Case Letter

To the Editor:

Phytophotodermatitis is common in dermatology during the summer months, especially in individuals who spend time outdoors; however, identification of the offending plant can be challenging. We report a case of phytophotodermatitis in which the causative plant, common rue, was not identified until it was revealed that the patient was a butterfly enthusiast.

A 60-year-old woman presented to the outpatient dermatology clinic in late summer for a routine skin examination. An eruption was noted over the right thigh and knee that had first appeared approximately 2 weeks prior. The rash started as pruritic blisters but gradually progressed to erythema and then eventually to brown markings, which were observed at the current presentation. Physical examination revealed hyperpigmented, brown, streaky, linear patches and plaques over the right thigh, knee, and lower leg (Figure). When asked about her hobbies, the patient reported an affinity for butterflies and noted that she attracts them with specific species of plants in her garden. She recalled recently planting the herb of grace, or common rue, to attract the giant swallowtail butterfly (Papilio cresphontes). Upon further inquiry, she remembered working in the garden on her knees and digging up roots near the common rue plant while wearing shorts approximately 2 weeks prior to the current presentation. Given the streaky linear pattern of the eruption along with recent sun exposure and exposure to the common rue plant, a diagnosis of phytophotodermatitis was made. No further treatment was sought, as the eruption was not bothersome to her. She was intrigued that the common rue plant had caused the dermatitis and planned on taking proper precautions when working near the plant in the future.

In this case, the observed phototoxic skin findings resulted from exposure to common rue (Ruta graveolens),a pungently scented evergreen shrub native to the Mediterranean region and a member of the Rutaceae family. Extracts have been used in homeopathic practices for bruises, sprains, headache, neck stiffness, rheumatologic pain, neuralgia, stomach problems, and phlebitis, as well as in seasonings, soaps, creams, and perfumes.¹ The most commonly encountered plants known to cause phytophotodermatitis belong to the Apiaceae and Rutaceae families.² Members of Apiaceae include angelica, celery, dill, fennel, hogweed, parsley, and parsnip. Aside from the common rue plant, the Rutaceae family also includes bergamot orange, bitter orange, burning bush (or gas plant), grapefruit, lemon, and lime. Other potential offending agents are fig, mustard, buttercup, St. John’s wort, and scurfpea. The phototoxic properties are due to furocoumarins, which include psoralens and angelicins. They are inert until activated by UVA radiation, which inflicts direct cellular damage, causing vacuolization and apoptosis of keratinocytes, similar to a sunburn.³ Clinical findings typically present 24 hours after sun exposure with erythema, edema, pain, and occasionally vesicles or bullae in severe cases. Unlike sunburn, lesions often present in linear, streaky, or bizarre patterns, reflective of the direct contact with the plant. The lesions eventually transition to hyperpigmentation, which may take months to years to resolve.

Other considerations in cases of suspected phytophotodermatitis include polymorphic light eruption, actinic prurigo, hydroa vacciniforme, chronic actinic dermatitis, solar urticaria, drug reactions, porphyria, Smith-Lemli-Opitz syndrome, lupus erythematosus, and dermatomyositis.⁴ Clinicians should suspect phytophotodermatitis with phototoxic findings in bartenders, citrus farm workers, gardeners, chefs, and kitchen workers, especially those handling limes and celery. As in our case, phytophotodermatitis also should be considered in butterfly enthusiasts trying to attract the giant swallowtail butterfly. The caterpillars feed on the leaves of the common rue plant, one of a select few plants that giant swallowtail butterflies use as a host due to its bitter leaves that aid in avoiding predators.⁵

This case illustrates a unique perspective of phytophotodermatitis, as butterfly enthusiasm is not commonly reported in association with the common rue plant with respect to phytophotodermatitis. This case underscores the importance of inquiring about patients’ professions and hobbies, both in dermatology and other specialties.

To the Editor:

Phytophotodermatitis is common in dermatology during the summer months, especially in individuals who spend time outdoors; however, identification of the offending plant can be challenging. We report a case of phytophotodermatitis in which the causative plant, common rue, was not identified until it was revealed that the patient was a butterfly enthusiast.

A 60-year-old woman presented to the outpatient dermatology clinic in late summer for a routine skin examination. An eruption was noted over the right thigh and knee that had first appeared approximately 2 weeks prior. The rash started as pruritic blisters but gradually progressed to erythema and then eventually to brown markings, which were observed at the current presentation. Physical examination revealed hyperpigmented, brown, streaky, linear patches and plaques over the right thigh, knee, and lower leg (Figure). When asked about her hobbies, the patient reported an affinity for butterflies and noted that she attracts them with specific species of plants in her garden. She recalled recently planting the herb of grace, or common rue, to attract the giant swallowtail butterfly (Papilio cresphontes). Upon further inquiry, she remembered working in the garden on her knees and digging up roots near the common rue plant while wearing shorts approximately 2 weeks prior to the current presentation. Given the streaky linear pattern of the eruption along with recent sun exposure and exposure to the common rue plant, a diagnosis of phytophotodermatitis was made. No further treatment was sought, as the eruption was not bothersome to her. She was intrigued that the common rue plant had caused the dermatitis and planned on taking proper precautions when working near the plant in the future.

In this case, the observed phototoxic skin findings resulted from exposure to common rue (Ruta graveolens),a pungently scented evergreen shrub native to the Mediterranean region and a member of the Rutaceae family. Extracts have been used in homeopathic practices for bruises, sprains, headache, neck stiffness, rheumatologic pain, neuralgia, stomach problems, and phlebitis, as well as in seasonings, soaps, creams, and perfumes.¹ The most commonly encountered plants known to cause phytophotodermatitis belong to the Apiaceae and Rutaceae families.² Members of Apiaceae include angelica, celery, dill, fennel, hogweed, parsley, and parsnip. Aside from the common rue plant, the Rutaceae family also includes bergamot orange, bitter orange, burning bush (or gas plant), grapefruit, lemon, and lime. Other potential offending agents are fig, mustard, buttercup, St. John’s wort, and scurfpea. The phototoxic properties are due to furocoumarins, which include psoralens and angelicins. They are inert until activated by UVA radiation, which inflicts direct cellular damage, causing vacuolization and apoptosis of keratinocytes, similar to a sunburn.³ Clinical findings typically present 24 hours after sun exposure with erythema, edema, pain, and occasionally vesicles or bullae in severe cases. Unlike sunburn, lesions often present in linear, streaky, or bizarre patterns, reflective of the direct contact with the plant. The lesions eventually transition to hyperpigmentation, which may take months to years to resolve.

Other considerations in cases of suspected phytophotodermatitis include polymorphic light eruption, actinic prurigo, hydroa vacciniforme, chronic actinic dermatitis, solar urticaria, drug reactions, porphyria, Smith-Lemli-Opitz syndrome, lupus erythematosus, and dermatomyositis.⁴ Clinicians should suspect phytophotodermatitis with phototoxic findings in bartenders, citrus farm workers, gardeners, chefs, and kitchen workers, especially those handling limes and celery. As in our case, phytophotodermatitis also should be considered in butterfly enthusiasts trying to attract the giant swallowtail butterfly. The caterpillars feed on the leaves of the common rue plant, one of a select few plants that giant swallowtail butterflies use as a host due to its bitter leaves that aid in avoiding predators.⁵

This case illustrates a unique perspective of phytophotodermatitis, as butterfly enthusiasm is not commonly reported in association with the common rue plant with respect to phytophotodermatitis. This case underscores the importance of inquiring about patients’ professions and hobbies, both in dermatology and other specialties.

To the Editor:

Phytophotodermatitis is common in dermatology during the summer months, especially in individuals who spend time outdoors; however, identification of the offending plant can be challenging. We report a case of phytophotodermatitis in which the causative plant, common rue, was not identified until it was revealed that the patient was a butterfly enthusiast.

A 60-year-old woman presented to the outpatient dermatology clinic in late summer for a routine skin examination. An eruption was noted over the right thigh and knee that had first appeared approximately 2 weeks prior. The rash started as pruritic blisters but gradually progressed to erythema and then eventually to brown markings, which were observed at the current presentation. Physical examination revealed hyperpigmented, brown, streaky, linear patches and plaques over the right thigh, knee, and lower leg (Figure). When asked about her hobbies, the patient reported an affinity for butterflies and noted that she attracts them with specific species of plants in her garden. She recalled recently planting the herb of grace, or common rue, to attract the giant swallowtail butterfly (Papilio cresphontes). Upon further inquiry, she remembered working in the garden on her knees and digging up roots near the common rue plant while wearing shorts approximately 2 weeks prior to the current presentation. Given the streaky linear pattern of the eruption along with recent sun exposure and exposure to the common rue plant, a diagnosis of phytophotodermatitis was made. No further treatment was sought, as the eruption was not bothersome to her. She was intrigued that the common rue plant had caused the dermatitis and planned on taking proper precautions when working near the plant in the future.

In this case, the observed phototoxic skin findings resulted from exposure to common rue (Ruta graveolens),a pungently scented evergreen shrub native to the Mediterranean region and a member of the Rutaceae family. Extracts have been used in homeopathic practices for bruises, sprains, headache, neck stiffness, rheumatologic pain, neuralgia, stomach problems, and phlebitis, as well as in seasonings, soaps, creams, and perfumes.¹ The most commonly encountered plants known to cause phytophotodermatitis belong to the Apiaceae and Rutaceae families.² Members of Apiaceae include angelica, celery, dill, fennel, hogweed, parsley, and parsnip. Aside from the common rue plant, the Rutaceae family also includes bergamot orange, bitter orange, burning bush (or gas plant), grapefruit, lemon, and lime. Other potential offending agents are fig, mustard, buttercup, St. John’s wort, and scurfpea. The phototoxic properties are due to furocoumarins, which include psoralens and angelicins. They are inert until activated by UVA radiation, which inflicts direct cellular damage, causing vacuolization and apoptosis of keratinocytes, similar to a sunburn.³ Clinical findings typically present 24 hours after sun exposure with erythema, edema, pain, and occasionally vesicles or bullae in severe cases. Unlike sunburn, lesions often present in linear, streaky, or bizarre patterns, reflective of the direct contact with the plant. The lesions eventually transition to hyperpigmentation, which may take months to years to resolve.

Other considerations in cases of suspected phytophotodermatitis include polymorphic light eruption, actinic prurigo, hydroa vacciniforme, chronic actinic dermatitis, solar urticaria, drug reactions, porphyria, Smith-Lemli-Opitz syndrome, lupus erythematosus, and dermatomyositis.⁴ Clinicians should suspect phytophotodermatitis with phototoxic findings in bartenders, citrus farm workers, gardeners, chefs, and kitchen workers, especially those handling limes and celery. As in our case, phytophotodermatitis also should be considered in butterfly enthusiasts trying to attract the giant swallowtail butterfly. The caterpillars feed on the leaves of the common rue plant, one of a select few plants that giant swallowtail butterflies use as a host due to its bitter leaves that aid in avoiding predators.⁵

This case illustrates a unique perspective of phytophotodermatitis, as butterfly enthusiasm is not commonly reported in association with the common rue plant with respect to phytophotodermatitis. This case underscores the importance of inquiring about patients’ professions and hobbies, both in dermatology and other specialties.

To the Editor:

The use of sunless tanners has become an alternative for individuals who wish to have tan skin without exposure to UV radiation.¹ We present a case of a patient who experienced persistent hyperpigmented patches on the hands months after the use of a sunless tanner containing dihydroxyacetone (DHA), a carbohydrate that reacts with amino acids in the stratum corneum to produce pigments called melanoidins. The hyperpigmentation caused by DHA is due to the Maillard reaction, which is the nonenzymatic glycation of amino groups of proteins by the carbonyl groups of sugar.² Many sunless tanners contain DHA at varying concentrations. Dermatologists should be aware of the benefits and potential side effects of these alternative products so that they can appropriately counsel patients.

A 20-year-old woman with no history of skin disease presented for evaluation of hyperpigmented patches on the dorsal hands of several months’ duration. Physical examination revealed ill-defined hyperpigmented patches on the dorsal fingers without associated scale or erythema (Figure 1). She had a remote history of Hodgkin lymphoma treated with chemotherapy and was in remission for 5 years prior to the current presentation. Her hematologists referred her to dermatology for evaluation, as they did not believe the patches could be related to her chemotherapy given that she had completed the treatment years before.

A punch biopsy of one of the patches was obtained to elucidate the origin of the hyperpigmentation, which had no obvious triggers according to the patient. Histopathologic examination revealed hyperpigmented parakeratosis and lentiginous hyperplasia along with pigmentation of the stratum corneum (Figures 2A and 2B) with black pigment, which stained positive with Fontana-Masson (Figure 2C).

Upon further questioning, it was revealed that our patient had used a sunless tanner 3 months prior to the development of the pigmented patches. She also used urea cream to hasten exfoliation, which resulted in lighter but still apparent hyperpigmentation at follow-up 6 months after the initial presentation.

There has been a rapid growth of the sunless tanning industry in the last several years due to effective public education against UV tanning. Generally, patients apply the sunless tanner and notice an increase in tan within the following 48 hours. Typically, the tan progressively fades with the normal skin exfoliation over the span of weeks. Although most of the DHA binds proteins in the stratum corneum, the US Food and Drug Administration released a report speculating that approximately 11% of the compound reaches the epidermis and dermis.³ There are limited data regarding the effects of the compound should it pass the stratum corneum into the living skin cells.

Products with DHA only confer a sun protection factor of approximately 3⁴; although patients may appear tan, they have no actual decreased risk for sunburn after use. Reports have shown that the use of sunless tanners containing DHA can alter the appearance of melanocytic lesions clinically and has caused pseudochromhidrosis on the palms.^3,5,6 A study performed on a human keratinocyte cell line, HaCaT, showed that DHA can induce DNA damage, cell-cycle block, and apoptosis.⁷ In addition, as described in our case, patients may experience prolonged hyperpigmentation after use.

This case demonstrates the potential for persistent hyperpigmentation months after the use of sunless tanners containing DHA. Asking patients specific questions regarding their history of tanning product use is essential in identifying the pathology. Although a skin biopsy may not be strictly indicated, it may aid diagnosis, especially when the history is unclear. As more dermatologists support the use of sunless tanner, we must be aware of this possible outcome, especially on more cosmetically sensitive areas such as the fingers in this patient. Clinicians should be aware that the US Food and Drug Administration recommends avoiding contact with mucous membranes when applying products containing DHA and also recommends use of a test spot prior to treating the entire body with the product.⁸ Patients must not only be educated on the benefits of using sunless tanners but on the potential side effects with use of these products as well.

To the Editor:

The use of sunless tanners has become an alternative for individuals who wish to have tan skin without exposure to UV radiation.¹ We present a case of a patient who experienced persistent hyperpigmented patches on the hands months after the use of a sunless tanner containing dihydroxyacetone (DHA), a carbohydrate that reacts with amino acids in the stratum corneum to produce pigments called melanoidins. The hyperpigmentation caused by DHA is due to the Maillard reaction, which is the nonenzymatic glycation of amino groups of proteins by the carbonyl groups of sugar.² Many sunless tanners contain DHA at varying concentrations. Dermatologists should be aware of the benefits and potential side effects of these alternative products so that they can appropriately counsel patients.

A 20-year-old woman with no history of skin disease presented for evaluation of hyperpigmented patches on the dorsal hands of several months’ duration. Physical examination revealed ill-defined hyperpigmented patches on the dorsal fingers without associated scale or erythema (Figure 1). She had a remote history of Hodgkin lymphoma treated with chemotherapy and was in remission for 5 years prior to the current presentation. Her hematologists referred her to dermatology for evaluation, as they did not believe the patches could be related to her chemotherapy given that she had completed the treatment years before.

A punch biopsy of one of the patches was obtained to elucidate the origin of the hyperpigmentation, which had no obvious triggers according to the patient. Histopathologic examination revealed hyperpigmented parakeratosis and lentiginous hyperplasia along with pigmentation of the stratum corneum (Figures 2A and 2B) with black pigment, which stained positive with Fontana-Masson (Figure 2C).

Upon further questioning, it was revealed that our patient had used a sunless tanner 3 months prior to the development of the pigmented patches. She also used urea cream to hasten exfoliation, which resulted in lighter but still apparent hyperpigmentation at follow-up 6 months after the initial presentation.

