with generalized blisters and erythema over the entire body, including the face and soles, of 2 days’ duration. She was evaluated for the LP 1 week prior in a referral dermatology clinic, and in addition to topical corticosteroids, she received 1 injection of 40 mg intramuscular triamcinolone acetonide. Hours following the injection she developed nausea, vomiting, and fever. The patient reported that her last menstrual period was 3 weeks prior to the current presentation.

Physical examination revealed numerous lichenified, flat-topped, pink-violaceous, hyperpigmented, scaly papules and plaques (Figure 1), as well as tense, yellow, fluid-filled vesicles and bullae of various sizes on the neck, arms (Figure 2), legs, trunk, and dorsal aspect of the feet. The vesicles occurred on both normal skin and the lichenified plaques with a negative Nikolsky sign. There also were urticarial erythematous papules and plaques on the arms, trunk, neck, and face, some of which had vesicles or a violaceous dusky central hue (Figure 3). Vesicles were noted within both nostrils (nasal mucosa), and there were extremely tender erythematous patches and thick sheets of scales on the soles.

An elevated β human chorionic gonadotropin level and transvaginal ultrasonography confirmed an intrauterine pregnancy of 12 weeks’ gestation despite the patient’s report of the last menstrual period.

Histologic examination of a vesicle on the right arm revealed hyperkeratosis with hypergranulosis, vacuolar alteration of the basal layer with a paucicellular subepidermal vesicle, and melanophages in the superficial dermis consistent with vesicular LP (Figure 4). Histologic examination of an erythematous edematous plaque on the right upper leg revealed edema in the upper dermis with a perivascular and interstitial lymphocytic infiltrate with eosinophils. A third biopsy of a lichenoid flat-topped papule on the left arm revealed a mild bandlike infiltrate of lymphocytes and scattered eosinophils, eosinophilic colloid bodies and edema in the papillary dermis, and subepidermal vesicles and vacuolar alteration of the basal layer consistent with a vesicular lichenoid dermatitis (Figure 5). Direct immunofluorescence (DIF) of perilesional skin showed linear deposition of C3 and IgM along the basement membrane zone (BMZ) in addition to a shaggy pattern with cytoid bodies (Figure 6). There also was a faint linear deposit of IgA along the BMZ with cytoid bodies but negative for IgG. These results were interpreted as consistent with LP pemphigoides (LPP). Neither an enzyme-linked immunosorbent assay nor an immunoblot analysis was performed.

Because the patient was pregnant and had failed to respond to topical and intramuscular corticosteroids, she was started on intravenous methylprednisolone in the emergency department until new lesions stopped appearing. She was then discharged home on oral prednisone 50 mg (0.5 mg/kg/d), with close observation by her obstetrician. She also used clobetasol propionate ointment 0.05% for more severe lesions and triamcinolone acetonide cream 0.1% for less severe lesions until lesions resolved.

During treatment, the patient developed cellulitis on the leg that presented as pustules and erythema at a site of an eroded bulla, inframammary and axillary cutaneous candidiasis, and hyperglycemia at 19 weeks’ gestation. The cutaneous infections resolved with oral clindamycin 300 mg 3 times daily for 10 days. Topical mupirocin was used to treat the cellulitis and a mixture of zinc oxide, econazole cream, and desonide cream twice daily treated the candidiasis. Her obstetrician managed the hyperglycemia.

The bullous lesions and LP completely resolved after 2 months of treatment with oral prednisone 50 mg daily. The patient tolerated a corticosteroid taper (dose decreased by 5 mg every 2 weeks) until arriving at 10 mg, which was then decreased to 7.5 mg until delivery. A cesarean delivery was performed due to a large-for-gestational-age fetus, and an internist was consulted for the necessary precautions to increase the steroid dose during delivery due to the stress of the surgery and the risk for a hypothalamic crisis. There were no peripartum complications, and the baby was born without cutaneous lesions and remains healthy 1 year later. The patient remained disease free over 2 months postpartum, until new LP lesions developed without vesicles or bullae, which were then controlled with topical therapy. She was subsequently lost to follow-up.

Comment

Kaposi first described LPP in 1892 and used the term lichen ruber pemphigoides to describe a case of typical LP together with a widespread bullous eruption. Lichen planus pemphigoides is characterized by tense blisters that arise on lesions of LP as well as on skin unaffected by LP. In contrast, bullous LP blisters are confined to LP lesions only and occur from intense lichenoid inflammation and extensive liquefactive degeneration of basal keratinocytes. The vesicle formation in LPP is a result of autoantibodies to the bullous pemphigoid (BP) antigen BPAg2, which can be explained by the epitope spreading epiphenomenon whereby epidermotropic cytotoxic T cells damage the basal keratinocytes in LP by targeting unknown epidermal antigens, resulting in the exposure of BP180 and therefore instigating the autoimmune response.¹ The process of epitope spreading takes months to develop; the mean duration of LP before LPP is 8 weeks in children and 12 weeks in adults,² which is comparable to the current case.

Pathogenesis

Lichen planus pemphigoides usually is idiopathic; however, there have been cases reported in association with various medications including calcium channel blockers such as diltiazem, Chinese herbs,³ simvastatin,⁴ ramipril,^5,6 captopril,⁷ psoralen plus UVA phototherapy,⁸ and cinnarizine.⁹ In addition, in a case-controlled study, the use of neuroleptics or diuretics was found to be a risk factor for LPP development.¹⁰

This case is unique because it shows an association of LPP with an intrauterine pregnancy. Despite the fact that we did not perform the required studies to determine the exact cause, there probably exists an association between LPP and the pregnancy, as the patient presented with a 5-month history of severe LP prior to vesicle formation. The patient only developed the vesicular lesions during pregnancy, which were later controlled with systemic steroids and then recurred postpartum only as LP lesions, suggesting that the patient’s pregnancy may have contributed in the pathogenesis as an inducing factor. We suspect that the LP was aggravated by the pregnancy and continued to worsen, so much as to cause epitope spreading and lead to the bullous eruption at the end of the first trimester.²