There has been a rapid growth of the sunless tanning industry in the last several years due to effective public education against UV tanning. Generally, patients apply the sunless tanner and notice an increase in tan within the following 48 hours. Typically, the tan progressively fades with the normal skin exfoliation over the span of weeks. Although most of the DHA binds proteins in the stratum corneum, the US Food and Drug Administration released a report speculating that approximately 11% of the compound reaches the epidermis and dermis.³ There are limited data regarding the effects of the compound should it pass the stratum corneum into the living skin cells.

Products with DHA only confer a sun protection factor of approximately 3⁴; although patients may appear tan, they have no actual decreased risk for sunburn after use. Reports have shown that the use of sunless tanners containing DHA can alter the appearance of melanocytic lesions clinically and has caused pseudochromhidrosis on the palms.^3,5,6 A study performed on a human keratinocyte cell line, HaCaT, showed that DHA can induce DNA damage, cell-cycle block, and apoptosis.⁷ In addition, as described in our case, patients may experience prolonged hyperpigmentation after use.

This case demonstrates the potential for persistent hyperpigmentation months after the use of sunless tanners containing DHA. Asking patients specific questions regarding their history of tanning product use is essential in identifying the pathology. Although a skin biopsy may not be strictly indicated, it may aid diagnosis, especially when the history is unclear. As more dermatologists support the use of sunless tanner, we must be aware of this possible outcome, especially on more cosmetically sensitive areas such as the fingers in this patient. Clinicians should be aware that the US Food and Drug Administration recommends avoiding contact with mucous membranes when applying products containing DHA and also recommends use of a test spot prior to treating the entire body with the product.⁸ Patients must not only be educated on the benefits of using sunless tanners but on the potential side effects with use of these products as well.

To the Editor:

The use of sunless tanners has become an alternative for individuals who wish to have tan skin without exposure to UV radiation.¹ We present a case of a patient who experienced persistent hyperpigmented patches on the hands months after the use of a sunless tanner containing dihydroxyacetone (DHA), a carbohydrate that reacts with amino acids in the stratum corneum to produce pigments called melanoidins. The hyperpigmentation caused by DHA is due to the Maillard reaction, which is the nonenzymatic glycation of amino groups of proteins by the carbonyl groups of sugar.² Many sunless tanners contain DHA at varying concentrations. Dermatologists should be aware of the benefits and potential side effects of these alternative products so that they can appropriately counsel patients.

A 20-year-old woman with no history of skin disease presented for evaluation of hyperpigmented patches on the dorsal hands of several months’ duration. Physical examination revealed ill-defined hyperpigmented patches on the dorsal fingers without associated scale or erythema (Figure 1). She had a remote history of Hodgkin lymphoma treated with chemotherapy and was in remission for 5 years prior to the current presentation. Her hematologists referred her to dermatology for evaluation, as they did not believe the patches could be related to her chemotherapy given that she had completed the treatment years before.

A punch biopsy of one of the patches was obtained to elucidate the origin of the hyperpigmentation, which had no obvious triggers according to the patient. Histopathologic examination revealed hyperpigmented parakeratosis and lentiginous hyperplasia along with pigmentation of the stratum corneum (Figures 2A and 2B) with black pigment, which stained positive with Fontana-Masson (Figure 2C).

Upon further questioning, it was revealed that our patient had used a sunless tanner 3 months prior to the development of the pigmented patches. She also used urea cream to hasten exfoliation, which resulted in lighter but still apparent hyperpigmentation at follow-up 6 months after the initial presentation.

There has been a rapid growth of the sunless tanning industry in the last several years due to effective public education against UV tanning. Generally, patients apply the sunless tanner and notice an increase in tan within the following 48 hours. Typically, the tan progressively fades with the normal skin exfoliation over the span of weeks. Although most of the DHA binds proteins in the stratum corneum, the US Food and Drug Administration released a report speculating that approximately 11% of the compound reaches the epidermis and dermis.³ There are limited data regarding the effects of the compound should it pass the stratum corneum into the living skin cells.

Products with DHA only confer a sun protection factor of approximately 3⁴; although patients may appear tan, they have no actual decreased risk for sunburn after use. Reports have shown that the use of sunless tanners containing DHA can alter the appearance of melanocytic lesions clinically and has caused pseudochromhidrosis on the palms.^3,5,6 A study performed on a human keratinocyte cell line, HaCaT, showed that DHA can induce DNA damage, cell-cycle block, and apoptosis.⁷ In addition, as described in our case, patients may experience prolonged hyperpigmentation after use.

This case demonstrates the potential for persistent hyperpigmentation months after the use of sunless tanners containing DHA. Asking patients specific questions regarding their history of tanning product use is essential in identifying the pathology. Although a skin biopsy may not be strictly indicated, it may aid diagnosis, especially when the history is unclear. As more dermatologists support the use of sunless tanner, we must be aware of this possible outcome, especially on more cosmetically sensitive areas such as the fingers in this patient. Clinicians should be aware that the US Food and Drug Administration recommends avoiding contact with mucous membranes when applying products containing DHA and also recommends use of a test spot prior to treating the entire body with the product.⁸ Patients must not only be educated on the benefits of using sunless tanners but on the potential side effects with use of these products as well.

To the Editor:

Pseudoepitheliomatous hyperplasia (PEH) is an uncommon type of reactive epidermal proliferation that can occur from a variety of causes, including an underlying infection, inflammation, neoplastic condition, or trauma induced from tattooing.¹ Diagnosis can be challenging and requires clinicopathologic correlation, as PEH can mimic malignancy on histopathology.^2-4 Histologically, PEH shows irregular hyperplasia of the epidermis and adnexal epithelium, elongation of the rete ridges, and extension of the reactive proliferation into the dermis. Absence of cytologic atypia is key to the diagnosis of PEH, helping to distinguish it from squamous cell carcinoma and keratoacanthoma. Clinically, patients typically present with well-demarcated, erythematous, scaly plaques or nodules in reactive areas, which can be symptomatically pruritic.

A 48-year-old woman presented with scaly and crusted verrucous plaques of 2 months’ duration that were isolated to the areas of purple pigment within a tattoo on the right lower leg. The patient reported pruritus in the affected areas that occurred immediately after obtaining the tattoo, which was her first and only tattoo. She denied any pertinent medical history, including an absence of immunosuppression and autoimmune or chronic inflammatory diseases.

Physical examination revealed scaly and crusted plaques isolated to areas of purple tattoo pigment (Figure 1). Areas of red, green, black, and blue pigmentation within the tattoo were uninvolved. With the initial suspicion of allergic contact dermatitis, two 6-mm punch biopsies were taken from adjacent linear plaques on the right leg for histology and tissue culture. Histopathologic evaluation revealed dermal tattoo pigment with overlying PEH and was negative for signs of infection (Figure 2). Infectious stains such as periodic acid–Schiff, Grocott-Gomori methenamine-silver, and Gram stains were performed and found to be negative. In addition, culture for mycobacteria came back negative. Prurigo was on the differential; however, histopathologic changes were more compatible with a PEH reaction to the tattoo.

Upon diagnosis, the patient was treated with clobetasol ointment 0.05% under occlusion for 1 month without reported improvement. The patient subsequently elected to undergo treatment with intralesional triamcinolone 5 mg/mL to all areas of PEH, except the areas immediately surrounding the healing biopsy sites. Twice-daily application of tacrolimus ointment 0.1% to all affected areas also was initiated. At follow-up 1 month later, she reported symptomatic relief of pruritus with a notable reduction in the thickness of the plaques in all treated areas (Figure 3). A second course of intralesional triamcinolone 5 mg/mL was performed. No additional plaques appeared during the treatment course, and the patient reported high satisfaction with the final result that was achieved.

An increase in the popularity of tattooing has led to more reports of various tattoo skin reactions.^4-6 The differential diagnosis is broad for tattoo reactions and includes granulomatous inflammation, sarcoidosis, psoriasis (Köbner phenomenon), allergic contact dermatitis, lichen planus, morphealike reactions, squamous cell carcinoma, and keratoacanthoma,⁵ which makes clinicopathologic correlation essential for accurate diagnosis. Our case demonstrated the characteristic epithelial hyperplasia in the absence of cytologic atypia. In addition, the presence of mixed dermal inflammation histologically was noted in our patient.

Pseudoepitheliomatous hyperplasia development from a tattoo in areas of both mercury-based and non–mercury-based red pigment is a known association.^7-9 Balfour et al¹⁰ also reported a case of PEH occurring secondary to manganese-based purple pigment. Because few cases have been reported, the epidemiology for PEH currently is unknown. Treatment of this condition primarily is anecdotal, with prior cases showing success with topical or intralesional steroids.^5,7 As with any steroid-based treatment, we recommend less aggressive treatments initially with close follow-up and adaptation as needed to minimize adverse effects such as unwanted atrophy. Some success has been reported with the use of the Q-switched Nd:YAG laser in the setting of a PEH tattoo reaction.⁵ Similar to other tattoo reactions, surgical removal can be considered with failure of more conservative treatment methods and focal involvement.

We report an unusual case of PEH occurring secondary to purple tattoo pigment. Our report also demonstrates the clinical and symptomatic improvement of PEH that can be achieved through the use of intralesional corticosteroid therapy. Our patient represents a case of PEH reactive to tattooing with purple ink. Further research to elucidate the precise pathogenesis of PEH tattoo reactions would be helpful in identifying high-risk patients and determining the most efficacious treatments.

To the Editor:

Pseudoepitheliomatous hyperplasia (PEH) is an uncommon type of reactive epidermal proliferation that can occur from a variety of causes, including an underlying infection, inflammation, neoplastic condition, or trauma induced from tattooing.¹ Diagnosis can be challenging and requires clinicopathologic correlation, as PEH can mimic malignancy on histopathology.^2-4 Histologically, PEH shows irregular hyperplasia of the epidermis and adnexal epithelium, elongation of the rete ridges, and extension of the reactive proliferation into the dermis. Absence of cytologic atypia is key to the diagnosis of PEH, helping to distinguish it from squamous cell carcinoma and keratoacanthoma. Clinically, patients typically present with well-demarcated, erythematous, scaly plaques or nodules in reactive areas, which can be symptomatically pruritic.

A 48-year-old woman presented with scaly and crusted verrucous plaques of 2 months’ duration that were isolated to the areas of purple pigment within a tattoo on the right lower leg. The patient reported pruritus in the affected areas that occurred immediately after obtaining the tattoo, which was her first and only tattoo. She denied any pertinent medical history, including an absence of immunosuppression and autoimmune or chronic inflammatory diseases.

Physical examination revealed scaly and crusted plaques isolated to areas of purple tattoo pigment (Figure 1). Areas of red, green, black, and blue pigmentation within the tattoo were uninvolved. With the initial suspicion of allergic contact dermatitis, two 6-mm punch biopsies were taken from adjacent linear plaques on the right leg for histology and tissue culture. Histopathologic evaluation revealed dermal tattoo pigment with overlying PEH and was negative for signs of infection (Figure 2). Infectious stains such as periodic acid–Schiff, Grocott-Gomori methenamine-silver, and Gram stains were performed and found to be negative. In addition, culture for mycobacteria came back negative. Prurigo was on the differential; however, histopathologic changes were more compatible with a PEH reaction to the tattoo.

Upon diagnosis, the patient was treated with clobetasol ointment 0.05% under occlusion for 1 month without reported improvement. The patient subsequently elected to undergo treatment with intralesional triamcinolone 5 mg/mL to all areas of PEH, except the areas immediately surrounding the healing biopsy sites. Twice-daily application of tacrolimus ointment 0.1% to all affected areas also was initiated. At follow-up 1 month later, she reported symptomatic relief of pruritus with a notable reduction in the thickness of the plaques in all treated areas (Figure 3). A second course of intralesional triamcinolone 5 mg/mL was performed. No additional plaques appeared during the treatment course, and the patient reported high satisfaction with the final result that was achieved.

An increase in the popularity of tattooing has led to more reports of various tattoo skin reactions.^4-6 The differential diagnosis is broad for tattoo reactions and includes granulomatous inflammation, sarcoidosis, psoriasis (Köbner phenomenon), allergic contact dermatitis, lichen planus, morphealike reactions, squamous cell carcinoma, and keratoacanthoma,⁵ which makes clinicopathologic correlation essential for accurate diagnosis. Our case demonstrated the characteristic epithelial hyperplasia in the absence of cytologic atypia. In addition, the presence of mixed dermal inflammation histologically was noted in our patient.

Pseudoepitheliomatous hyperplasia development from a tattoo in areas of both mercury-based and non–mercury-based red pigment is a known association.^7-9 Balfour et al¹⁰ also reported a case of PEH occurring secondary to manganese-based purple pigment. Because few cases have been reported, the epidemiology for PEH currently is unknown. Treatment of this condition primarily is anecdotal, with prior cases showing success with topical or intralesional steroids.^5,7 As with any steroid-based treatment, we recommend less aggressive treatments initially with close follow-up and adaptation as needed to minimize adverse effects such as unwanted atrophy. Some success has been reported with the use of the Q-switched Nd:YAG laser in the setting of a PEH tattoo reaction.⁵ Similar to other tattoo reactions, surgical removal can be considered with failure of more conservative treatment methods and focal involvement.

We report an unusual case of PEH occurring secondary to purple tattoo pigment. Our report also demonstrates the clinical and symptomatic improvement of PEH that can be achieved through the use of intralesional corticosteroid therapy. Our patient represents a case of PEH reactive to tattooing with purple ink. Further research to elucidate the precise pathogenesis of PEH tattoo reactions would be helpful in identifying high-risk patients and determining the most efficacious treatments.

To the Editor:

Pseudoepitheliomatous hyperplasia (PEH) is an uncommon type of reactive epidermal proliferation that can occur from a variety of causes, including an underlying infection, inflammation, neoplastic condition, or trauma induced from tattooing.¹ Diagnosis can be challenging and requires clinicopathologic correlation, as PEH can mimic malignancy on histopathology.^2-4 Histologically, PEH shows irregular hyperplasia of the epidermis and adnexal epithelium, elongation of the rete ridges, and extension of the reactive proliferation into the dermis. Absence of cytologic atypia is key to the diagnosis of PEH, helping to distinguish it from squamous cell carcinoma and keratoacanthoma. Clinically, patients typically present with well-demarcated, erythematous, scaly plaques or nodules in reactive areas, which can be symptomatically pruritic.

A 48-year-old woman presented with scaly and crusted verrucous plaques of 2 months’ duration that were isolated to the areas of purple pigment within a tattoo on the right lower leg. The patient reported pruritus in the affected areas that occurred immediately after obtaining the tattoo, which was her first and only tattoo. She denied any pertinent medical history, including an absence of immunosuppression and autoimmune or chronic inflammatory diseases.

Physical examination revealed scaly and crusted plaques isolated to areas of purple tattoo pigment (Figure 1). Areas of red, green, black, and blue pigmentation within the tattoo were uninvolved. With the initial suspicion of allergic contact dermatitis, two 6-mm punch biopsies were taken from adjacent linear plaques on the right leg for histology and tissue culture. Histopathologic evaluation revealed dermal tattoo pigment with overlying PEH and was negative for signs of infection (Figure 2). Infectious stains such as periodic acid–Schiff, Grocott-Gomori methenamine-silver, and Gram stains were performed and found to be negative. In addition, culture for mycobacteria came back negative. Prurigo was on the differential; however, histopathologic changes were more compatible with a PEH reaction to the tattoo.

Upon diagnosis, the patient was treated with clobetasol ointment 0.05% under occlusion for 1 month without reported improvement. The patient subsequently elected to undergo treatment with intralesional triamcinolone 5 mg/mL to all areas of PEH, except the areas immediately surrounding the healing biopsy sites. Twice-daily application of tacrolimus ointment 0.1% to all affected areas also was initiated. At follow-up 1 month later, she reported symptomatic relief of pruritus with a notable reduction in the thickness of the plaques in all treated areas (Figure 3). A second course of intralesional triamcinolone 5 mg/mL was performed. No additional plaques appeared during the treatment course, and the patient reported high satisfaction with the final result that was achieved.

An increase in the popularity of tattooing has led to more reports of various tattoo skin reactions.^4-6 The differential diagnosis is broad for tattoo reactions and includes granulomatous inflammation, sarcoidosis, psoriasis (Köbner phenomenon), allergic contact dermatitis, lichen planus, morphealike reactions, squamous cell carcinoma, and keratoacanthoma,⁵ which makes clinicopathologic correlation essential for accurate diagnosis. Our case demonstrated the characteristic epithelial hyperplasia in the absence of cytologic atypia. In addition, the presence of mixed dermal inflammation histologically was noted in our patient.

Pseudoepitheliomatous hyperplasia development from a tattoo in areas of both mercury-based and non–mercury-based red pigment is a known association.^7-9 Balfour et al¹⁰ also reported a case of PEH occurring secondary to manganese-based purple pigment. Because few cases have been reported, the epidemiology for PEH currently is unknown. Treatment of this condition primarily is anecdotal, with prior cases showing success with topical or intralesional steroids.^5,7 As with any steroid-based treatment, we recommend less aggressive treatments initially with close follow-up and adaptation as needed to minimize adverse effects such as unwanted atrophy. Some success has been reported with the use of the Q-switched Nd:YAG laser in the setting of a PEH tattoo reaction.⁵ Similar to other tattoo reactions, surgical removal can be considered with failure of more conservative treatment methods and focal involvement.

We report an unusual case of PEH occurring secondary to purple tattoo pigment. Our report also demonstrates the clinical and symptomatic improvement of PEH that can be achieved through the use of intralesional corticosteroid therapy. Our patient represents a case of PEH reactive to tattooing with purple ink. Further research to elucidate the precise pathogenesis of PEH tattoo reactions would be helpful in identifying high-risk patients and determining the most efficacious treatments.

To the Editor:

Lymphomatoid papulosis is a rare chronic skin disorder characterized by recurrent, self-healing crops of papulonodular eruptions, often resembling cutaneous T-cell lymphoma.¹ Oral bexarotene, a retinoid X receptor–selective retinoid, can be used to control the disease.^2,3 Lichen planopilaris (LPP) is a type of cicatricial alopecia characterized by irreversible hair loss, perifollicular inflammation, and follicular hyperkeratosis, commonly affecting the scalp vertex in adults.⁴ We report a case of a patient with lymphomatoid papulosis who was treated with bexarotene and subsequently developed LPP. We also discuss a proposed mechanism by which bexarotene may have influenced the onset of LPP.

A 35-year-old woman who was previously healthy initially presented with recurrent pruritic papular eruptions on the flank, axillae, and groin of several months’ duration. The lesions appeared as 2-mm, flat-topped, violaceous papules. The patient had no known drug allergies, no medical or family history of skin disease, and was only taking 3000 mg/d of omega-3 fatty acids (fish oil). Histopathologic examination of a biopsy specimen from the inner thigh showed enlarged, atypical, dermal lymphocytes that were CD30⁺ (Figure 1). These findings were consistent with lymphomatoid papulosis. As she had undergone tubal ligation several years prior, she was prescribed oral bexarotene 300 mg once daily in addition to triamcinolone cream 0.1% twice daily, as needed. Symptoms were well controlled on this regimen.

Six months later the patient returned, presenting with a new central patch of scarring alopecia on the vertex of the scalp (Figure 2). Adjacent to the area of hair loss were areas of prominent perifollicular scale that were slightly violaceous in color. Two 4-mm punch biopsies of the scalp showed dermal scarring with perifollicular lamellar fibrosis surrounded by a rim of lymphoplasmacytic inflammation (Figure 3). Sebaceous glands were found to be reduced in number. These findings were consistent with cicatricial alopecia, which was further classified as LPP in conjunction with the clinical findings. No CD30⁺ lymphocytes were identified in these specimens.

Baseline fasting triglycerides were 123 mg/dL (desirable: <150 mg/dL; borderline: 150–199 mg/dL; high: ≥200 mg/dL) and were stable over the first 4 months on bexarotene. After 5 months of therapy, the triglycerides increased to a high of 255 mg/dL, which corresponded with the onset of LPP. She was treated for the hypertriglyceridemia with omega-3 fatty acids (fish oil), and subsequent triglyceride levels have normalized and been stable. Her alopecia has not progressed but is persistent. She continues to have central hypothyroidism due to bexarotene and is on levothyroxine. The lymphomatoid papulosis also remains stable with no signs of progression to cutaneous T-cell lymphoma.

Although the exact mechanism of LPP is not fully understood, studies have suggested that cellular lipid metabolism may be responsible for the inflammation of the pilosebaceous unit.^4-11 Hyperlipidemia is the most common side effect of oral bexarotene, typically occurring within the first 2 to 4 weeks of treatment.^3,12 Considering the insights into the role of lipid regulation on LPP pathogenesis, it is reasonable to suspect that the dyslipidemia caused by bexarotene may have triggered the onset of LPP in our patient. The patient’s lipid values mostly remained within reference range throughout the course of treatment, though she did have elevation of triglycerides around the onset of LPP. Dyslipidemia has been reported in patients with lichen planus but not in patients with LPP. One case-control study showed no dyslipidemia in patients with LPP, but the triglyceride levels were not tracked over time and patients had varying durations since onset of disease at presentation.^9-11,13 In our case, we were fortunate to have this information, and it may suggest an interaction between lipid dysregulation and the development of LPP. It would be interesting to explore this further in a larger patient population and to evaluate if control of dyslipidemia reduces progression of disease as it appears to have done for our patient.

To the Editor:

Lymphomatoid papulosis is a rare chronic skin disorder characterized by recurrent, self-healing crops of papulonodular eruptions, often resembling cutaneous T-cell lymphoma.¹ Oral bexarotene, a retinoid X receptor–selective retinoid, can be used to control the disease.^2,3 Lichen planopilaris (LPP) is a type of cicatricial alopecia characterized by irreversible hair loss, perifollicular inflammation, and follicular hyperkeratosis, commonly affecting the scalp vertex in adults.⁴ We report a case of a patient with lymphomatoid papulosis who was treated with bexarotene and subsequently developed LPP. We also discuss a proposed mechanism by which bexarotene may have influenced the onset of LPP.

A 35-year-old woman who was previously healthy initially presented with recurrent pruritic papular eruptions on the flank, axillae, and groin of several months’ duration. The lesions appeared as 2-mm, flat-topped, violaceous papules. The patient had no known drug allergies, no medical or family history of skin disease, and was only taking 3000 mg/d of omega-3 fatty acids (fish oil). Histopathologic examination of a biopsy specimen from the inner thigh showed enlarged, atypical, dermal lymphocytes that were CD30⁺ (Figure 1). These findings were consistent with lymphomatoid papulosis. As she had undergone tubal ligation several years prior, she was prescribed oral bexarotene 300 mg once daily in addition to triamcinolone cream 0.1% twice daily, as needed. Symptoms were well controlled on this regimen.

Six months later the patient returned, presenting with a new central patch of scarring alopecia on the vertex of the scalp (Figure 2). Adjacent to the area of hair loss were areas of prominent perifollicular scale that were slightly violaceous in color. Two 4-mm punch biopsies of the scalp showed dermal scarring with perifollicular lamellar fibrosis surrounded by a rim of lymphoplasmacytic inflammation (Figure 3). Sebaceous glands were found to be reduced in number. These findings were consistent with cicatricial alopecia, which was further classified as LPP in conjunction with the clinical findings. No CD30⁺ lymphocytes were identified in these specimens.

Baseline fasting triglycerides were 123 mg/dL (desirable: <150 mg/dL; borderline: 150–199 mg/dL; high: ≥200 mg/dL) and were stable over the first 4 months on bexarotene. After 5 months of therapy, the triglycerides increased to a high of 255 mg/dL, which corresponded with the onset of LPP. She was treated for the hypertriglyceridemia with omega-3 fatty acids (fish oil), and subsequent triglyceride levels have normalized and been stable. Her alopecia has not progressed but is persistent. She continues to have central hypothyroidism due to bexarotene and is on levothyroxine. The lymphomatoid papulosis also remains stable with no signs of progression to cutaneous T-cell lymphoma.

Although the exact mechanism of LPP is not fully understood, studies have suggested that cellular lipid metabolism may be responsible for the inflammation of the pilosebaceous unit.^4-11 Hyperlipidemia is the most common side effect of oral bexarotene, typically occurring within the first 2 to 4 weeks of treatment.^3,12 Considering the insights into the role of lipid regulation on LPP pathogenesis, it is reasonable to suspect that the dyslipidemia caused by bexarotene may have triggered the onset of LPP in our patient. The patient’s lipid values mostly remained within reference range throughout the course of treatment, though she did have elevation of triglycerides around the onset of LPP. Dyslipidemia has been reported in patients with lichen planus but not in patients with LPP. One case-control study showed no dyslipidemia in patients with LPP, but the triglyceride levels were not tracked over time and patients had varying durations since onset of disease at presentation.^9-11,13 In our case, we were fortunate to have this information, and it may suggest an interaction between lipid dysregulation and the development of LPP. It would be interesting to explore this further in a larger patient population and to evaluate if control of dyslipidemia reduces progression of disease as it appears to have done for our patient.

To the Editor:

Lymphomatoid papulosis is a rare chronic skin disorder characterized by recurrent, self-healing crops of papulonodular eruptions, often resembling cutaneous T-cell lymphoma.¹ Oral bexarotene, a retinoid X receptor–selective retinoid, can be used to control the disease.^2,3 Lichen planopilaris (LPP) is a type of cicatricial alopecia characterized by irreversible hair loss, perifollicular inflammation, and follicular hyperkeratosis, commonly affecting the scalp vertex in adults.⁴ We report a case of a patient with lymphomatoid papulosis who was treated with bexarotene and subsequently developed LPP. We also discuss a proposed mechanism by which bexarotene may have influenced the onset of LPP.

A 35-year-old woman who was previously healthy initially presented with recurrent pruritic papular eruptions on the flank, axillae, and groin of several months’ duration. The lesions appeared as 2-mm, flat-topped, violaceous papules. The patient had no known drug allergies, no medical or family history of skin disease, and was only taking 3000 mg/d of omega-3 fatty acids (fish oil). Histopathologic examination of a biopsy specimen from the inner thigh showed enlarged, atypical, dermal lymphocytes that were CD30⁺ (Figure 1). These findings were consistent with lymphomatoid papulosis. As she had undergone tubal ligation several years prior, she was prescribed oral bexarotene 300 mg once daily in addition to triamcinolone cream 0.1% twice daily, as needed. Symptoms were well controlled on this regimen.

Six months later the patient returned, presenting with a new central patch of scarring alopecia on the vertex of the scalp (Figure 2). Adjacent to the area of hair loss were areas of prominent perifollicular scale that were slightly violaceous in color. Two 4-mm punch biopsies of the scalp showed dermal scarring with perifollicular lamellar fibrosis surrounded by a rim of lymphoplasmacytic inflammation (Figure 3). Sebaceous glands were found to be reduced in number. These findings were consistent with cicatricial alopecia, which was further classified as LPP in conjunction with the clinical findings. No CD30⁺ lymphocytes were identified in these specimens.

Baseline fasting triglycerides were 123 mg/dL (desirable: <150 mg/dL; borderline: 150–199 mg/dL; high: ≥200 mg/dL) and were stable over the first 4 months on bexarotene. After 5 months of therapy, the triglycerides increased to a high of 255 mg/dL, which corresponded with the onset of LPP. She was treated for the hypertriglyceridemia with omega-3 fatty acids (fish oil), and subsequent triglyceride levels have normalized and been stable. Her alopecia has not progressed but is persistent. She continues to have central hypothyroidism due to bexarotene and is on levothyroxine. The lymphomatoid papulosis also remains stable with no signs of progression to cutaneous T-cell lymphoma.

Although the exact mechanism of LPP is not fully understood, studies have suggested that cellular lipid metabolism may be responsible for the inflammation of the pilosebaceous unit.^4-11 Hyperlipidemia is the most common side effect of oral bexarotene, typically occurring within the first 2 to 4 weeks of treatment.^3,12 Considering the insights into the role of lipid regulation on LPP pathogenesis, it is reasonable to suspect that the dyslipidemia caused by bexarotene may have triggered the onset of LPP in our patient. The patient’s lipid values mostly remained within reference range throughout the course of treatment, though she did have elevation of triglycerides around the onset of LPP. Dyslipidemia has been reported in patients with lichen planus but not in patients with LPP. One case-control study showed no dyslipidemia in patients with LPP, but the triglyceride levels were not tracked over time and patients had varying durations since onset of disease at presentation.^9-11,13 In our case, we were fortunate to have this information, and it may suggest an interaction between lipid dysregulation and the development of LPP. It would be interesting to explore this further in a larger patient population and to evaluate if control of dyslipidemia reduces progression of disease as it appears to have done for our patient.

 

To the Editor:

A 3-year-old boy with a history of tuberous sclerosis presented to our clinic for evaluation of bumps on the second and third fingers of the left hand. Physical examination revealed firm rubbery nodules on the palmar third metacarpophalangeal joint extending to the palm and the lateral aspect of the distal third dorsal finger. There also was asymmetric overgrowth of the left second and third digits consistent with bony segmental overgrowth (Figure).

Tuberous sclerosis and overgrowth syndromes including Proteus syndrome have mutations that share a common pathway, namely the PI3K/AKT/mTOR (phosphoinositide 3-kinase/alpha serine/threonine-protein kinase/mammalian target of rapamycin) pathway.¹ The mutations in tuberous sclerosis involve the loss of TSC1 (TSC complex subunit 1) on chromosome 9 or TSC2 (TSC complex subunit 2) on chromosome 16.² The protein products of these genes, hamartin and tuberin, act together as a tumor suppressor complex.³ The inheritance pattern of tuberous sclerosis is autosomal dominant, though two-thirds of cases are due to de novo germline mutations.⁴ The second copy of the gene must be lost spontaneously in any particular cell for the deleterious effects of the disease to manifest. The mutation in overgrowth syndromes including Proteus syndrome involves the activation of AKT1 (AKT serine/threonine kinase 1) on chromosome 14. This mutation occurs in somatic cells as opposed to germ cells, as in tuberous sclerosis. This difference accounts for the mosaic expression of segmental overgrowth syndromes. This concept has been demonstrated in overgrowth syndromes such as Proteus syndrome, with cells from unaffected areas having different genetic makeup than those from affected tissues.⁵ These mutations, though different, result in the downstream effects of unchecked messenger RNA translation and dysregulated cellular growth.

In our patient, we hypothesized that a small proportion of his postfertilization somatic cells underwent a second de novo mutation in the AKT1 pathway, resulting in the bony overgrowth seen on the left hand. We suspected that this second mutation could be an activation of AKT1, the mutation seen in Proteus syndrome. Sequencing of the tissue may be performed in the future, especially if segmental overgrowth continues and necessitates therapy.

 

To the Editor:

A 3-year-old boy with a history of tuberous sclerosis presented to our clinic for evaluation of bumps on the second and third fingers of the left hand. Physical examination revealed firm rubbery nodules on the palmar third metacarpophalangeal joint extending to the palm and the lateral aspect of the distal third dorsal finger. There also was asymmetric overgrowth of the left second and third digits consistent with bony segmental overgrowth (Figure).

Tuberous sclerosis and overgrowth syndromes including Proteus syndrome have mutations that share a common pathway, namely the PI3K/AKT/mTOR (phosphoinositide 3-kinase/alpha serine/threonine-protein kinase/mammalian target of rapamycin) pathway.¹ The mutations in tuberous sclerosis involve the loss of TSC1 (TSC complex subunit 1) on chromosome 9 or TSC2 (TSC complex subunit 2) on chromosome 16.² The protein products of these genes, hamartin and tuberin, act together as a tumor suppressor complex.³ The inheritance pattern of tuberous sclerosis is autosomal dominant, though two-thirds of cases are due to de novo germline mutations.⁴ The second copy of the gene must be lost spontaneously in any particular cell for the deleterious effects of the disease to manifest. The mutation in overgrowth syndromes including Proteus syndrome involves the activation of AKT1 (AKT serine/threonine kinase 1) on chromosome 14. This mutation occurs in somatic cells as opposed to germ cells, as in tuberous sclerosis. This difference accounts for the mosaic expression of segmental overgrowth syndromes. This concept has been demonstrated in overgrowth syndromes such as Proteus syndrome, with cells from unaffected areas having different genetic makeup than those from affected tissues.⁵ These mutations, though different, result in the downstream effects of unchecked messenger RNA translation and dysregulated cellular growth.

In our patient, we hypothesized that a small proportion of his postfertilization somatic cells underwent a second de novo mutation in the AKT1 pathway, resulting in the bony overgrowth seen on the left hand. We suspected that this second mutation could be an activation of AKT1, the mutation seen in Proteus syndrome. Sequencing of the tissue may be performed in the future, especially if segmental overgrowth continues and necessitates therapy.