Differential Diagnosis

Initially, we suspected a diagnosis of pemphigoid gestationis (PG), previously known as herpes gestationis. The classic presentation of PG starts with an intense pruritus followed by the emergence of pruritic urticarial papules and plaques in the umbilical or periumbilical areas. The lesions may become targetlike or polycyclic and may spread to other areas of the trunk, arms, and legs, often including the palms and soles.^11-15 Just as in our case, vesicles and bullous lesions appear at both the site of the urticarial plaques as well as on normal skin.16 The clinical features noted in our patient that were not typical of PG included the multiple lesions on the face and inside the nostrils. Only 20% of PG cases are associated with mucosal involvement,^11,12,15 and there are no documented reports of PG occurring in a patient with LP, according to a PubMed search of articles indexed for MEDLINE using the search terms pemphigoid gestationis, herpes gestationis, and lichen planus.

Lichen planus pemphigoides can be easily differentiated from BP. Lichen planus pemphigoides occurs in younger patients, with a mean age of 35 years, unlike BP, which commonly affects elderly men.¹⁷ Lichen planus pemphigoides also is less severe and has a better response to treatment than BP. It also affects the palms and soles, which are rarely affected in BP. There are no reports in the literature of BP developing during pregnancy, according to a PubMed search using the terms bullous pemphigoid and pregnancy. However, LPP and BP share a common antibody, the BP180 antigen, and differences exist in the epitope where the antibody binds in each condition.^18,19

Diagnosing LPP

In LPP, DIF typically shows linear deposits of IgG, IgM, IgA, fibrinogen, and C3 along the BMZ, of which IgG and C3 are most commonly seen.³ Our patient had linear deposition of C3, IgM, and IgA along the BMZ, which excluded bullous LP from the differential diagnosis. Bullous LP is not an autoimmune condition but rather is on the severe spectrum of LP where Max Joseph spaces become so large so as to lead to vesicle and bullae formation. In addition to the linear deposit at the BMZ, LPP typically reveals immunoglobulin (mainly IgM but also IgA), C3, and fibrinogen staining of colloid bodies in the papillary dermis on DIF; however, some cases of LPP only present with a linear deposition of C3 along the BMZ, which is why, similar to PG, these diagnoses by DIF are similar. Direct immunofluorescence of PG reveals linear IgG1 and IgG3 along the BMZ. IgG1 and IgG3 immunoglobulins are known to fix complement better than other immunoglobulins, thus linear C3 along the BMZ is the most consistently positive immunoreactant. Less common positive immunoreactivity with the same pattern has been seen with IgA, IgM, C1, and C4 (Table).^14,15,18 The lack of linear IgG and the presence of IgM is more suggestive of LPP.

The differential diagnosis of the subepidermal autoimmune blistering diseases associated with antibodies against BP180, including BP, LPP, and PG, often is challenging.¹⁵ However, LPP can now be distinguished by immunological studies including immunoblot analysis of the immunodominant region of NC16A of the BP180 antigen and the immunoglobulin subclass that reacts to 180-, 200-,²⁰ and 230-kDa antigens within the BMZ (Table).^15,18-20 The Table summarizes the different autoantibodies, antigens, and epitopes to distinguish subepidermal autoimmune blistering diseases.

Despite not performing these studies in our patient, we concluded that the clinical, histological, and DIF findings of this case are more consistent with LPP than with the other subepidermal blistering diseases. However, we cannot exclude the possibility of the patient having a new entity with a unique antibody from epitope spreading.

Conclusion

We present a case of lichenoid papules and plaques consistent with LP, with the development of vesicles and bullae after the first trimester of pregnancy. The clinical, pathologic, and DIF findings were highly suggestive of LPP. Although the exact pathogenic mechanism is not fully known, we suspect that pregnancy may have contributed to the origin of the disease. Further evaluation of pregnant patients with lichenoid lesions who develop blisters are needed for the elucidation of the mechanism, which may be secondary to epitope spreading that led to new autoantibody formation.

Case Report

A 25-year-old woman with a 5-month history of severe lichen planus (LP) on the arms, legs, and trunk presented to the emergency department with generalized blisters and erythema over the entire body, including the face and soles, of 2 days’ duration. She was evaluated for the LP 1 week prior in a referral dermatology clinic, and in addition to topical corticosteroids, she received 1 injection of 40 mg intramuscular triamcinolone acetonide. Hours following the injection she developed nausea, vomiting, and fever. The patient reported that her last menstrual period was 3 weeks prior to the current presentation.

Physical examination revealed numerous lichenified, flat-topped, pink-violaceous, hyperpigmented, scaly papules and plaques (Figure 1), as well as tense, yellow, fluid-filled vesicles and bullae of various sizes on the neck, arms (Figure 2), legs, trunk, and dorsal aspect of the feet. The vesicles occurred on both normal skin and the lichenified plaques with a negative Nikolsky sign. There also were urticarial erythematous papules and plaques on the arms, trunk, neck, and face, some of which had vesicles or a violaceous dusky central hue (Figure 3). Vesicles were noted within both nostrils (nasal mucosa), and there were extremely tender erythematous patches and thick sheets of scales on the soles.

An elevated β human chorionic gonadotropin level and transvaginal ultrasonography confirmed an intrauterine pregnancy of 12 weeks’ gestation despite the patient’s report of the last menstrual period.