 

To the Editor:

A 3-year-old boy with a history of tuberous sclerosis presented to our clinic for evaluation of bumps on the second and third fingers of the left hand. Physical examination revealed firm rubbery nodules on the palmar third metacarpophalangeal joint extending to the palm and the lateral aspect of the distal third dorsal finger. There also was asymmetric overgrowth of the left second and third digits consistent with bony segmental overgrowth (Figure).

Tuberous sclerosis and overgrowth syndromes including Proteus syndrome have mutations that share a common pathway, namely the PI3K/AKT/mTOR (phosphoinositide 3-kinase/alpha serine/threonine-protein kinase/mammalian target of rapamycin) pathway.¹ The mutations in tuberous sclerosis involve the loss of TSC1 (TSC complex subunit 1) on chromosome 9 or TSC2 (TSC complex subunit 2) on chromosome 16.² The protein products of these genes, hamartin and tuberin, act together as a tumor suppressor complex.³ The inheritance pattern of tuberous sclerosis is autosomal dominant, though two-thirds of cases are due to de novo germline mutations.⁴ The second copy of the gene must be lost spontaneously in any particular cell for the deleterious effects of the disease to manifest. The mutation in overgrowth syndromes including Proteus syndrome involves the activation of AKT1 (AKT serine/threonine kinase 1) on chromosome 14. This mutation occurs in somatic cells as opposed to germ cells, as in tuberous sclerosis. This difference accounts for the mosaic expression of segmental overgrowth syndromes. This concept has been demonstrated in overgrowth syndromes such as Proteus syndrome, with cells from unaffected areas having different genetic makeup than those from affected tissues.⁵ These mutations, though different, result in the downstream effects of unchecked messenger RNA translation and dysregulated cellular growth.

In our patient, we hypothesized that a small proportion of his postfertilization somatic cells underwent a second de novo mutation in the AKT1 pathway, resulting in the bony overgrowth seen on the left hand. We suspected that this second mutation could be an activation of AKT1, the mutation seen in Proteus syndrome. Sequencing of the tissue may be performed in the future, especially if segmental overgrowth continues and necessitates therapy.

 

To the Editor:

A 59-year-old man presented with a lesion on the right frontal scalp of 4 months’ duration and a lesion on the left frontal scalp of 1 month’s duration. Both lesions were tender, bleeding, nonhealing, and growing in size. The patient reported no improvement with the use of triple antibiotic ointment. He denied any associated symptoms or trauma to the affected areas. He had a history of stage IV esophageal adenocarcinoma that initially had been surgically removed 6 years prior but metastasized to the lungs and bone. The patient subsequently underwent treatment with FOLFOX (folinic acid, fluorouracil, oxaliplatin), trastuzumab, and radiation therapy.

Physical examination revealed a hyperkeratotic pink nodule with a central erosion and crust on the right frontal scalp measuring 1.5×2 cm in diameter (Figure 1A). The left frontal scalp lesion was a smooth pearly papule measuring 5×5 mm in diameter (Figure 1B). The differential diagnosis included basal cell carcinoma, squamous cell carcinoma, and cutaneous metastases from esophageal adenocarcinoma. Shave biopsies were taken of both scalp lesions.

Histologic examination of both scalp lesions demonstrated a dermal gland-forming neoplasm with an infiltrative distribution that was comprised of irregular cribriform glands containing cellular debris (Figure 2). The cells of interest were enlarged and contained pleomorphic crowded nuclei that formed aberrant mitotic division figures. Both biopsies were positive for cytokeratin 7 and negative for cytokeratin 20 and CDX2. The final diagnosis for both scalp lesions was poorly differentiated adenocarcinoma, which was most suggestive of cutaneous metastases of the patient’s known esophageal adenocarcinoma. Given further metastasis, the patient was ultimately switched to ramucirumab and paclitaxel per oncology.

Esophageal carcinoma is the eighth most common cause of death related to cancer worldwide. Adenocarcinoma is the most prevalent histologic type of esophageal carcinoma, with an incidence as high as 5.69 per 100,000 individuals in the United States.¹ Internal malignancies that lead to cutaneous metastases are not uncommon; however, the literature is limited on cutaneous scalp metastases from esophageal cancer. Cutaneous metastases secondary to internal malignancies present in less than 10% of overall cases; tend to derive from the breasts, lungs, and large bowel; and usually present in the sixth to seventh decades of life.² Further, roughly 1% of all skin metastases originate from the esophagus.³ When there are cutaneous metastases to the scalp, they often arise from breast carcinomas and renal cell carcinomas.^4,5 Rarely does esophageal cancer spread to the scalp.^2,6-9 When cutaneous metastases originate from the esophagus, multiple cancers such as squamous cell carcinomas, mucoepidermoid carcinomas, small cell carcinomas, and adenocarcinomas can be the etiology of origin.¹⁰ Metastases originating from esophageal carcinomas frequently are diagnosed in the abdominal lymph nodes (45%), liver (35%), lungs (20%), cervical/supraclavicular lymph nodes (18%), bones (9%), adrenals (5%), peritoneum (2%), brain (2%), stomach (1%), pancreas (1%), pleura (1%), skin/body wall (1%), pericardium (1%), and spleen (1%).³ Additionally, multiple cutaneous scalp metastases from esophageal adenocarcinoma have been reported,^7,9 as were seen in our case.

The clinical appearance of cutaneous scalp metastases has been described as inflammatory papules, indurated plaques, or nodules,² which is consistent with our case, though the spectrum of presentation is admittedly broad. Histopathology of lesions characteristically shows prominent intraluminal necrotic cellular debris, which is common for adenocarcinomas of the gastrointestinal tract.⁷ However, utilizing immunohistochemical stains to detect specific antigens within tumor cells allows for better specificity of the tumor origin. More specifically, cytokeratin 7 and cytokeratin 20 are stained in esophageal metaplasia, such as Barrett esophagus, rather than in intestinal metaplasia inside the stomach.^2,11 Therefore, discerning the location of the adenocarcinoma proves fruitful when using cytokeratin 7 and cytokeratin 20. Although CDX2 is an additional marker that can be used for gastrointestinal adenocarcinomas with decent sensitivity and specificity, it can still be expressed in mucinous ovarian carcinomas and urinary bladder adenocarcinomas.¹² In our patient, the strong reactivity of cytokeratin 7 in addition to the characteristic morphology in both presenting biopsies was sufficient to make the diagnosis of cutaneous metastasis of esophageal adenocarcinoma to the scalp.

Our case highlights multiple cutaneous metastases of the scalp from a primary esophageal adenocarcinoma. Although cutaneous scalp metastasis of esophageal adenocarcinoma is rare, it is essential to provide a full-body skin examination, including the scalp, in patients with a history of esophageal cancer and to biopsy any suspicious nodules or plaques. The 1-year survival rate after diagnosis of esophageal carcinoma is less than 50%, and the 5-year survival rate is less than 10%.¹³ Identifying cutaneous metastasis of an esophageal adenocarcinoma can either change the staging of the cancer (if it was the first distant metastasis noted) or indicate an insufficient response to treatment in a patient with known metastatic disease, prompting a potential change in treatment.⁷

This case illustrates a rare site of metastasis of a fairly common cancer and highlights the histopathology and accompanying immunohistochemical stains that can be useful in diagnosis as well as the spectrum of its clinical presentation.

 

To the Editor:

A 59-year-old man presented with a lesion on the right frontal scalp of 4 months’ duration and a lesion on the left frontal scalp of 1 month’s duration. Both lesions were tender, bleeding, nonhealing, and growing in size. The patient reported no improvement with the use of triple antibiotic ointment. He denied any associated symptoms or trauma to the affected areas. He had a history of stage IV esophageal adenocarcinoma that initially had been surgically removed 6 years prior but metastasized to the lungs and bone. The patient subsequently underwent treatment with FOLFOX (folinic acid, fluorouracil, oxaliplatin), trastuzumab, and radiation therapy.

Physical examination revealed a hyperkeratotic pink nodule with a central erosion and crust on the right frontal scalp measuring 1.5×2 cm in diameter (Figure 1A). The left frontal scalp lesion was a smooth pearly papule measuring 5×5 mm in diameter (Figure 1B). The differential diagnosis included basal cell carcinoma, squamous cell carcinoma, and cutaneous metastases from esophageal adenocarcinoma. Shave biopsies were taken of both scalp lesions.

Histologic examination of both scalp lesions demonstrated a dermal gland-forming neoplasm with an infiltrative distribution that was comprised of irregular cribriform glands containing cellular debris (Figure 2). The cells of interest were enlarged and contained pleomorphic crowded nuclei that formed aberrant mitotic division figures. Both biopsies were positive for cytokeratin 7 and negative for cytokeratin 20 and CDX2. The final diagnosis for both scalp lesions was poorly differentiated adenocarcinoma, which was most suggestive of cutaneous metastases of the patient’s known esophageal adenocarcinoma. Given further metastasis, the patient was ultimately switched to ramucirumab and paclitaxel per oncology.

Esophageal carcinoma is the eighth most common cause of death related to cancer worldwide. Adenocarcinoma is the most prevalent histologic type of esophageal carcinoma, with an incidence as high as 5.69 per 100,000 individuals in the United States.¹ Internal malignancies that lead to cutaneous metastases are not uncommon; however, the literature is limited on cutaneous scalp metastases from esophageal cancer. Cutaneous metastases secondary to internal malignancies present in less than 10% of overall cases; tend to derive from the breasts, lungs, and large bowel; and usually present in the sixth to seventh decades of life.² Further, roughly 1% of all skin metastases originate from the esophagus.³ When there are cutaneous metastases to the scalp, they often arise from breast carcinomas and renal cell carcinomas.^4,5 Rarely does esophageal cancer spread to the scalp.^2,6-9 When cutaneous metastases originate from the esophagus, multiple cancers such as squamous cell carcinomas, mucoepidermoid carcinomas, small cell carcinomas, and adenocarcinomas can be the etiology of origin.¹⁰ Metastases originating from esophageal carcinomas frequently are diagnosed in the abdominal lymph nodes (45%), liver (35%), lungs (20%), cervical/supraclavicular lymph nodes (18%), bones (9%), adrenals (5%), peritoneum (2%), brain (2%), stomach (1%), pancreas (1%), pleura (1%), skin/body wall (1%), pericardium (1%), and spleen (1%).³ Additionally, multiple cutaneous scalp metastases from esophageal adenocarcinoma have been reported,^7,9 as were seen in our case.

The clinical appearance of cutaneous scalp metastases has been described as inflammatory papules, indurated plaques, or nodules,² which is consistent with our case, though the spectrum of presentation is admittedly broad. Histopathology of lesions characteristically shows prominent intraluminal necrotic cellular debris, which is common for adenocarcinomas of the gastrointestinal tract.⁷ However, utilizing immunohistochemical stains to detect specific antigens within tumor cells allows for better specificity of the tumor origin. More specifically, cytokeratin 7 and cytokeratin 20 are stained in esophageal metaplasia, such as Barrett esophagus, rather than in intestinal metaplasia inside the stomach.^2,11 Therefore, discerning the location of the adenocarcinoma proves fruitful when using cytokeratin 7 and cytokeratin 20. Although CDX2 is an additional marker that can be used for gastrointestinal adenocarcinomas with decent sensitivity and specificity, it can still be expressed in mucinous ovarian carcinomas and urinary bladder adenocarcinomas.¹² In our patient, the strong reactivity of cytokeratin 7 in addition to the characteristic morphology in both presenting biopsies was sufficient to make the diagnosis of cutaneous metastasis of esophageal adenocarcinoma to the scalp.

Our case highlights multiple cutaneous metastases of the scalp from a primary esophageal adenocarcinoma. Although cutaneous scalp metastasis of esophageal adenocarcinoma is rare, it is essential to provide a full-body skin examination, including the scalp, in patients with a history of esophageal cancer and to biopsy any suspicious nodules or plaques. The 1-year survival rate after diagnosis of esophageal carcinoma is less than 50%, and the 5-year survival rate is less than 10%.¹³ Identifying cutaneous metastasis of an esophageal adenocarcinoma can either change the staging of the cancer (if it was the first distant metastasis noted) or indicate an insufficient response to treatment in a patient with known metastatic disease, prompting a potential change in treatment.⁷

This case illustrates a rare site of metastasis of a fairly common cancer and highlights the histopathology and accompanying immunohistochemical stains that can be useful in diagnosis as well as the spectrum of its clinical presentation.

 

To the Editor:

A 59-year-old man presented with a lesion on the right frontal scalp of 4 months’ duration and a lesion on the left frontal scalp of 1 month’s duration. Both lesions were tender, bleeding, nonhealing, and growing in size. The patient reported no improvement with the use of triple antibiotic ointment. He denied any associated symptoms or trauma to the affected areas. He had a history of stage IV esophageal adenocarcinoma that initially had been surgically removed 6 years prior but metastasized to the lungs and bone. The patient subsequently underwent treatment with FOLFOX (folinic acid, fluorouracil, oxaliplatin), trastuzumab, and radiation therapy.

Physical examination revealed a hyperkeratotic pink nodule with a central erosion and crust on the right frontal scalp measuring 1.5×2 cm in diameter (Figure 1A). The left frontal scalp lesion was a smooth pearly papule measuring 5×5 mm in diameter (Figure 1B). The differential diagnosis included basal cell carcinoma, squamous cell carcinoma, and cutaneous metastases from esophageal adenocarcinoma. Shave biopsies were taken of both scalp lesions.

Histologic examination of both scalp lesions demonstrated a dermal gland-forming neoplasm with an infiltrative distribution that was comprised of irregular cribriform glands containing cellular debris (Figure 2). The cells of interest were enlarged and contained pleomorphic crowded nuclei that formed aberrant mitotic division figures. Both biopsies were positive for cytokeratin 7 and negative for cytokeratin 20 and CDX2. The final diagnosis for both scalp lesions was poorly differentiated adenocarcinoma, which was most suggestive of cutaneous metastases of the patient’s known esophageal adenocarcinoma. Given further metastasis, the patient was ultimately switched to ramucirumab and paclitaxel per oncology.

Esophageal carcinoma is the eighth most common cause of death related to cancer worldwide. Adenocarcinoma is the most prevalent histologic type of esophageal carcinoma, with an incidence as high as 5.69 per 100,000 individuals in the United States.¹ Internal malignancies that lead to cutaneous metastases are not uncommon; however, the literature is limited on cutaneous scalp metastases from esophageal cancer. Cutaneous metastases secondary to internal malignancies present in less than 10% of overall cases; tend to derive from the breasts, lungs, and large bowel; and usually present in the sixth to seventh decades of life.² Further, roughly 1% of all skin metastases originate from the esophagus.³ When there are cutaneous metastases to the scalp, they often arise from breast carcinomas and renal cell carcinomas.^4,5 Rarely does esophageal cancer spread to the scalp.^2,6-9 When cutaneous metastases originate from the esophagus, multiple cancers such as squamous cell carcinomas, mucoepidermoid carcinomas, small cell carcinomas, and adenocarcinomas can be the etiology of origin.¹⁰ Metastases originating from esophageal carcinomas frequently are diagnosed in the abdominal lymph nodes (45%), liver (35%), lungs (20%), cervical/supraclavicular lymph nodes (18%), bones (9%), adrenals (5%), peritoneum (2%), brain (2%), stomach (1%), pancreas (1%), pleura (1%), skin/body wall (1%), pericardium (1%), and spleen (1%).³ Additionally, multiple cutaneous scalp metastases from esophageal adenocarcinoma have been reported,^7,9 as were seen in our case.

The clinical appearance of cutaneous scalp metastases has been described as inflammatory papules, indurated plaques, or nodules,² which is consistent with our case, though the spectrum of presentation is admittedly broad. Histopathology of lesions characteristically shows prominent intraluminal necrotic cellular debris, which is common for adenocarcinomas of the gastrointestinal tract.⁷ However, utilizing immunohistochemical stains to detect specific antigens within tumor cells allows for better specificity of the tumor origin. More specifically, cytokeratin 7 and cytokeratin 20 are stained in esophageal metaplasia, such as Barrett esophagus, rather than in intestinal metaplasia inside the stomach.^2,11 Therefore, discerning the location of the adenocarcinoma proves fruitful when using cytokeratin 7 and cytokeratin 20. Although CDX2 is an additional marker that can be used for gastrointestinal adenocarcinomas with decent sensitivity and specificity, it can still be expressed in mucinous ovarian carcinomas and urinary bladder adenocarcinomas.¹² In our patient, the strong reactivity of cytokeratin 7 in addition to the characteristic morphology in both presenting biopsies was sufficient to make the diagnosis of cutaneous metastasis of esophageal adenocarcinoma to the scalp.