Histologic examination of a vesicle on the right arm revealed hyperkeratosis with hypergranulosis, vacuolar alteration of the basal layer with a paucicellular subepidermal vesicle, and melanophages in the superficial dermis consistent with vesicular LP (Figure 4). Histologic examination of an erythematous edematous plaque on the right upper leg revealed edema in the upper dermis with a perivascular and interstitial lymphocytic infiltrate with eosinophils. A third biopsy of a lichenoid flat-topped papule on the left arm revealed a mild bandlike infiltrate of lymphocytes and scattered eosinophils, eosinophilic colloid bodies and edema in the papillary dermis, and subepidermal vesicles and vacuolar alteration of the basal layer consistent with a vesicular lichenoid dermatitis (Figure 5). Direct immunofluorescence (DIF) of perilesional skin showed linear deposition of C3 and IgM along the basement membrane zone (BMZ) in addition to a shaggy pattern with cytoid bodies (Figure 6). There also was a faint linear deposit of IgA along the BMZ with cytoid bodies but negative for IgG. These results were interpreted as consistent with LP pemphigoides (LPP). Neither an enzyme-linked immunosorbent assay nor an immunoblot analysis was performed.

Because the patient was pregnant and had failed to respond to topical and intramuscular corticosteroids, she was started on intravenous methylprednisolone in the emergency department until new lesions stopped appearing. She was then discharged home on oral prednisone 50 mg (0.5 mg/kg/d), with close observation by her obstetrician. She also used clobetasol propionate ointment 0.05% for more severe lesions and triamcinolone acetonide cream 0.1% for less severe lesions until lesions resolved.

During treatment, the patient developed cellulitis on the leg that presented as pustules and erythema at a site of an eroded bulla, inframammary and axillary cutaneous candidiasis, and hyperglycemia at 19 weeks’ gestation. The cutaneous infections resolved with oral clindamycin 300 mg 3 times daily for 10 days. Topical mupirocin was used to treat the cellulitis and a mixture of zinc oxide, econazole cream, and desonide cream twice daily treated the candidiasis. Her obstetrician managed the hyperglycemia.

The bullous lesions and LP completely resolved after 2 months of treatment with oral prednisone 50 mg daily. The patient tolerated a corticosteroid taper (dose decreased by 5 mg every 2 weeks) until arriving at 10 mg, which was then decreased to 7.5 mg until delivery. A cesarean delivery was performed due to a large-for-gestational-age fetus, and an internist was consulted for the necessary precautions to increase the steroid dose during delivery due to the stress of the surgery and the risk for a hypothalamic crisis. There were no peripartum complications, and the baby was born without cutaneous lesions and remains healthy 1 year later. The patient remained disease free over 2 months postpartum, until new LP lesions developed without vesicles or bullae, which were then controlled with topical therapy. She was subsequently lost to follow-up.

Comment

Kaposi first described LPP in 1892 and used the term lichen ruber pemphigoides to describe a case of typical LP together with a widespread bullous eruption. Lichen planus pemphigoides is characterized by tense blisters that arise on lesions of LP as well as on skin unaffected by LP. In contrast, bullous LP blisters are confined to LP lesions only and occur from intense lichenoid inflammation and extensive liquefactive degeneration of basal keratinocytes. The vesicle formation in LPP is a result of autoantibodies to the bullous pemphigoid (BP) antigen BPAg2, which can be explained by the epitope spreading epiphenomenon whereby epidermotropic cytotoxic T cells damage the basal keratinocytes in LP by targeting unknown epidermal antigens, resulting in the exposure of BP180 and therefore instigating the autoimmune response.¹ The process of epitope spreading takes months to develop; the mean duration of LP before LPP is 8 weeks in children and 12 weeks in adults,² which is comparable to the current case.

Pathogenesis

Lichen planus pemphigoides usually is idiopathic; however, there have been cases reported in association with various medications including calcium channel blockers such as diltiazem, Chinese herbs,³ simvastatin,⁴ ramipril,^5,6 captopril,⁷ psoralen plus UVA phototherapy,⁸ and cinnarizine.⁹ In addition, in a case-controlled study, the use of neuroleptics or diuretics was found to be a risk factor for LPP development.¹⁰

This case is unique because it shows an association of LPP with an intrauterine pregnancy. Despite the fact that we did not perform the required studies to determine the exact cause, there probably exists an association between LPP and the pregnancy, as the patient presented with a 5-month history of severe LP prior to vesicle formation. The patient only developed the vesicular lesions during pregnancy, which were later controlled with systemic steroids and then recurred postpartum only as LP lesions, suggesting that the patient’s pregnancy may have contributed in the pathogenesis as an inducing factor. We suspect that the LP was aggravated by the pregnancy and continued to worsen, so much as to cause epitope spreading and lead to the bullous eruption at the end of the first trimester.²

Differential Diagnosis

Initially, we suspected a diagnosis of pemphigoid gestationis (PG), previously known as herpes gestationis. The classic presentation of PG starts with an intense pruritus followed by the emergence of pruritic urticarial papules and plaques in the umbilical or periumbilical areas. The lesions may become targetlike or polycyclic and may spread to other areas of the trunk, arms, and legs, often including the palms and soles.^11-15 Just as in our case, vesicles and bullous lesions appear at both the site of the urticarial plaques as well as on normal skin.16 The clinical features noted in our patient that were not typical of PG included the multiple lesions on the face and inside the nostrils. Only 20% of PG cases are associated with mucosal involvement,^11,12,15 and there are no documented reports of PG occurring in a patient with LP, according to a PubMed search of articles indexed for MEDLINE using the search terms pemphigoid gestationis, herpes gestationis, and lichen planus.

Lichen planus pemphigoides can be easily differentiated from BP. Lichen planus pemphigoides occurs in younger patients, with a mean age of 35 years, unlike BP, which commonly affects elderly men.¹⁷ Lichen planus pemphigoides also is less severe and has a better response to treatment than BP. It also affects the palms and soles, which are rarely affected in BP. There are no reports in the literature of BP developing during pregnancy, according to a PubMed search using the terms bullous pemphigoid and pregnancy. However, LPP and BP share a common antibody, the BP180 antigen, and differences exist in the epitope where the antibody binds in each condition.^18,19

Diagnosing LPP

In LPP, DIF typically shows linear deposits of IgG, IgM, IgA, fibrinogen, and C3 along the BMZ, of which IgG and C3 are most commonly seen.³ Our patient had linear deposition of C3, IgM, and IgA along the BMZ, which excluded bullous LP from the differential diagnosis. Bullous LP is not an autoimmune condition but rather is on the severe spectrum of LP where Max Joseph spaces become so large so as to lead to vesicle and bullae formation. In addition to the linear deposit at the BMZ, LPP typically reveals immunoglobulin (mainly IgM but also IgA), C3, and fibrinogen staining of colloid bodies in the papillary dermis on DIF; however, some cases of LPP only present with a linear deposition of C3 along the BMZ, which is why, similar to PG, these diagnoses by DIF are similar. Direct immunofluorescence of PG reveals linear IgG1 and IgG3 along the BMZ. IgG1 and IgG3 immunoglobulins are known to fix complement better than other immunoglobulins, thus linear C3 along the BMZ is the most consistently positive immunoreactant. Less common positive immunoreactivity with the same pattern has been seen with IgA, IgM, C1, and C4 (Table).^14,15,18 The lack of linear IgG and the presence of IgM is more suggestive of LPP.

The differential diagnosis of the subepidermal autoimmune blistering diseases associated with antibodies against BP180, including BP, LPP, and PG, often is challenging.¹⁵ However, LPP can now be distinguished by immunological studies including immunoblot analysis of the immunodominant region of NC16A of the BP180 antigen and the immunoglobulin subclass that reacts to 180-, 200-,²⁰ and 230-kDa antigens within the BMZ (Table).^15,18-20 The Table summarizes the different autoantibodies, antigens, and epitopes to distinguish subepidermal autoimmune blistering diseases.

Despite not performing these studies in our patient, we concluded that the clinical, histological, and DIF findings of this case are more consistent with LPP than with the other subepidermal blistering diseases. However, we cannot exclude the possibility of the patient having a new entity with a unique antibody from epitope spreading.

Conclusion

We present a case of lichenoid papules and plaques consistent with LP, with the development of vesicles and bullae after the first trimester of pregnancy. The clinical, pathologic, and DIF findings were highly suggestive of LPP. Although the exact pathogenic mechanism is not fully known, we suspect that pregnancy may have contributed to the origin of the disease. Further evaluation of pregnant patients with lichenoid lesions who develop blisters are needed for the elucidation of the mechanism, which may be secondary to epitope spreading that led to new autoantibody formation.

To the Editor:

Pemphigus vulgaris (PV) is an acquired autoimmune bullous disease with notable morbidity and mortality if not treated appropriately due to loss of epidermal barrier function and subsequent infection and loss of body fluids. Although the use of systemic corticosteroids and immunosuppressive agents has improved the prognosis, these drugs also may have severe adverse effects, especially in elderly patients. Hence, alternative and safer therapies with anti-inflammatory and immunomodulatory agents such as tetracyclines and nicotinamide have been used with variable results. We report a case of PV that was successfully treated with doxycycline.

An 81-year-old man presented with well-demarcated erosions with overlying yellow crust as well as vesicles and pustules on the scalp (Figure 1A), forehead, bilateral cheeks, and upper back (Figure 1B) of 6 months’ duration. He used topical fluorouracil in the month prior to presentation for suspected actinic keratosis but had stopped its use after 2 weeks. At the first visit, a diagnosis of a reaction to topical fluorouracil with secondary bacterial infection was made and he was prescribed doxycycline hyclate 100 mg twice daily. The patient returned 4 weeks later for follow-up and reported initial notable improvement with subsequent worsening of lesions after he ran out of doxycycline. On physical examination the lesions had considerably improved from the last visit, but he still had a few erosions on the scalp and a few in the oral mucosa. A 1-cm shallow erosion with minimal surrounding erythema on the forehead was present, along with fewer scattered, edematous, erythematous plaques on the back and chest. Pemphigus vulgaris was suspected and 2 shave biopsies from the lesions on the back and cheek were obtained for confirmation. Histopathologic examination revealed epidermal hyperplasia and suprabasal acantholysis as well as moderate perivascular and perifollicular lymphocytic infiltrate with several eosinophils and plasma cells, characteristic of PV (Figure 2). Direct immunofluorescence showed moderate intercellular deposition of IgG within the basal layer and to a lesser extent within suprabasal layers as well as moderate intercellular deposition of C3 within the basal layer, characteristic of PV. IgA and IgM were not present. Indirect immunofluorescence using monkey esophagus revealed no antibodies against the intercellular space of the basement membrane zone. Due to the dramatic response, he continued on doxycycline 100 mg twice daily and remained in complete remission. Ten months after initiating treatment he discontinued doxycycline for 2 days and developed a 1-cm lesion on the left cheek. He resumed treatment with clearing of lesions and was slowly tapered to 50 mg of doxycycline once daily, remaining in complete remission (Figure 3). Doxycycline was discontinued 16 months after initiation; he has remained clear at 13 weeks.

The treatment of PV is challenging given the multiple side effects of steroids, especially in elderly patients. Tetracyclines have an advantageous side-effect profile and they have been shown to be efficacious in treating PV when combined with nicotinamide or when used as adjuvant therapy to steroids.^1-3 Our case shows a patient who was treated exclusively with doxycycline and achieved complete remission.

Tetracyclines have multiple biological activities in addition to their antimicrobial function that may provide a therapeutic benefit in PV. They possess immunomodulatory and anti-inflammatory effects by inhibiting leukocyte chemotaxis and activation^4-8 and inhibiting cytokine release. They inhibit matrix metalloproteinases, which are the major enzymes responsible for breakdown of the extracellular matrix,⁹ and they indirectly inhibit neutrophil elastase by protecting α₁-protease inhibitor from matrix metalloproteinase degradation.¹⁰ Additionally, tetracyclines increase the cohesion of the dermoepidermal junction¹¹; whether they increase the adhesion between epidermal cells is unknown. It has been determined that CD4⁺ T cells play an essential role in the pathogenesis of PV by promoting anti-desmoglein 3 antibody production.¹² Szeto et al¹³ reported that minocycline, a member of the tetracycline family, has suppressive effects on CD4⁺ T-cell activation by hindering the activation of nuclear factor of activated T cells (NFAT), a key regulatory factor in T-cell activation. We hypothesize that doxycycline exerted what appears to be immunomodulatory properties in our patient by suppressing CD4⁺ T-cell activity.