Our case highlights multiple cutaneous metastases of the scalp from a primary esophageal adenocarcinoma. Although cutaneous scalp metastasis of esophageal adenocarcinoma is rare, it is essential to provide a full-body skin examination, including the scalp, in patients with a history of esophageal cancer and to biopsy any suspicious nodules or plaques. The 1-year survival rate after diagnosis of esophageal carcinoma is less than 50%, and the 5-year survival rate is less than 10%.¹³ Identifying cutaneous metastasis of an esophageal adenocarcinoma can either change the staging of the cancer (if it was the first distant metastasis noted) or indicate an insufficient response to treatment in a patient with known metastatic disease, prompting a potential change in treatment.⁷

This case illustrates a rare site of metastasis of a fairly common cancer and highlights the histopathology and accompanying immunohistochemical stains that can be useful in diagnosis as well as the spectrum of its clinical presentation.

To the Editor:

Calciphylaxis (also known as calcific uremic arteriolopathy and calcifying panniculitis) is a rare vasculopathy affecting the small vessels.¹ It is characterized by cutaneous ischemia and necrosis secondary to calcification. It is most commonly seen in patients with end-stage renal disease (ESRD) and hyperparathyroidism.^1-3 Histopathologic features that are consistent with the diagnosis of calciphylaxis include calcification of medium-sized vessels in the deep dermis or subcutaneous fat as well as smaller distal vessels that supply the papillary dermis and epidermis.^4,5 Although it commonly presents as well-demarcated, painful, purplish lesions that evolve into necrotic eschars, calciphylaxis rarely can present with hemorrhagic or serous bullous lesions followed by ulceration, as was seen in our patient.^1,5,6 We report this uncommon presentation to highlight the variety in clinical appearance of calciphylaxis and the importance of early diagnosis.

A 43-year-old woman presented to the emergency department for evaluation of chest and abdominal pain that began 1 day prior to presentation. She had a history of systemic lupus erythematosus and ESRD secondary to poststreptococcal glomerulonephritis and was currently on peritoneal dialysis. The patient was admitted for peritonitis and treated with broad-spectrum antibiotics. At the time of admission, the patient also was noted to have several painful bullae on the legs. Her medical history also was remarkable for cerebral infarction, fibromyalgia, cerebral artery occlusion with cerebral infarction, sciatica, hyperlipidemia, deep vein thrombosis, and seizures. She had no history of herpes simplex virus. Surgical history was remarkable for tubal ligation, nephrectomy and kidney transplant, parathyroidectomy, and cholecystectomy. The patient’s medications included sevelamer carbonate, prednisone, epogen, calcium carbonate, esomeprazole, ondansetron, topical gentamicin, and atorvastatin.

Skin examination was performed by the inpatient dermatology service and revealed several tense, 1- to 5-cm, nonhemorrhagic bullae on the thighs and lower legs, some that had ruptured. The lesions were notably tender to palpation. No surrounding erythema, ecchymosis, or warmth was appreciated. The Nikolsky sign was negative. The patient also was noted to have at least grade 2 to 3+ pitting edema of the bilateral legs. The oral and conjunctival mucosae were unremarkable.

Antinuclear antibody, double-stranded DNA, and anti-Smith antibody levels were negative. A punch biopsy of the left lateral thigh revealed intraepidermal vesicular dermatitis with dermal edema suggestive of edema bullae and direct immunofluorescence was negative for immune complex and complement deposition.

Conservative therapy with wound care was recommended. The patient continued to report persistent severe skin pain and developed a subcutaneous nodule on the right inner thigh 1 week later, prompting a second biopsy. Results of the excisional biopsy were nondiagnostic but were suggestive of calciphylaxis, revealing subepidermal bullae with epidermal necrosis, a scant perivascular lymphocytic infiltrate, and extravasated erythrocytes. No evidence of calcification was seen within the vessels. The patient was then started on sodium thiosulfate with hemodialysis for treatment of presumed calciphylaxis.

Despite meticulous wound care and treatment with sodium thiosulfate, the patient developed ulcerations with necrotic eschars on the bilateral buttocks, hips, and thighs 1 month later (Figure 1). She subsequently worsened over the next few weeks. She developed sepsis and was transferred to the intensive care unit. A third biopsy was performed, finally confirming the diagnosis of calciphylaxis. Histopathology revealed small blood vessels with basophilic granular deposits in the walls consistent with calcium in the subcutaneous tissue (highlighted with the von Kossa stain), as well as thrombi in the lumens of some vessels; early fat necrosis; focal epidermal necrosis with underlying congested blood vessels with deposits in their walls; a perivascular infiltrate predominately of lymphocytes and neutrophils with scattered nuclear dust; and thick, hyalinized, closely crowded collagen bundles in the reticular dermis and in a widened subcutaneous septum (Figures 2 and 3).

Supportive care and pain control were continued, but the overall prognosis was determined to be very poor, and the patient eventually was discharged to hospice and died.

Although calciphylaxis is commonly seen in patients with ESRD and hyperparathyroidism, patients without renal disease also may develop the condition.^2,3 Prior epidemiologic studies have shown a prevalence of 1% in patients with chronic kidney disease and up to 4% in those receiving dialysis.^2-5 The average age at presentation is 48 years.^6,7 Although calciphylaxis has been noted to affect males and females equally, some studies have suggested a female predominance.^5-8

The etiology of calciphylaxis is unknown, but ESRD requiring dialysis, primary or secondary hyperparathyroidism, obesity, diabetes mellitus, skin trauma, and/or a hypercoagulable state may put patients at increased risk for developing this disease.^2,3 Other risk factors include systemic corticosteroids, liver disease, increased serum aluminum, and increased erythrocyte sedimentation rate. Although high calcium-phosphate product has been noted as a risk factor in prior studies, one retrospective study found that it does not reliably confirm or exclude a diagnosis of calciphylaxis.⁸

 

The pathogenesis of calciphylaxis is not well understood; however, some researchers suggest that an imbalance in calcium-phosphate homeostasis may lead to calciphylaxis; that is, elevated calcium and phosphate levels exceed their solubility and deposit in the walls of small- and medium-sized arteries, which consequently leads to ischemic necrosis and gangrene of the surrounding tissue.⁹

Clinically, calciphylaxis has an indolent onset and usually presents as well-demarcated, painful, purplish, mottled lesions that evolve into necrotic gray-black eschars and gangrene in adjacent tissues.^1,5,6 The ischemic process may even extend to the muscle layer.⁵ Other common presentations include mild erythematous patches; livedo reticularis; painful nodules; necrotic ulcerating lesions; and more rarely flaccid, hemorrhagic, or serous bullous lesions followed by ulceration, as was seen in our patient.^6,9,10 Lesions usually begin at sites of trauma and seem to be distributed symmetrically.^5,6 The most commonly affected locations are the legs, specifically the medial thighs, as well as the abdomen and buttocks, but lesions also can be found at more distal sites such as the breasts, tongue, vulva, penis, fingers, and toes.^5,6,10 The head and neck region rarely is affected. Although uncommon, calciphylaxis may affect other organs, including the lungs, stomach, kidneys, and adrenal glands.⁵ The accompanying systemic symptoms and findings may include muscle weakness, tenderness, or myositis with rhabdomyolysis; calcific cerebral embolism; dementia and infarction of the central nervous system; acute respiratory failure; heart disease; atrioventricular block; and calcification of the cardiac conduction system.⁶ Unlike other forms of peripheral vascular disease, distal pulses are present in calciphylaxis, as blood flow usually is preserved distal and deep to the areas of necrosis.^5,6

A careful history and thorough physical examination are important first steps in the diagnosis of this condition.^2,10 Although there are no definitive laboratory tests, elevated serum calcium, phosphorous, and calcium-phosphate product levels, as well as parathyroid hormone level, may be suggestive of calciphylaxis.^2,5 Leukocytosis may occur if an infection is present.⁵

The most accurate method to confirm the diagnosis is a deep incisional biopsy from an erythematous, slightly purpuric area adjacent to the necrotic lesion.^2,10,11 The histopathologic features used to make the diagnosis include calcification of medium-sized vessels, particularly the intimal or medial layers, in the deep dermis and subcutaneous fat in addition to lobular capillaries of the subcutaneous fat.^5,10 These vessels, including the smaller distal vessels that supply the papillary dermis and epidermis, also may be thrombosed due to calcification, leading to vascular occlusion and subsequently ischemic necrosis of the overlying epidermis.¹⁰ Other findings may include pseudoxanthoma elasticum changes, panniculitis, and subcutaneous fat necrosis.^4,10

The differential diagnosis for calciphylaxis includes peripheral vascular disease, vasculitis, juvenile dermatomyositis, proteins C and S deficiencies, cryofibrinogenemia, calcinosis cutis, and tumoral calcinosis.² Polyarteritis nodosa, Sjögren syndrome, atherosclerotic peripheral vascular disease, pyoderma gangrenosum, systemic lupus erythematosus, necrotizing fasciitis, septic embolism, and necrosis secondary to warfarin and heparin may mimic calciphylaxis.⁵

Treatment of calciphylaxis is multidimensional but primarily is supportive.^6,11 Controlling calcium and phosphate levels and secondary hyperparathyroidism through diet and phosphate binders (eg, sevelamer hydrochloride) has been shown to be effective.⁶ Pamidronate, a bisphosphonate, inhibits arterial calcification in animal models and has been reported to treat calciphylaxis, resulting in marked pain reduction and ulcer healing.^4,6 Cinacalcet, which functions as a calcimimetic, has been implicated in the treatment of calciphylaxis. It has been used to treat primary and secondary hyperparathyroidism and to normalize serum calcium levels; it also may be used as an alternative to parathyroidectomy.^4,6 Intravenous administration of sodium thiosulfate, a potent antioxidant and chelator of calcium, has been helpful in reversing signs and symptoms of calciphylaxis.^6,12 It also has been shown to effectively remove extra calcium during peritoneal dialysis.⁶ Parathyroidectomy has been useful in patients with markedly elevated parathyroid hormone levels, as it suppresses or eliminates the sensitizing agent causing hypercalcemia, elevated calcium-phosphate product, and hyperparathyroidism.^1,2,6,13

Wound care and prevention of sepsis are essential in the treatment of calciphylaxis. Management options include surgical debridement, hydrocolloid and biologic dressings, skin grafts, systemic antibiotics, oral pentoxifylline combined with maggot therapy, nutritional support, hyperbaric oxygen therapy, and revascularization and amputation when other interventions have failed. Pain control with analgesics and correction of thrombosis in the skin and blood vessels via anticoagulation therapy also are important complementary treatments.⁶

The clinical outcome of calciphylaxis is dependent on early diagnosis, antimicrobial therapy, and wound management,⁹ but overall, the prognosis usually is poor and has a high mortality rate. The most common causes of death are infection and sepsis.^1,9 A study of 7 cases reported 100% mortality,¹⁴ but other studies have suggested a mortality rate of 60% to 80%.^4,10 Female sex and obesity are poor prognostic indicators.² A better prognosis has been appreciated in cases in which lesions occur at distal sites (eg, lower legs, hands) compared to more proximal sites (eg, abdomen), where 25% and 75% mortalities have been noted, respectively.^10,14,15 In one study, the overall mortality rate was 45% in patients with calciphylaxis at 1 year.⁶ The rate was 41% in patients with plaques only and 67% in those who presented with ulceration. Patients who survive often experience a high degree of morbidity and prolonged hospitalization; these patients often are severely debilitated, especially in the case of limb amputation.⁶

Our report of calciphylaxis demonstrates the diversity in clinical presentation and emphasizes the importance of early and accurate diagnosis in reducing morbidity and mortality. In our case, the patient presented with skin pain and tense nonhemorrhagic bullae without underlying ecchymotic or erythematous lesions as the earliest sign of calciphylaxis. Physicians should have a high degree of suspicion in the setting of dialysis-dependent ESRD patients with bullae, extreme pain, and continuous decline. We hope that this case will help increase awareness of the varying presentations of this condition.

To the Editor:

Calciphylaxis (also known as calcific uremic arteriolopathy and calcifying panniculitis) is a rare vasculopathy affecting the small vessels.¹ It is characterized by cutaneous ischemia and necrosis secondary to calcification. It is most commonly seen in patients with end-stage renal disease (ESRD) and hyperparathyroidism.^1-3 Histopathologic features that are consistent with the diagnosis of calciphylaxis include calcification of medium-sized vessels in the deep dermis or subcutaneous fat as well as smaller distal vessels that supply the papillary dermis and epidermis.^4,5 Although it commonly presents as well-demarcated, painful, purplish lesions that evolve into necrotic eschars, calciphylaxis rarely can present with hemorrhagic or serous bullous lesions followed by ulceration, as was seen in our patient.^1,5,6 We report this uncommon presentation to highlight the variety in clinical appearance of calciphylaxis and the importance of early diagnosis.

A 43-year-old woman presented to the emergency department for evaluation of chest and abdominal pain that began 1 day prior to presentation. She had a history of systemic lupus erythematosus and ESRD secondary to poststreptococcal glomerulonephritis and was currently on peritoneal dialysis. The patient was admitted for peritonitis and treated with broad-spectrum antibiotics. At the time of admission, the patient also was noted to have several painful bullae on the legs. Her medical history also was remarkable for cerebral infarction, fibromyalgia, cerebral artery occlusion with cerebral infarction, sciatica, hyperlipidemia, deep vein thrombosis, and seizures. She had no history of herpes simplex virus. Surgical history was remarkable for tubal ligation, nephrectomy and kidney transplant, parathyroidectomy, and cholecystectomy. The patient’s medications included sevelamer carbonate, prednisone, epogen, calcium carbonate, esomeprazole, ondansetron, topical gentamicin, and atorvastatin.

Skin examination was performed by the inpatient dermatology service and revealed several tense, 1- to 5-cm, nonhemorrhagic bullae on the thighs and lower legs, some that had ruptured. The lesions were notably tender to palpation. No surrounding erythema, ecchymosis, or warmth was appreciated. The Nikolsky sign was negative. The patient also was noted to have at least grade 2 to 3+ pitting edema of the bilateral legs. The oral and conjunctival mucosae were unremarkable.

Antinuclear antibody, double-stranded DNA, and anti-Smith antibody levels were negative. A punch biopsy of the left lateral thigh revealed intraepidermal vesicular dermatitis with dermal edema suggestive of edema bullae and direct immunofluorescence was negative for immune complex and complement deposition.

Conservative therapy with wound care was recommended. The patient continued to report persistent severe skin pain and developed a subcutaneous nodule on the right inner thigh 1 week later, prompting a second biopsy. Results of the excisional biopsy were nondiagnostic but were suggestive of calciphylaxis, revealing subepidermal bullae with epidermal necrosis, a scant perivascular lymphocytic infiltrate, and extravasated erythrocytes. No evidence of calcification was seen within the vessels. The patient was then started on sodium thiosulfate with hemodialysis for treatment of presumed calciphylaxis.

Despite meticulous wound care and treatment with sodium thiosulfate, the patient developed ulcerations with necrotic eschars on the bilateral buttocks, hips, and thighs 1 month later (Figure 1). She subsequently worsened over the next few weeks. She developed sepsis and was transferred to the intensive care unit. A third biopsy was performed, finally confirming the diagnosis of calciphylaxis. Histopathology revealed small blood vessels with basophilic granular deposits in the walls consistent with calcium in the subcutaneous tissue (highlighted with the von Kossa stain), as well as thrombi in the lumens of some vessels; early fat necrosis; focal epidermal necrosis with underlying congested blood vessels with deposits in their walls; a perivascular infiltrate predominately of lymphocytes and neutrophils with scattered nuclear dust; and thick, hyalinized, closely crowded collagen bundles in the reticular dermis and in a widened subcutaneous septum (Figures 2 and 3).

Supportive care and pain control were continued, but the overall prognosis was determined to be very poor, and the patient eventually was discharged to hospice and died.