In conclusion, tetracyclines can be an effective and promising therapy for PV given their relatively few side effects and immunomodulating properties. However, further randomized controlled trials will be important to support our conclusion.

To the Editor:

Pemphigus vulgaris (PV) is an acquired autoimmune bullous disease with notable morbidity and mortality if not treated appropriately due to loss of epidermal barrier function and subsequent infection and loss of body fluids. Although the use of systemic corticosteroids and immunosuppressive agents has improved the prognosis, these drugs also may have severe adverse effects, especially in elderly patients. Hence, alternative and safer therapies with anti-inflammatory and immunomodulatory agents such as tetracyclines and nicotinamide have been used with variable results. We report a case of PV that was successfully treated with doxycycline.

An 81-year-old man presented with well-demarcated erosions with overlying yellow crust as well as vesicles and pustules on the scalp (Figure 1A), forehead, bilateral cheeks, and upper back (Figure 1B) of 6 months’ duration. He used topical fluorouracil in the month prior to presentation for suspected actinic keratosis but had stopped its use after 2 weeks. At the first visit, a diagnosis of a reaction to topical fluorouracil with secondary bacterial infection was made and he was prescribed doxycycline hyclate 100 mg twice daily. The patient returned 4 weeks later for follow-up and reported initial notable improvement with subsequent worsening of lesions after he ran out of doxycycline. On physical examination the lesions had considerably improved from the last visit, but he still had a few erosions on the scalp and a few in the oral mucosa. A 1-cm shallow erosion with minimal surrounding erythema on the forehead was present, along with fewer scattered, edematous, erythematous plaques on the back and chest. Pemphigus vulgaris was suspected and 2 shave biopsies from the lesions on the back and cheek were obtained for confirmation. Histopathologic examination revealed epidermal hyperplasia and suprabasal acantholysis as well as moderate perivascular and perifollicular lymphocytic infiltrate with several eosinophils and plasma cells, characteristic of PV (Figure 2). Direct immunofluorescence showed moderate intercellular deposition of IgG within the basal layer and to a lesser extent within suprabasal layers as well as moderate intercellular deposition of C3 within the basal layer, characteristic of PV. IgA and IgM were not present. Indirect immunofluorescence using monkey esophagus revealed no antibodies against the intercellular space of the basement membrane zone. Due to the dramatic response, he continued on doxycycline 100 mg twice daily and remained in complete remission. Ten months after initiating treatment he discontinued doxycycline for 2 days and developed a 1-cm lesion on the left cheek. He resumed treatment with clearing of lesions and was slowly tapered to 50 mg of doxycycline once daily, remaining in complete remission (Figure 3). Doxycycline was discontinued 16 months after initiation; he has remained clear at 13 weeks.

The treatment of PV is challenging given the multiple side effects of steroids, especially in elderly patients. Tetracyclines have an advantageous side-effect profile and they have been shown to be efficacious in treating PV when combined with nicotinamide or when used as adjuvant therapy to steroids.^1-3 Our case shows a patient who was treated exclusively with doxycycline and achieved complete remission.

Tetracyclines have multiple biological activities in addition to their antimicrobial function that may provide a therapeutic benefit in PV. They possess immunomodulatory and anti-inflammatory effects by inhibiting leukocyte chemotaxis and activation^4-8 and inhibiting cytokine release. They inhibit matrix metalloproteinases, which are the major enzymes responsible for breakdown of the extracellular matrix,⁹ and they indirectly inhibit neutrophil elastase by protecting α₁-protease inhibitor from matrix metalloproteinase degradation.¹⁰ Additionally, tetracyclines increase the cohesion of the dermoepidermal junction¹¹; whether they increase the adhesion between epidermal cells is unknown. It has been determined that CD4⁺ T cells play an essential role in the pathogenesis of PV by promoting anti-desmoglein 3 antibody production.¹² Szeto et al¹³ reported that minocycline, a member of the tetracycline family, has suppressive effects on CD4⁺ T-cell activation by hindering the activation of nuclear factor of activated T cells (NFAT), a key regulatory factor in T-cell activation. We hypothesize that doxycycline exerted what appears to be immunomodulatory properties in our patient by suppressing CD4⁺ T-cell activity.

In conclusion, tetracyclines can be an effective and promising therapy for PV given their relatively few side effects and immunomodulating properties. However, further randomized controlled trials will be important to support our conclusion.

To the Editor:

Pemphigus vulgaris (PV) is an acquired autoimmune bullous disease with notable morbidity and mortality if not treated appropriately due to loss of epidermal barrier function and subsequent infection and loss of body fluids. Although the use of systemic corticosteroids and immunosuppressive agents has improved the prognosis, these drugs also may have severe adverse effects, especially in elderly patients. Hence, alternative and safer therapies with anti-inflammatory and immunomodulatory agents such as tetracyclines and nicotinamide have been used with variable results. We report a case of PV that was successfully treated with doxycycline.