Although calciphylaxis is commonly seen in patients with ESRD and hyperparathyroidism, patients without renal disease also may develop the condition.^2,3 Prior epidemiologic studies have shown a prevalence of 1% in patients with chronic kidney disease and up to 4% in those receiving dialysis.^2-5 The average age at presentation is 48 years.^6,7 Although calciphylaxis has been noted to affect males and females equally, some studies have suggested a female predominance.^5-8

The etiology of calciphylaxis is unknown, but ESRD requiring dialysis, primary or secondary hyperparathyroidism, obesity, diabetes mellitus, skin trauma, and/or a hypercoagulable state may put patients at increased risk for developing this disease.^2,3 Other risk factors include systemic corticosteroids, liver disease, increased serum aluminum, and increased erythrocyte sedimentation rate. Although high calcium-phosphate product has been noted as a risk factor in prior studies, one retrospective study found that it does not reliably confirm or exclude a diagnosis of calciphylaxis.⁸

 

The pathogenesis of calciphylaxis is not well understood; however, some researchers suggest that an imbalance in calcium-phosphate homeostasis may lead to calciphylaxis; that is, elevated calcium and phosphate levels exceed their solubility and deposit in the walls of small- and medium-sized arteries, which consequently leads to ischemic necrosis and gangrene of the surrounding tissue.⁹

Clinically, calciphylaxis has an indolent onset and usually presents as well-demarcated, painful, purplish, mottled lesions that evolve into necrotic gray-black eschars and gangrene in adjacent tissues.^1,5,6 The ischemic process may even extend to the muscle layer.⁵ Other common presentations include mild erythematous patches; livedo reticularis; painful nodules; necrotic ulcerating lesions; and more rarely flaccid, hemorrhagic, or serous bullous lesions followed by ulceration, as was seen in our patient.^6,9,10 Lesions usually begin at sites of trauma and seem to be distributed symmetrically.^5,6 The most commonly affected locations are the legs, specifically the medial thighs, as well as the abdomen and buttocks, but lesions also can be found at more distal sites such as the breasts, tongue, vulva, penis, fingers, and toes.^5,6,10 The head and neck region rarely is affected. Although uncommon, calciphylaxis may affect other organs, including the lungs, stomach, kidneys, and adrenal glands.⁵ The accompanying systemic symptoms and findings may include muscle weakness, tenderness, or myositis with rhabdomyolysis; calcific cerebral embolism; dementia and infarction of the central nervous system; acute respiratory failure; heart disease; atrioventricular block; and calcification of the cardiac conduction system.⁶ Unlike other forms of peripheral vascular disease, distal pulses are present in calciphylaxis, as blood flow usually is preserved distal and deep to the areas of necrosis.^5,6

A careful history and thorough physical examination are important first steps in the diagnosis of this condition.^2,10 Although there are no definitive laboratory tests, elevated serum calcium, phosphorous, and calcium-phosphate product levels, as well as parathyroid hormone level, may be suggestive of calciphylaxis.^2,5 Leukocytosis may occur if an infection is present.⁵

The most accurate method to confirm the diagnosis is a deep incisional biopsy from an erythematous, slightly purpuric area adjacent to the necrotic lesion.^2,10,11 The histopathologic features used to make the diagnosis include calcification of medium-sized vessels, particularly the intimal or medial layers, in the deep dermis and subcutaneous fat in addition to lobular capillaries of the subcutaneous fat.^5,10 These vessels, including the smaller distal vessels that supply the papillary dermis and epidermis, also may be thrombosed due to calcification, leading to vascular occlusion and subsequently ischemic necrosis of the overlying epidermis.¹⁰ Other findings may include pseudoxanthoma elasticum changes, panniculitis, and subcutaneous fat necrosis.^4,10

The differential diagnosis for calciphylaxis includes peripheral vascular disease, vasculitis, juvenile dermatomyositis, proteins C and S deficiencies, cryofibrinogenemia, calcinosis cutis, and tumoral calcinosis.² Polyarteritis nodosa, Sjögren syndrome, atherosclerotic peripheral vascular disease, pyoderma gangrenosum, systemic lupus erythematosus, necrotizing fasciitis, septic embolism, and necrosis secondary to warfarin and heparin may mimic calciphylaxis.⁵

Treatment of calciphylaxis is multidimensional but primarily is supportive.^6,11 Controlling calcium and phosphate levels and secondary hyperparathyroidism through diet and phosphate binders (eg, sevelamer hydrochloride) has been shown to be effective.⁶ Pamidronate, a bisphosphonate, inhibits arterial calcification in animal models and has been reported to treat calciphylaxis, resulting in marked pain reduction and ulcer healing.^4,6 Cinacalcet, which functions as a calcimimetic, has been implicated in the treatment of calciphylaxis. It has been used to treat primary and secondary hyperparathyroidism and to normalize serum calcium levels; it also may be used as an alternative to parathyroidectomy.^4,6 Intravenous administration of sodium thiosulfate, a potent antioxidant and chelator of calcium, has been helpful in reversing signs and symptoms of calciphylaxis.^6,12 It also has been shown to effectively remove extra calcium during peritoneal dialysis.⁶ Parathyroidectomy has been useful in patients with markedly elevated parathyroid hormone levels, as it suppresses or eliminates the sensitizing agent causing hypercalcemia, elevated calcium-phosphate product, and hyperparathyroidism.^1,2,6,13

Wound care and prevention of sepsis are essential in the treatment of calciphylaxis. Management options include surgical debridement, hydrocolloid and biologic dressings, skin grafts, systemic antibiotics, oral pentoxifylline combined with maggot therapy, nutritional support, hyperbaric oxygen therapy, and revascularization and amputation when other interventions have failed. Pain control with analgesics and correction of thrombosis in the skin and blood vessels via anticoagulation therapy also are important complementary treatments.⁶

The clinical outcome of calciphylaxis is dependent on early diagnosis, antimicrobial therapy, and wound management,⁹ but overall, the prognosis usually is poor and has a high mortality rate. The most common causes of death are infection and sepsis.^1,9 A study of 7 cases reported 100% mortality,¹⁴ but other studies have suggested a mortality rate of 60% to 80%.^4,10 Female sex and obesity are poor prognostic indicators.² A better prognosis has been appreciated in cases in which lesions occur at distal sites (eg, lower legs, hands) compared to more proximal sites (eg, abdomen), where 25% and 75% mortalities have been noted, respectively.^10,14,15 In one study, the overall mortality rate was 45% in patients with calciphylaxis at 1 year.⁶ The rate was 41% in patients with plaques only and 67% in those who presented with ulceration. Patients who survive often experience a high degree of morbidity and prolonged hospitalization; these patients often are severely debilitated, especially in the case of limb amputation.⁶

Our report of calciphylaxis demonstrates the diversity in clinical presentation and emphasizes the importance of early and accurate diagnosis in reducing morbidity and mortality. In our case, the patient presented with skin pain and tense nonhemorrhagic bullae without underlying ecchymotic or erythematous lesions as the earliest sign of calciphylaxis. Physicians should have a high degree of suspicion in the setting of dialysis-dependent ESRD patients with bullae, extreme pain, and continuous decline. We hope that this case will help increase awareness of the varying presentations of this condition.

To the Editor:

Calciphylaxis (also known as calcific uremic arteriolopathy and calcifying panniculitis) is a rare vasculopathy affecting the small vessels.¹ It is characterized by cutaneous ischemia and necrosis secondary to calcification. It is most commonly seen in patients with end-stage renal disease (ESRD) and hyperparathyroidism.^1-3 Histopathologic features that are consistent with the diagnosis of calciphylaxis include calcification of medium-sized vessels in the deep dermis or subcutaneous fat as well as smaller distal vessels that supply the papillary dermis and epidermis.^4,5 Although it commonly presents as well-demarcated, painful, purplish lesions that evolve into necrotic eschars, calciphylaxis rarely can present with hemorrhagic or serous bullous lesions followed by ulceration, as was seen in our patient.^1,5,6 We report this uncommon presentation to highlight the variety in clinical appearance of calciphylaxis and the importance of early diagnosis.

A 43-year-old woman presented to the emergency department for evaluation of chest and abdominal pain that began 1 day prior to presentation. She had a history of systemic lupus erythematosus and ESRD secondary to poststreptococcal glomerulonephritis and was currently on peritoneal dialysis. The patient was admitted for peritonitis and treated with broad-spectrum antibiotics. At the time of admission, the patient also was noted to have several painful bullae on the legs. Her medical history also was remarkable for cerebral infarction, fibromyalgia, cerebral artery occlusion with cerebral infarction, sciatica, hyperlipidemia, deep vein thrombosis, and seizures. She had no history of herpes simplex virus. Surgical history was remarkable for tubal ligation, nephrectomy and kidney transplant, parathyroidectomy, and cholecystectomy. The patient’s medications included sevelamer carbonate, prednisone, epogen, calcium carbonate, esomeprazole, ondansetron, topical gentamicin, and atorvastatin.

Skin examination was performed by the inpatient dermatology service and revealed several tense, 1- to 5-cm, nonhemorrhagic bullae on the thighs and lower legs, some that had ruptured. The lesions were notably tender to palpation. No surrounding erythema, ecchymosis, or warmth was appreciated. The Nikolsky sign was negative. The patient also was noted to have at least grade 2 to 3+ pitting edema of the bilateral legs. The oral and conjunctival mucosae were unremarkable.

Antinuclear antibody, double-stranded DNA, and anti-Smith antibody levels were negative. A punch biopsy of the left lateral thigh revealed intraepidermal vesicular dermatitis with dermal edema suggestive of edema bullae and direct immunofluorescence was negative for immune complex and complement deposition.

Conservative therapy with wound care was recommended. The patient continued to report persistent severe skin pain and developed a subcutaneous nodule on the right inner thigh 1 week later, prompting a second biopsy. Results of the excisional biopsy were nondiagnostic but were suggestive of calciphylaxis, revealing subepidermal bullae with epidermal necrosis, a scant perivascular lymphocytic infiltrate, and extravasated erythrocytes. No evidence of calcification was seen within the vessels. The patient was then started on sodium thiosulfate with hemodialysis for treatment of presumed calciphylaxis.

Despite meticulous wound care and treatment with sodium thiosulfate, the patient developed ulcerations with necrotic eschars on the bilateral buttocks, hips, and thighs 1 month later (Figure 1). She subsequently worsened over the next few weeks. She developed sepsis and was transferred to the intensive care unit. A third biopsy was performed, finally confirming the diagnosis of calciphylaxis. Histopathology revealed small blood vessels with basophilic granular deposits in the walls consistent with calcium in the subcutaneous tissue (highlighted with the von Kossa stain), as well as thrombi in the lumens of some vessels; early fat necrosis; focal epidermal necrosis with underlying congested blood vessels with deposits in their walls; a perivascular infiltrate predominately of lymphocytes and neutrophils with scattered nuclear dust; and thick, hyalinized, closely crowded collagen bundles in the reticular dermis and in a widened subcutaneous septum (Figures 2 and 3).

Supportive care and pain control were continued, but the overall prognosis was determined to be very poor, and the patient eventually was discharged to hospice and died.

Although calciphylaxis is commonly seen in patients with ESRD and hyperparathyroidism, patients without renal disease also may develop the condition.^2,3 Prior epidemiologic studies have shown a prevalence of 1% in patients with chronic kidney disease and up to 4% in those receiving dialysis.^2-5 The average age at presentation is 48 years.^6,7 Although calciphylaxis has been noted to affect males and females equally, some studies have suggested a female predominance.^5-8

The etiology of calciphylaxis is unknown, but ESRD requiring dialysis, primary or secondary hyperparathyroidism, obesity, diabetes mellitus, skin trauma, and/or a hypercoagulable state may put patients at increased risk for developing this disease.^2,3 Other risk factors include systemic corticosteroids, liver disease, increased serum aluminum, and increased erythrocyte sedimentation rate. Although high calcium-phosphate product has been noted as a risk factor in prior studies, one retrospective study found that it does not reliably confirm or exclude a diagnosis of calciphylaxis.⁸

 

The pathogenesis of calciphylaxis is not well understood; however, some researchers suggest that an imbalance in calcium-phosphate homeostasis may lead to calciphylaxis; that is, elevated calcium and phosphate levels exceed their solubility and deposit in the walls of small- and medium-sized arteries, which consequently leads to ischemic necrosis and gangrene of the surrounding tissue.⁹

Clinically, calciphylaxis has an indolent onset and usually presents as well-demarcated, painful, purplish, mottled lesions that evolve into necrotic gray-black eschars and gangrene in adjacent tissues.^1,5,6 The ischemic process may even extend to the muscle layer.⁵ Other common presentations include mild erythematous patches; livedo reticularis; painful nodules; necrotic ulcerating lesions; and more rarely flaccid, hemorrhagic, or serous bullous lesions followed by ulceration, as was seen in our patient.^6,9,10 Lesions usually begin at sites of trauma and seem to be distributed symmetrically.^5,6 The most commonly affected locations are the legs, specifically the medial thighs, as well as the abdomen and buttocks, but lesions also can be found at more distal sites such as the breasts, tongue, vulva, penis, fingers, and toes.^5,6,10 The head and neck region rarely is affected. Although uncommon, calciphylaxis may affect other organs, including the lungs, stomach, kidneys, and adrenal glands.⁵ The accompanying systemic symptoms and findings may include muscle weakness, tenderness, or myositis with rhabdomyolysis; calcific cerebral embolism; dementia and infarction of the central nervous system; acute respiratory failure; heart disease; atrioventricular block; and calcification of the cardiac conduction system.⁶ Unlike other forms of peripheral vascular disease, distal pulses are present in calciphylaxis, as blood flow usually is preserved distal and deep to the areas of necrosis.^5,6

A careful history and thorough physical examination are important first steps in the diagnosis of this condition.^2,10 Although there are no definitive laboratory tests, elevated serum calcium, phosphorous, and calcium-phosphate product levels, as well as parathyroid hormone level, may be suggestive of calciphylaxis.^2,5 Leukocytosis may occur if an infection is present.⁵

The most accurate method to confirm the diagnosis is a deep incisional biopsy from an erythematous, slightly purpuric area adjacent to the necrotic lesion.^2,10,11 The histopathologic features used to make the diagnosis include calcification of medium-sized vessels, particularly the intimal or medial layers, in the deep dermis and subcutaneous fat in addition to lobular capillaries of the subcutaneous fat.^5,10 These vessels, including the smaller distal vessels that supply the papillary dermis and epidermis, also may be thrombosed due to calcification, leading to vascular occlusion and subsequently ischemic necrosis of the overlying epidermis.¹⁰ Other findings may include pseudoxanthoma elasticum changes, panniculitis, and subcutaneous fat necrosis.^4,10

The differential diagnosis for calciphylaxis includes peripheral vascular disease, vasculitis, juvenile dermatomyositis, proteins C and S deficiencies, cryofibrinogenemia, calcinosis cutis, and tumoral calcinosis.² Polyarteritis nodosa, Sjögren syndrome, atherosclerotic peripheral vascular disease, pyoderma gangrenosum, systemic lupus erythematosus, necrotizing fasciitis, septic embolism, and necrosis secondary to warfarin and heparin may mimic calciphylaxis.⁵

Treatment of calciphylaxis is multidimensional but primarily is supportive.^6,11 Controlling calcium and phosphate levels and secondary hyperparathyroidism through diet and phosphate binders (eg, sevelamer hydrochloride) has been shown to be effective.⁶ Pamidronate, a bisphosphonate, inhibits arterial calcification in animal models and has been reported to treat calciphylaxis, resulting in marked pain reduction and ulcer healing.^4,6 Cinacalcet, which functions as a calcimimetic, has been implicated in the treatment of calciphylaxis. It has been used to treat primary and secondary hyperparathyroidism and to normalize serum calcium levels; it also may be used as an alternative to parathyroidectomy.^4,6 Intravenous administration of sodium thiosulfate, a potent antioxidant and chelator of calcium, has been helpful in reversing signs and symptoms of calciphylaxis.^6,12 It also has been shown to effectively remove extra calcium during peritoneal dialysis.⁶ Parathyroidectomy has been useful in patients with markedly elevated parathyroid hormone levels, as it suppresses or eliminates the sensitizing agent causing hypercalcemia, elevated calcium-phosphate product, and hyperparathyroidism.^1,2,6,13

Wound care and prevention of sepsis are essential in the treatment of calciphylaxis. Management options include surgical debridement, hydrocolloid and biologic dressings, skin grafts, systemic antibiotics, oral pentoxifylline combined with maggot therapy, nutritional support, hyperbaric oxygen therapy, and revascularization and amputation when other interventions have failed. Pain control with analgesics and correction of thrombosis in the skin and blood vessels via anticoagulation therapy also are important complementary treatments.⁶

The clinical outcome of calciphylaxis is dependent on early diagnosis, antimicrobial therapy, and wound management,⁹ but overall, the prognosis usually is poor and has a high mortality rate. The most common causes of death are infection and sepsis.^1,9 A study of 7 cases reported 100% mortality,¹⁴ but other studies have suggested a mortality rate of 60% to 80%.^4,10 Female sex and obesity are poor prognostic indicators.² A better prognosis has been appreciated in cases in which lesions occur at distal sites (eg, lower legs, hands) compared to more proximal sites (eg, abdomen), where 25% and 75% mortalities have been noted, respectively.^10,14,15 In one study, the overall mortality rate was 45% in patients with calciphylaxis at 1 year.⁶ The rate was 41% in patients with plaques only and 67% in those who presented with ulceration. Patients who survive often experience a high degree of morbidity and prolonged hospitalization; these patients often are severely debilitated, especially in the case of limb amputation.⁶

Our report of calciphylaxis demonstrates the diversity in clinical presentation and emphasizes the importance of early and accurate diagnosis in reducing morbidity and mortality. In our case, the patient presented with skin pain and tense nonhemorrhagic bullae without underlying ecchymotic or erythematous lesions as the earliest sign of calciphylaxis. Physicians should have a high degree of suspicion in the setting of dialysis-dependent ESRD patients with bullae, extreme pain, and continuous decline. We hope that this case will help increase awareness of the varying presentations of this condition.

To the Editor:

In recent years, noninvasive brain stimulation techniques have gained growing importance in the treatment of psychiatric¹ and neurologic disorders as well as in neurologic rehabilitation (eg, after a stroke).² One of these techniques is transcranial electrical stimulation (tES), which includes transcranial direct current stimulation (tDCS), transcranial random noise stimulation, and transcranial alternating current stimulation. The current is administered through rubber electrodes covered by saline-soaked sponges that are attached to the skull over the dysfunctional brain areas using broad rubber bands.

Transcranial direct current stimulation ameliorates brain function by anodal stimulation after a series of 5 to 10 stimulations.¹ Recently, commercially available brain stimulation devices have been developed to improve working memory for online/video gaming³; however, application of a direct current (eg, 1–2 mA) over longer periods of time (15–20 minutes) can cause skin burns due to drying out of the electrode.⁴ Inhomogeneities in skin-electrode contact can lead to current bridges, resulting in quick evaporation of the contact medium (sodium chloride solution) and subsequent thermic damage of the skin. Another possible cause of skin lesions associated with tES is skin contact with the rubber electrode due to incorrect positioning of the electrode in the sponge covering. We report 2 cases of burns caused by tDCS.

A 55-year-old woman who was treated with tDCS (2 mA; 20 minutes) for recurrent depressive disorder developed a 0.5-cm, round, erosive, second-degree burn with hemorrhagic crust on the skin in the middle of the area where a 5×7-cm electrode (cathode) was positioned over the right orbit (Figure 1). It was the fifth stimulation with tDCS. The anode was positioned over the left dorsolateral prefrontal cortex. It was determined that the saline-soaked sponge covering the rubber electrode dried out during treatment and caused the burn. Transcranial direct current stimulation subsequently was stopped, and the lesion healed without intervention within 4 to 5 weeks, resulting in a small scar.

A 20-year-old man who was treated with tDCS (2 mA; 20 minutes) for schizophrenia developed a superficial stripe-shaped burn on the skin over the right orbit after the eighth stimulation because the 5×7-cm rubber electrode (cathode) was not fully covered by the saline-soaked sponge and the skin came into direct contact with the short side of the electrode (Figure 2). Transcranial direct current stimulation was stopped, and the skin lesion healed without intervention within 4 to 5 weeks with no scar.

The main factor associated with thermic skin damage in tES is incorrect application of the electrodes; therefore, a high standard should be applied when soaking sponges and placing and fixing the electrodes but likely is only guaranteed in specialized services and not when utilizing tES at home. Dermatologists may be confronted with an increasing number of burns due to the widespread use of tES for modulating neuropsychiatric disorders but also due to the use of tES as a lifestyle brain tuning instrument.³

To the Editor:

In recent years, noninvasive brain stimulation techniques have gained growing importance in the treatment of psychiatric¹ and neurologic disorders as well as in neurologic rehabilitation (eg, after a stroke).² One of these techniques is transcranial electrical stimulation (tES), which includes transcranial direct current stimulation (tDCS), transcranial random noise stimulation, and transcranial alternating current stimulation. The current is administered through rubber electrodes covered by saline-soaked sponges that are attached to the skull over the dysfunctional brain areas using broad rubber bands.

Transcranial direct current stimulation ameliorates brain function by anodal stimulation after a series of 5 to 10 stimulations.¹ Recently, commercially available brain stimulation devices have been developed to improve working memory for online/video gaming³; however, application of a direct current (eg, 1–2 mA) over longer periods of time (15–20 minutes) can cause skin burns due to drying out of the electrode.⁴ Inhomogeneities in skin-electrode contact can lead to current bridges, resulting in quick evaporation of the contact medium (sodium chloride solution) and subsequent thermic damage of the skin. Another possible cause of skin lesions associated with tES is skin contact with the rubber electrode due to incorrect positioning of the electrode in the sponge covering. We report 2 cases of burns caused by tDCS.

A 55-year-old woman who was treated with tDCS (2 mA; 20 minutes) for recurrent depressive disorder developed a 0.5-cm, round, erosive, second-degree burn with hemorrhagic crust on the skin in the middle of the area where a 5×7-cm electrode (cathode) was positioned over the right orbit (Figure 1). It was the fifth stimulation with tDCS. The anode was positioned over the left dorsolateral prefrontal cortex. It was determined that the saline-soaked sponge covering the rubber electrode dried out during treatment and caused the burn. Transcranial direct current stimulation subsequently was stopped, and the lesion healed without intervention within 4 to 5 weeks, resulting in a small scar.

A 20-year-old man who was treated with tDCS (2 mA; 20 minutes) for schizophrenia developed a superficial stripe-shaped burn on the skin over the right orbit after the eighth stimulation because the 5×7-cm rubber electrode (cathode) was not fully covered by the saline-soaked sponge and the skin came into direct contact with the short side of the electrode (Figure 2). Transcranial direct current stimulation was stopped, and the skin lesion healed without intervention within 4 to 5 weeks with no scar.

The main factor associated with thermic skin damage in tES is incorrect application of the electrodes; therefore, a high standard should be applied when soaking sponges and placing and fixing the electrodes but likely is only guaranteed in specialized services and not when utilizing tES at home. Dermatologists may be confronted with an increasing number of burns due to the widespread use of tES for modulating neuropsychiatric disorders but also due to the use of tES as a lifestyle brain tuning instrument.³

To the Editor:

In recent years, noninvasive brain stimulation techniques have gained growing importance in the treatment of psychiatric¹ and neurologic disorders as well as in neurologic rehabilitation (eg, after a stroke).² One of these techniques is transcranial electrical stimulation (tES), which includes transcranial direct current stimulation (tDCS), transcranial random noise stimulation, and transcranial alternating current stimulation. The current is administered through rubber electrodes covered by saline-soaked sponges that are attached to the skull over the dysfunctional brain areas using broad rubber bands.

Transcranial direct current stimulation ameliorates brain function by anodal stimulation after a series of 5 to 10 stimulations.¹ Recently, commercially available brain stimulation devices have been developed to improve working memory for online/video gaming³; however, application of a direct current (eg, 1–2 mA) over longer periods of time (15–20 minutes) can cause skin burns due to drying out of the electrode.⁴ Inhomogeneities in skin-electrode contact can lead to current bridges, resulting in quick evaporation of the contact medium (sodium chloride solution) and subsequent thermic damage of the skin. Another possible cause of skin lesions associated with tES is skin contact with the rubber electrode due to incorrect positioning of the electrode in the sponge covering. We report 2 cases of burns caused by tDCS.

A 55-year-old woman who was treated with tDCS (2 mA; 20 minutes) for recurrent depressive disorder developed a 0.5-cm, round, erosive, second-degree burn with hemorrhagic crust on the skin in the middle of the area where a 5×7-cm electrode (cathode) was positioned over the right orbit (Figure 1). It was the fifth stimulation with tDCS. The anode was positioned over the left dorsolateral prefrontal cortex. It was determined that the saline-soaked sponge covering the rubber electrode dried out during treatment and caused the burn. Transcranial direct current stimulation subsequently was stopped, and the lesion healed without intervention within 4 to 5 weeks, resulting in a small scar.

A 20-year-old man who was treated with tDCS (2 mA; 20 minutes) for schizophrenia developed a superficial stripe-shaped burn on the skin over the right orbit after the eighth stimulation because the 5×7-cm rubber electrode (cathode) was not fully covered by the saline-soaked sponge and the skin came into direct contact with the short side of the electrode (Figure 2). Transcranial direct current stimulation was stopped, and the skin lesion healed without intervention within 4 to 5 weeks with no scar.

The main factor associated with thermic skin damage in tES is incorrect application of the electrodes; therefore, a high standard should be applied when soaking sponges and placing and fixing the electrodes but likely is only guaranteed in specialized services and not when utilizing tES at home. Dermatologists may be confronted with an increasing number of burns due to the widespread use of tES for modulating neuropsychiatric disorders but also due to the use of tES as a lifestyle brain tuning instrument.³

To the Editor:

Afatinib is a small molecule covalently binding and inhibiting the epidermal growth factor receptor (EGFR) as well as HER2 and HER4 receptor tyrosine kinases.¹ The EGFR family is part of a complex signal transduction network that is central to several critical cellular processes.² The human EGFR family is dysregulated in many solid tumors, making it an attractive target for anticancer therapy.² In 2013, the US Food and Drug Administration approved afatinib as a first-line treatment of patients with metastatic non–small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.³

Treatment with afatinib and other EGFR inhibitors is frequently associated with cutaneous adverse effects that occur in up to 90% of patients. These cutaneous reactions are typical for this drug family and distinct from the skin adverse effects related to other types of anticancer chemotherapy.⁴ The most frequent skin manifestations following afatinib treatment consist of an acneform pustular eruption in up to 90% of patients.^5,6 Other dermatologic reactions include nonspecific maculopapular rashes (90%), stomatitis (71%), paronychia with some nail changes (58%), xerosis (31%), pruritus (21%), and hand-foot syndrome (7%)^5,6; however, grade 3 dermatologic reactions occurred in only 0.15% of patients.

Inflammatory changes in both preexisting and undetected actinic keratoses (AKs) and even progression to squamous cell carcinoma (SCC) have been previously described as uncommon dermatologic adverse effects of 2 EGFR inhibitors, sorafenib and erlotinib.^7-9 Seven of 131 patients with metastatic renal cell carcinoma treated with single-agent sorafenib developed cutaneous SCC and 3 more had AKs.⁹ One patient demonstrated self-limited inflammatory flare-up of AKs during erlotinib treatment.⁸ We report acute inflammation of AKs from afatinib treatment.

A 78-year-old woman with fair skin who was previously treated for several AKs in sun-exposed areas presented with inflammatory changes that appeared at the site of AKs on photoexposed areas 110 days after initiating afatinib therapy (40 mg/d). Physical examination revealed multiple erythematous scaly plaques on the face, neck, chest, and forearms (Figure 1).

In the previous 2 decades, lesions that were surgically removed and histopathologically examined included Bowen disease (2 lesions), 2 basal cell carcinomas, 2 blue nevi, and a seborrheic keratosis. Several AKs also were surgically removed and confirmed histopathologically.

 

Eighteen months prior to the current presentation, the patient was diagnosed with locally advanced, inoperable, stage IIIA adenocarcinoma of the lung with deletion in exon 19 of the EGFR gene. She received definitive concomitant chemoradiation with the carboplatin-vinorelbine regimen and 60-Gy radiation. Four months later, a positron emission tomography (PET)–fludeoxyglucose scan revealed a single bone lesion in the L5 vertebra leading to irradiation to the lumbar spine. Subsequently, new metastases to the neck, right lung, T5 vertebra, and left acetabulum were detected by PET–computed tomography. One year later, afatinib 40 mg/d was initiated. A PET scan after 2 months of treatment showed excellent response.

At the current presentation, a punch biopsy obtained from an inflammatory lesion on the left dorsal forearm revealed findings consistent with an eroded and inflamed AK; the biopsy showed marked dysplasia of the keratinocytes that was predominately located in the basal layer of the epidermis. The lesion was accompanied by a dense mixed inflammatory cell infiltrate that was centered in the papillary dermis and extended to the epidermis (Figure 2). Because of this grade 3 skin toxicity, the afatinib dosage was reduced to 20 mg/d, and betamethasone cream 0.1% and emollients were applied locally for 2 weeks. A reduction in the number of AKs and clinical regression of the inflammatory changes was observed 2 weeks later (Figure 3).

Chronically sun-exposed skin is prone to develop AKs that are at risk to progress to SCC.^10-12 These lesions are increasingly diagnosed in older patients when internal cancers also are prevalent.¹³ Inflammatory flare-up of AKs is typically present during the regression phase^14,15 but also during progression to SCC.¹⁶

There are many strategies for treating AKs. Physical procedures for destroying the lesions are commonly used. Some topical drugs, including imiquimod, 5-fluorouracil, and diclofenac sodium, also have proven efficacy.¹⁷

Conventional chemotherapeutic agents that have been described to be associated with the inflammation of AKs include docetaxel; doxorubicin; capecitabine; pentostatin; and the combination of dactinomycin, vincristine, dacarbazine and doxorubicin, cytarabine, and 6-thioguanine.^7,18 The mechanism leading to this effect is unknown, though abnormal DNA synthesis and a type of radiation recall phenomenon have been postulated.⁷

We described inflammatory changes in AKs associated with afatinib treatment. The precise mechanism by which afatinib induces inflammation in AK has not been elucidated; however, it is known that EGFR normally downregulates chemokine expression in keratinocytes. Conversely, EGFR signaling blockade produces opposite effects, with increased CCL2, CCL5, and CXCL10, as well as reduced CXCL8 expression, leading to enhanced skin inflammation.¹⁹ Afatinib is a targeted agent that modulates the Ras/Raf/MEK/ERK signaling circuit, which is a key intracellular signal transduction pathway.²⁰ This pathway and its downstream effectors have been implicated in cutaneous squamous cell carcinogenesis that might be accompanied by inflammatory changes.^21,22 The remarkable clinical improvement of the AKs in our patient following the inflammatory flare-up supports the notion that the anticancer effect on intraepidermal neoplasms might be mediated by inflammation.²³

To the Editor:

Afatinib is a small molecule covalently binding and inhibiting the epidermal growth factor receptor (EGFR) as well as HER2 and HER4 receptor tyrosine kinases.¹ The EGFR family is part of a complex signal transduction network that is central to several critical cellular processes.² The human EGFR family is dysregulated in many solid tumors, making it an attractive target for anticancer therapy.² In 2013, the US Food and Drug Administration approved afatinib as a first-line treatment of patients with metastatic non–small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.³

Treatment with afatinib and other EGFR inhibitors is frequently associated with cutaneous adverse effects that occur in up to 90% of patients. These cutaneous reactions are typical for this drug family and distinct from the skin adverse effects related to other types of anticancer chemotherapy.⁴ The most frequent skin manifestations following afatinib treatment consist of an acneform pustular eruption in up to 90% of patients.^5,6 Other dermatologic reactions include nonspecific maculopapular rashes (90%), stomatitis (71%), paronychia with some nail changes (58%), xerosis (31%), pruritus (21%), and hand-foot syndrome (7%)^5,6; however, grade 3 dermatologic reactions occurred in only 0.15% of patients.

Inflammatory changes in both preexisting and undetected actinic keratoses (AKs) and even progression to squamous cell carcinoma (SCC) have been previously described as uncommon dermatologic adverse effects of 2 EGFR inhibitors, sorafenib and erlotinib.^7-9 Seven of 131 patients with metastatic renal cell carcinoma treated with single-agent sorafenib developed cutaneous SCC and 3 more had AKs.⁹ One patient demonstrated self-limited inflammatory flare-up of AKs during erlotinib treatment.⁸ We report acute inflammation of AKs from afatinib treatment.

A 78-year-old woman with fair skin who was previously treated for several AKs in sun-exposed areas presented with inflammatory changes that appeared at the site of AKs on photoexposed areas 110 days after initiating afatinib therapy (40 mg/d). Physical examination revealed multiple erythematous scaly plaques on the face, neck, chest, and forearms (Figure 1).