An 81-year-old man presented with well-demarcated erosions with overlying yellow crust as well as vesicles and pustules on the scalp (Figure 1A), forehead, bilateral cheeks, and upper back (Figure 1B) of 6 months’ duration. He used topical fluorouracil in the month prior to presentation for suspected actinic keratosis but had stopped its use after 2 weeks. At the first visit, a diagnosis of a reaction to topical fluorouracil with secondary bacterial infection was made and he was prescribed doxycycline hyclate 100 mg twice daily. The patient returned 4 weeks later for follow-up and reported initial notable improvement with subsequent worsening of lesions after he ran out of doxycycline. On physical examination the lesions had considerably improved from the last visit, but he still had a few erosions on the scalp and a few in the oral mucosa. A 1-cm shallow erosion with minimal surrounding erythema on the forehead was present, along with fewer scattered, edematous, erythematous plaques on the back and chest. Pemphigus vulgaris was suspected and 2 shave biopsies from the lesions on the back and cheek were obtained for confirmation. Histopathologic examination revealed epidermal hyperplasia and suprabasal acantholysis as well as moderate perivascular and perifollicular lymphocytic infiltrate with several eosinophils and plasma cells, characteristic of PV (Figure 2). Direct immunofluorescence showed moderate intercellular deposition of IgG within the basal layer and to a lesser extent within suprabasal layers as well as moderate intercellular deposition of C3 within the basal layer, characteristic of PV. IgA and IgM were not present. Indirect immunofluorescence using monkey esophagus revealed no antibodies against the intercellular space of the basement membrane zone. Due to the dramatic response, he continued on doxycycline 100 mg twice daily and remained in complete remission. Ten months after initiating treatment he discontinued doxycycline for 2 days and developed a 1-cm lesion on the left cheek. He resumed treatment with clearing of lesions and was slowly tapered to 50 mg of doxycycline once daily, remaining in complete remission (Figure 3). Doxycycline was discontinued 16 months after initiation; he has remained clear at 13 weeks.

The treatment of PV is challenging given the multiple side effects of steroids, especially in elderly patients. Tetracyclines have an advantageous side-effect profile and they have been shown to be efficacious in treating PV when combined with nicotinamide or when used as adjuvant therapy to steroids.^1-3 Our case shows a patient who was treated exclusively with doxycycline and achieved complete remission.

Tetracyclines have multiple biological activities in addition to their antimicrobial function that may provide a therapeutic benefit in PV. They possess immunomodulatory and anti-inflammatory effects by inhibiting leukocyte chemotaxis and activation^4-8 and inhibiting cytokine release. They inhibit matrix metalloproteinases, which are the major enzymes responsible for breakdown of the extracellular matrix,⁹ and they indirectly inhibit neutrophil elastase by protecting α₁-protease inhibitor from matrix metalloproteinase degradation.¹⁰ Additionally, tetracyclines increase the cohesion of the dermoepidermal junction¹¹; whether they increase the adhesion between epidermal cells is unknown. It has been determined that CD4⁺ T cells play an essential role in the pathogenesis of PV by promoting anti-desmoglein 3 antibody production.¹² Szeto et al¹³ reported that minocycline, a member of the tetracycline family, has suppressive effects on CD4⁺ T-cell activation by hindering the activation of nuclear factor of activated T cells (NFAT), a key regulatory factor in T-cell activation. We hypothesize that doxycycline exerted what appears to be immunomodulatory properties in our patient by suppressing CD4⁺ T-cell activity.

In conclusion, tetracyclines can be an effective and promising therapy for PV given their relatively few side effects and immunomodulating properties. However, further randomized controlled trials will be important to support our conclusion.

The Diagnosis: Primary Cutaneous Mucinous Carcinoma

Primary cutaneous mucinous carcinoma is a rare tumor of the sweat glands that was first reported in 1952 by Lennox et al.¹ These tumors are slow growing and have a predilection for the head and neck, with the eyelid being the most commonly reported location.² In general, they present as erythematous asymptomatic nodules measuring less than 7 cm in diameter.^2-4 Primary cutaneous mucinous carcinoma tends to have a good prognosis with complete resection, but cases of metastasis and recurrence have been reported.² Although there is no standard of care, treatment typically consists of surgical management, as the tumors are nonresponsive to chemotherapy or radiation.⁴ Kamalpour et al² compared outcomes for Mohs micrographic surgery versus standard excision, the former showing a lower percentage of poor outcomes. Of note, there were fewer cases treated with Mohs surgery in this study; only more recently reported cases have been treated with Mohs surgery.

Histologically, primary cutaneous mucinous carcinoma is composed of cords, tubules, and lobules of epithelial cells floating in large pools of basophilic mucin, separated by thin fibrovascular septa.⁵ It can be difficult to distinguish a primary tumor from a mucinous carcinoma metastasis with histology alone, especially on the breasts and in the gastrointestinal tract. Immunohistochemistry can be helpful in determining the origin of the tumor. A homologue of p53, p63 expressed in basal and myoepithelial cells of the skin can aid in the confirmation of a primary tumor when present.^6,7 Negative staining for cytokeratin 20 and positive staining for cytokeratin 7 also are helpful in distinguishing a primary cutaneous mucinous carcinoma from a gastrointestinal tract metastasis.^4,8

In our patient, no other symptoms were present that raised concern for an internal malignancy. Findings that supported a primary versus metastatic tumor included the clinicopathologic findings (Figure) as well as positive p63, cytokeratin 7, and negative cytokeratin 20 staining. The initial standard excision had tumor cells within 1 mm of the specimen margin; thus, a subsequent wider reexcision was performed. Reexcision was negative for tumor cells. Close follow-up with a primary care physician was recommended, with emphasis on colon and breast cancer screening. A follow-up mammogram was negative for breast cancer.

The Diagnosis: Primary Cutaneous Mucinous Carcinoma

Primary cutaneous mucinous carcinoma is a rare tumor of the sweat glands that was first reported in 1952 by Lennox et al.¹ These tumors are slow growing and have a predilection for the head and neck, with the eyelid being the most commonly reported location.² In general, they present as erythematous asymptomatic nodules measuring less than 7 cm in diameter.^2-4 Primary cutaneous mucinous carcinoma tends to have a good prognosis with complete resection, but cases of metastasis and recurrence have been reported.² Although there is no standard of care, treatment typically consists of surgical management, as the tumors are nonresponsive to chemotherapy or radiation.⁴ Kamalpour et al² compared outcomes for Mohs micrographic surgery versus standard excision, the former showing a lower percentage of poor outcomes. Of note, there were fewer cases treated with Mohs surgery in this study; only more recently reported cases have been treated with Mohs surgery.

Histologically, primary cutaneous mucinous carcinoma is composed of cords, tubules, and lobules of epithelial cells floating in large pools of basophilic mucin, separated by thin fibrovascular septa.⁵ It can be difficult to distinguish a primary tumor from a mucinous carcinoma metastasis with histology alone, especially on the breasts and in the gastrointestinal tract. Immunohistochemistry can be helpful in determining the origin of the tumor. A homologue of p53, p63 expressed in basal and myoepithelial cells of the skin can aid in the confirmation of a primary tumor when present.^6,7 Negative staining for cytokeratin 20 and positive staining for cytokeratin 7 also are helpful in distinguishing a primary cutaneous mucinous carcinoma from a gastrointestinal tract metastasis.^4,8

In our patient, no other symptoms were present that raised concern for an internal malignancy. Findings that supported a primary versus metastatic tumor included the clinicopathologic findings (Figure) as well as positive p63, cytokeratin 7, and negative cytokeratin 20 staining. The initial standard excision had tumor cells within 1 mm of the specimen margin; thus, a subsequent wider reexcision was performed. Reexcision was negative for tumor cells. Close follow-up with a primary care physician was recommended, with emphasis on colon and breast cancer screening. A follow-up mammogram was negative for breast cancer.

The Diagnosis: Primary Cutaneous Mucinous Carcinoma

Primary cutaneous mucinous carcinoma is a rare tumor of the sweat glands that was first reported in 1952 by Lennox et al.¹ These tumors are slow growing and have a predilection for the head and neck, with the eyelid being the most commonly reported location.² In general, they present as erythematous asymptomatic nodules measuring less than 7 cm in diameter.^2-4 Primary cutaneous mucinous carcinoma tends to have a good prognosis with complete resection, but cases of metastasis and recurrence have been reported.² Although there is no standard of care, treatment typically consists of surgical management, as the tumors are nonresponsive to chemotherapy or radiation.⁴ Kamalpour et al² compared outcomes for Mohs micrographic surgery versus standard excision, the former showing a lower percentage of poor outcomes. Of note, there were fewer cases treated with Mohs surgery in this study; only more recently reported cases have been treated with Mohs surgery.

Histologically, primary cutaneous mucinous carcinoma is composed of cords, tubules, and lobules of epithelial cells floating in large pools of basophilic mucin, separated by thin fibrovascular septa.⁵ It can be difficult to distinguish a primary tumor from a mucinous carcinoma metastasis with histology alone, especially on the breasts and in the gastrointestinal tract. Immunohistochemistry can be helpful in determining the origin of the tumor. A homologue of p53, p63 expressed in basal and myoepithelial cells of the skin can aid in the confirmation of a primary tumor when present.^6,7 Negative staining for cytokeratin 20 and positive staining for cytokeratin 7 also are helpful in distinguishing a primary cutaneous mucinous carcinoma from a gastrointestinal tract metastasis.^4,8

In our patient, no other symptoms were present that raised concern for an internal malignancy. Findings that supported a primary versus metastatic tumor included the clinicopathologic findings (Figure) as well as positive p63, cytokeratin 7, and negative cytokeratin 20 staining. The initial standard excision had tumor cells within 1 mm of the specimen margin; thus, a subsequent wider reexcision was performed. Reexcision was negative for tumor cells. Close follow-up with a primary care physician was recommended, with emphasis on colon and breast cancer screening. A follow-up mammogram was negative for breast cancer.

The Diagnosis: Eccrine Angiomatous Hamartoma

Given the progression of symptoms 3 months prior to presentation, an excisional biopsy was performed (Figure 1). Hematoxylin and eosin staining showed prominent eccrine sweat glands and vessels surrounded by superficially located adipose tissue in the mid and deep dermis (Figure 2).

Eccrine angiomatous hamartoma (EAH) is an uncommon benign tumor typically located on the arms and legs or trunk. It is usually solitary, though cases with multiple lesions have been reported.^1,2 Most cases are diagnosed in childhood as either congenital or acquired lesions. However, EAHs can develop in adulthood and have been described in patients up to 70 years of age.³ The median age of diagnosis is 10 years,² indicating that EAH is primarily a pediatric tumor. There is no gender predilection.

Approximately 35% to 66% of patients report pain, pruritus, or hyperhidrosis associated with EAHs, though this incidence may be overrepresented because patients tend to present when the lesions become symptomatic.^2-5 The pain is attributed to nerve fibers infiltrating the tumor. Hypertrichosis also has been described and is thought to be due to hair follicles within the hamartoma.

Histologically, EAHs are characterized by normal-appearing eccrine glands mingled with venules and capillaries. Additional variable pathologic findings include lipomatous, pilar, lymphatic, or mucinous features.² Other vascular anomalies such as hemangiomas or arteriovenous malformations occasionally have been described in association with EAH. The vessels stain for ulex europaeus 1 and factor VIII. Eccrine glands stain for S-100 protein, carcinoembryonic antigen, epithelial membrane antigen, and cytokeratin CAM 5.2. In light of a publication proposing that EAH is a lymphatic proliferation,⁶ a D2-40 stain was performed on the specimen and was negative. 

Eccrine angiomatous hamartoma has been reported to grow mainly during childhood, puberty, or pregnancy, presumably due to hormonal influences.⁷ There are few reports of EAH enlarging in middle-aged adults, and even fewer without pain during the growth phase. It is unclear what triggered the growth in our otherwise healthy postmenopausal patient.

Eccrine angiomatous hamartoma does not have malignant potential and thus treatment is optional and based on relief of symptoms. Simple excision of the EAH usually is curative, but recurrences can occur.⁴ Botulinum toxin also has been used to treat hyperhidrosis in tumors that are too large for resection. Treatment with lasers such as the pulsed dye laser and Nd:YAG laser has not been successful.⁸ A case of spontaneous regression has been reported.¹

Liposuction was considered in our patient given the substantial adipose tissue on biopsy. The patient ultimately declined treatment. This case highlights that EAH can present in adulthood and should be considered in the differential diagnosis of an enlarging but otherwise asymptomatic vascular tumor.

The Diagnosis: Eccrine Angiomatous Hamartoma

Given the progression of symptoms 3 months prior to presentation, an excisional biopsy was performed (Figure 1). Hematoxylin and eosin staining showed prominent eccrine sweat glands and vessels surrounded by superficially located adipose tissue in the mid and deep dermis (Figure 2).

Eccrine angiomatous hamartoma (EAH) is an uncommon benign tumor typically located on the arms and legs or trunk. It is usually solitary, though cases with multiple lesions have been reported.^1,2 Most cases are diagnosed in childhood as either congenital or acquired lesions. However, EAHs can develop in adulthood and have been described in patients up to 70 years of age.³ The median age of diagnosis is 10 years,² indicating that EAH is primarily a pediatric tumor. There is no gender predilection.

Approximately 35% to 66% of patients report pain, pruritus, or hyperhidrosis associated with EAHs, though this incidence may be overrepresented because patients tend to present when the lesions become symptomatic.^2-5 The pain is attributed to nerve fibers infiltrating the tumor. Hypertrichosis also has been described and is thought to be due to hair follicles within the hamartoma.

Histologically, EAHs are characterized by normal-appearing eccrine glands mingled with venules and capillaries. Additional variable pathologic findings include lipomatous, pilar, lymphatic, or mucinous features.² Other vascular anomalies such as hemangiomas or arteriovenous malformations occasionally have been described in association with EAH. The vessels stain for ulex europaeus 1 and factor VIII. Eccrine glands stain for S-100 protein, carcinoembryonic antigen, epithelial membrane antigen, and cytokeratin CAM 5.2. In light of a publication proposing that EAH is a lymphatic proliferation,⁶ a D2-40 stain was performed on the specimen and was negative. 

Eccrine angiomatous hamartoma has been reported to grow mainly during childhood, puberty, or pregnancy, presumably due to hormonal influences.⁷ There are few reports of EAH enlarging in middle-aged adults, and even fewer without pain during the growth phase. It is unclear what triggered the growth in our otherwise healthy postmenopausal patient.

Eccrine angiomatous hamartoma does not have malignant potential and thus treatment is optional and based on relief of symptoms. Simple excision of the EAH usually is curative, but recurrences can occur.⁴ Botulinum toxin also has been used to treat hyperhidrosis in tumors that are too large for resection. Treatment with lasers such as the pulsed dye laser and Nd:YAG laser has not been successful.⁸ A case of spontaneous regression has been reported.¹

Liposuction was considered in our patient given the substantial adipose tissue on biopsy. The patient ultimately declined treatment. This case highlights that EAH can present in adulthood and should be considered in the differential diagnosis of an enlarging but otherwise asymptomatic vascular tumor.

The Diagnosis: Eccrine Angiomatous Hamartoma

Given the progression of symptoms 3 months prior to presentation, an excisional biopsy was performed (Figure 1). Hematoxylin and eosin staining showed prominent eccrine sweat glands and vessels surrounded by superficially located adipose tissue in the mid and deep dermis (Figure 2).

Eccrine angiomatous hamartoma (EAH) is an uncommon benign tumor typically located on the arms and legs or trunk. It is usually solitary, though cases with multiple lesions have been reported.^1,2 Most cases are diagnosed in childhood as either congenital or acquired lesions. However, EAHs can develop in adulthood and have been described in patients up to 70 years of age.³ The median age of diagnosis is 10 years,² indicating that EAH is primarily a pediatric tumor. There is no gender predilection.

Approximately 35% to 66% of patients report pain, pruritus, or hyperhidrosis associated with EAHs, though this incidence may be overrepresented because patients tend to present when the lesions become symptomatic.^2-5 The pain is attributed to nerve fibers infiltrating the tumor. Hypertrichosis also has been described and is thought to be due to hair follicles within the hamartoma.

Histologically, EAHs are characterized by normal-appearing eccrine glands mingled with venules and capillaries. Additional variable pathologic findings include lipomatous, pilar, lymphatic, or mucinous features.² Other vascular anomalies such as hemangiomas or arteriovenous malformations occasionally have been described in association with EAH. The vessels stain for ulex europaeus 1 and factor VIII. Eccrine glands stain for S-100 protein, carcinoembryonic antigen, epithelial membrane antigen, and cytokeratin CAM 5.2. In light of a publication proposing that EAH is a lymphatic proliferation,⁶ a D2-40 stain was performed on the specimen and was negative. 

Eccrine angiomatous hamartoma has been reported to grow mainly during childhood, puberty, or pregnancy, presumably due to hormonal influences.⁷ There are few reports of EAH enlarging in middle-aged adults, and even fewer without pain during the growth phase. It is unclear what triggered the growth in our otherwise healthy postmenopausal patient.

Eccrine angiomatous hamartoma does not have malignant potential and thus treatment is optional and based on relief of symptoms. Simple excision of the EAH usually is curative, but recurrences can occur.⁴ Botulinum toxin also has been used to treat hyperhidrosis in tumors that are too large for resection. Treatment with lasers such as the pulsed dye laser and Nd:YAG laser has not been successful.⁸ A case of spontaneous regression has been reported.¹

Liposuction was considered in our patient given the substantial adipose tissue on biopsy. The patient ultimately declined treatment. This case highlights that EAH can present in adulthood and should be considered in the differential diagnosis of an enlarging but otherwise asymptomatic vascular tumor.