In the previous 2 decades, lesions that were surgically removed and histopathologically examined included Bowen disease (2 lesions), 2 basal cell carcinomas, 2 blue nevi, and a seborrheic keratosis. Several AKs also were surgically removed and confirmed histopathologically.

 

Eighteen months prior to the current presentation, the patient was diagnosed with locally advanced, inoperable, stage IIIA adenocarcinoma of the lung with deletion in exon 19 of the EGFR gene. She received definitive concomitant chemoradiation with the carboplatin-vinorelbine regimen and 60-Gy radiation. Four months later, a positron emission tomography (PET)–fludeoxyglucose scan revealed a single bone lesion in the L5 vertebra leading to irradiation to the lumbar spine. Subsequently, new metastases to the neck, right lung, T5 vertebra, and left acetabulum were detected by PET–computed tomography. One year later, afatinib 40 mg/d was initiated. A PET scan after 2 months of treatment showed excellent response.

At the current presentation, a punch biopsy obtained from an inflammatory lesion on the left dorsal forearm revealed findings consistent with an eroded and inflamed AK; the biopsy showed marked dysplasia of the keratinocytes that was predominately located in the basal layer of the epidermis. The lesion was accompanied by a dense mixed inflammatory cell infiltrate that was centered in the papillary dermis and extended to the epidermis (Figure 2). Because of this grade 3 skin toxicity, the afatinib dosage was reduced to 20 mg/d, and betamethasone cream 0.1% and emollients were applied locally for 2 weeks. A reduction in the number of AKs and clinical regression of the inflammatory changes was observed 2 weeks later (Figure 3).

Chronically sun-exposed skin is prone to develop AKs that are at risk to progress to SCC.^10-12 These lesions are increasingly diagnosed in older patients when internal cancers also are prevalent.¹³ Inflammatory flare-up of AKs is typically present during the regression phase^14,15 but also during progression to SCC.¹⁶

There are many strategies for treating AKs. Physical procedures for destroying the lesions are commonly used. Some topical drugs, including imiquimod, 5-fluorouracil, and diclofenac sodium, also have proven efficacy.¹⁷

Conventional chemotherapeutic agents that have been described to be associated with the inflammation of AKs include docetaxel; doxorubicin; capecitabine; pentostatin; and the combination of dactinomycin, vincristine, dacarbazine and doxorubicin, cytarabine, and 6-thioguanine.^7,18 The mechanism leading to this effect is unknown, though abnormal DNA synthesis and a type of radiation recall phenomenon have been postulated.⁷

We described inflammatory changes in AKs associated with afatinib treatment. The precise mechanism by which afatinib induces inflammation in AK has not been elucidated; however, it is known that EGFR normally downregulates chemokine expression in keratinocytes. Conversely, EGFR signaling blockade produces opposite effects, with increased CCL2, CCL5, and CXCL10, as well as reduced CXCL8 expression, leading to enhanced skin inflammation.¹⁹ Afatinib is a targeted agent that modulates the Ras/Raf/MEK/ERK signaling circuit, which is a key intracellular signal transduction pathway.²⁰ This pathway and its downstream effectors have been implicated in cutaneous squamous cell carcinogenesis that might be accompanied by inflammatory changes.^21,22 The remarkable clinical improvement of the AKs in our patient following the inflammatory flare-up supports the notion that the anticancer effect on intraepidermal neoplasms might be mediated by inflammation.²³

To the Editor:

Afatinib is a small molecule covalently binding and inhibiting the epidermal growth factor receptor (EGFR) as well as HER2 and HER4 receptor tyrosine kinases.¹ The EGFR family is part of a complex signal transduction network that is central to several critical cellular processes.² The human EGFR family is dysregulated in many solid tumors, making it an attractive target for anticancer therapy.² In 2013, the US Food and Drug Administration approved afatinib as a first-line treatment of patients with metastatic non–small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.³

Treatment with afatinib and other EGFR inhibitors is frequently associated with cutaneous adverse effects that occur in up to 90% of patients. These cutaneous reactions are typical for this drug family and distinct from the skin adverse effects related to other types of anticancer chemotherapy.⁴ The most frequent skin manifestations following afatinib treatment consist of an acneform pustular eruption in up to 90% of patients.^5,6 Other dermatologic reactions include nonspecific maculopapular rashes (90%), stomatitis (71%), paronychia with some nail changes (58%), xerosis (31%), pruritus (21%), and hand-foot syndrome (7%)^5,6; however, grade 3 dermatologic reactions occurred in only 0.15% of patients.

Inflammatory changes in both preexisting and undetected actinic keratoses (AKs) and even progression to squamous cell carcinoma (SCC) have been previously described as uncommon dermatologic adverse effects of 2 EGFR inhibitors, sorafenib and erlotinib.^7-9 Seven of 131 patients with metastatic renal cell carcinoma treated with single-agent sorafenib developed cutaneous SCC and 3 more had AKs.⁹ One patient demonstrated self-limited inflammatory flare-up of AKs during erlotinib treatment.⁸ We report acute inflammation of AKs from afatinib treatment.

A 78-year-old woman with fair skin who was previously treated for several AKs in sun-exposed areas presented with inflammatory changes that appeared at the site of AKs on photoexposed areas 110 days after initiating afatinib therapy (40 mg/d). Physical examination revealed multiple erythematous scaly plaques on the face, neck, chest, and forearms (Figure 1).

In the previous 2 decades, lesions that were surgically removed and histopathologically examined included Bowen disease (2 lesions), 2 basal cell carcinomas, 2 blue nevi, and a seborrheic keratosis. Several AKs also were surgically removed and confirmed histopathologically.

 

Eighteen months prior to the current presentation, the patient was diagnosed with locally advanced, inoperable, stage IIIA adenocarcinoma of the lung with deletion in exon 19 of the EGFR gene. She received definitive concomitant chemoradiation with the carboplatin-vinorelbine regimen and 60-Gy radiation. Four months later, a positron emission tomography (PET)–fludeoxyglucose scan revealed a single bone lesion in the L5 vertebra leading to irradiation to the lumbar spine. Subsequently, new metastases to the neck, right lung, T5 vertebra, and left acetabulum were detected by PET–computed tomography. One year later, afatinib 40 mg/d was initiated. A PET scan after 2 months of treatment showed excellent response.

At the current presentation, a punch biopsy obtained from an inflammatory lesion on the left dorsal forearm revealed findings consistent with an eroded and inflamed AK; the biopsy showed marked dysplasia of the keratinocytes that was predominately located in the basal layer of the epidermis. The lesion was accompanied by a dense mixed inflammatory cell infiltrate that was centered in the papillary dermis and extended to the epidermis (Figure 2). Because of this grade 3 skin toxicity, the afatinib dosage was reduced to 20 mg/d, and betamethasone cream 0.1% and emollients were applied locally for 2 weeks. A reduction in the number of AKs and clinical regression of the inflammatory changes was observed 2 weeks later (Figure 3).

Chronically sun-exposed skin is prone to develop AKs that are at risk to progress to SCC.^10-12 These lesions are increasingly diagnosed in older patients when internal cancers also are prevalent.¹³ Inflammatory flare-up of AKs is typically present during the regression phase^14,15 but also during progression to SCC.¹⁶

There are many strategies for treating AKs. Physical procedures for destroying the lesions are commonly used. Some topical drugs, including imiquimod, 5-fluorouracil, and diclofenac sodium, also have proven efficacy.¹⁷

Conventional chemotherapeutic agents that have been described to be associated with the inflammation of AKs include docetaxel; doxorubicin; capecitabine; pentostatin; and the combination of dactinomycin, vincristine, dacarbazine and doxorubicin, cytarabine, and 6-thioguanine.^7,18 The mechanism leading to this effect is unknown, though abnormal DNA synthesis and a type of radiation recall phenomenon have been postulated.⁷

We described inflammatory changes in AKs associated with afatinib treatment. The precise mechanism by which afatinib induces inflammation in AK has not been elucidated; however, it is known that EGFR normally downregulates chemokine expression in keratinocytes. Conversely, EGFR signaling blockade produces opposite effects, with increased CCL2, CCL5, and CXCL10, as well as reduced CXCL8 expression, leading to enhanced skin inflammation.¹⁹ Afatinib is a targeted agent that modulates the Ras/Raf/MEK/ERK signaling circuit, which is a key intracellular signal transduction pathway.²⁰ This pathway and its downstream effectors have been implicated in cutaneous squamous cell carcinogenesis that might be accompanied by inflammatory changes.^21,22 The remarkable clinical improvement of the AKs in our patient following the inflammatory flare-up supports the notion that the anticancer effect on intraepidermal neoplasms might be mediated by inflammation.²³

To the Editor:

In 1998, 2-octyl-cyanoacrylate (2-CA) tissue adhesive gained US Food and Drug Administration approval for topical application to easily hold closed approximated skin edges from surgical excisions and simple trauma-induced lacerations.¹ It has since been employed for a number of off-label indications, including sutureless circumcision,² skin graft fixation,³ pericatheter leakage,⁴ and intracorporeal use to control air leaks during lung resection.⁵ Animal investigations additionally have attempted to elucidate potential future uses of 2-CA for procedures such as inguinal hernia repair,⁶ bowel anastomosis,⁷ incisional hernia repair with mesh,⁸ and microvascular anastomosis.⁹ Compared to sutures, 2-CA offers ease and rapidity of application, a water-resistant barrier, and equivalent cosmetic results, as well as eliminates the need for suture removal.¹⁰ As 2-CA is used with increasing frequency across a variety of settings, there arises a greater need to be mindful of the potential complications of its use, such as irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), and cutaneous id reaction.

A 14-year-old adolescent boy with no notable medical history and no known allergies underwent a minimally invasive Nuss procedure¹¹ (performed by P.L.G.) for the repair of severe pectus excavatum. Two 4-cm incisions were made—one in each lateral chest wall at the approximately eighth intercostal space—to facilitate the introduction of the Nuss bar. The surgical wounds were closed with 2 layers of running polyglactin 910 suture before 2-CA was applied topically to the incision sites. The surgery was well tolerated, and the patient’s wounds healed without incident. When the patient was evaluated for Nuss bar removal 3 years later, incision sites were noted to be well healed, and he exhibited no other skin lesions. The original incision sites (bilateral chest walls) were utilized to facilitate surgical Nuss bar removal. The wounds were closed in 4 layers and 2-CA was again applied topically to the incision sites. There were no intraoperative complications; no devices, drains, or tissue implants were left in the patient at the conclusion of the procedure.

One week later, via text message and digital photographs, the patient reported intense pruritus at the bilateral chest wall incision sites, which were now surrounded by symmetric 1-cm erythematous plaques and associated sparse erythematous satellite papules (Figure 1). The patient denied any fevers, pain, swelling, or purulent discharge from the wounds. He was started on hydrocortisone cream 1% twice daily as well as oral diphenhydramine 25 mg at bedtime with initial good effect.

Three days later, the patient sent digital photographs of a morphologically similar–appearing rash that had progressed beyond the lateral chest walls to include the central chest and bilateral upper and lower extremities (Figure 2). He continued to deny any local or systemic signs of infection. Dermatology was consulted, and a diagnosis of ACD with cutaneous id reaction was made. The patient’s medication regimen was modified to include triamcinolone acetonide cream 0.1% applied twice daily to the rash away from the wounds, clobetasol propionate ointment 0.05% applied twice daily to the rash at the wound sites, oral levocetirizine 5 mg once daily, and oral hydroxyzine 25 to 50 mg every 6 hours as needed for pruritus. Additional recommendations included the use of a fragrance-free soap and application of an over-the-counter anti-itch lotion containing menthol and camphor applied as needed. Within 24 hours of starting this modified treatment regimen, the patient began to notice an improvement in symptoms, with full resolution over the course of the ensuing 2 weeks. The patient was counseled to inform his physicians—present and future—of his allergy to 2-CA.

 

Contact dermatitis associated with the use of 2-CA has been described in the literature.^12-15 We report progression to an id reaction, which is characterized by the diffuse symmetric spread of a cutaneous eruption at a site distant from the primary localized dermatitis that develops within a few days of the primary lesion and exhibits the same morphologic and histopathologic findings.^16,17 In our patient, pruritic erythematous papules and plaques symmetrically distributed on the arms, legs, and chest appeared 3 days after he first reported a similar eruption at the 2-CA application sites. It is theorized that id reactions develop when the sensitization phase of a type IV hypersensitivity reaction generates a population of T cells that not only recognizes a hapten but also recognizes keratinocyte-derived epitopes.¹⁶ A hapten is a small molecule (<500 Da) that is capable of penetrating the stratum corneum and binding skin components. A contact allergen is a hapten that has bound epidermal proteins to create a new antigenic determinant.¹⁸ The secondary dermatitis that characterizes id reactions results from an abnormal autoimmune response. Id reactions associated with exposure to adhesive material are rare.¹⁹

Allergic contact dermatitis is a type IV hypersensitivity reaction that appears after initial sensitization to an allergen followed by re-exposure. Our patient presented with symmetric erythematous plaques at the surgical incision sites 1 week after 2-CA had been applied. During this interval, sensitization to the inciting allergen occurred. The allergen is taken up by antigen-presenting cells, which then migrate to lymph nodes where they encounter naïve T lymphocytes that subsequently undergo clonal expansion to produce a cohort of T cells that are capable of recognizing the allergen. If subsequent exposure to the specific allergen takes place, an elicitation phase occurs in which primed T cells are incited to release mediators of inflammation that engender the manifestations of ACD within 24 to 72 hours.^18,20 Sensitization may be promoted by skin barrier impairments such as dermatitis or a frank wound.^12,20 In most cases, the patient is unaware that sensitization has occurred, though a primary ACD within 5 to 15 days after initial exposure to the inciting allergen rarely may be observed.¹⁸ Although our patient had 2-CA applied to his surgical wounds at 14 years of age, it was unlikely that sensitization took place at that time, as it was 1 week rather than 1 to 3 days before he experienced the cutaneous eruption associated with his second 2-CA exposure at 17 years of age.

Cyanoacrylate tissue adhesive also may cause ICD resulting from histotoxic degradation products such as formaldehyde and cyanoacetate that are capable of compromising cutaneous barrier function. Keratinocytes that have had their membranes disturbed release proinflammatory cytokines, which recruit cells of the innate immune system as well as T lymphocytes to the site of insult to facilitate the inflammatory response. The manifestations of ICD include erythema, edema, and local necrosis that can compromise wound healing.²⁰ The speed at which a given cyanoacrylate adhesive degrades is proportional to the length of its carbon side chain. Those with shorter side chains—ethyl and methyl cyanoacrylate—degrade more rapidly into formaldehyde and cyanoacetate; 2-CA possesses a longer side chain and therefore degrades more slowly, which should, in theory, lessen its potential to cause ICD.²⁰ Because it may take 7 to 14 days before 2-CA will spontaneously peel from the application site, however, its potential to evoke ICD nevertheless exists.

Treatment of ICD entails removing the irritant while concurrently working to restore the skin’s barrier with emollients. Although topical corticosteroids often are reflexively prescribed to treat rashes, some believe that their use should be avoided in cases of ICD, as their inhibitory effects on epidermal lipid synthesis may further impair the skin’s barrier.²¹ For cases of ACD, with or without an accompanying id reaction, topical corticosteroids are the mainstay of therapy. It is customary to start with a higher-potency topical steroid such as clobetasol and taper to lower-potency steroids as the patient’s condition improves. Steroid ointments are petroleum based and are capable of causing 2-CA to separate from the skin.¹⁰ As a result, they should be used with care when being applied to an area where 2-CA is maintaining dermal closure. Systemic corticosteroids may be warranted in cases with involvement of more than 20% of the body surface area and should start to provide relief within 12 to 24 hours.²² Oral antihistamines and cold water compresses can be added to help address pruritus and discomfort in both ACD and ICD.

Instances of contact dermatitis caused by 2-CA are rare, and progression to an id reaction is rarer still. Physicians should be aware of the possibility of encountering a patient that manifests one or both of these complications whenever 2-CA is employed for skin closure. Physicians who employ 2-CA for skin closure should first ask patients about prior cutaneous reactions to cyanoacrylates including 2-CA and other commonly encountered acrylate-containing products including adhesive wound dressings, dental cements and prostheses, superglue, artificial nails, and adhesives for wigs and false eyelashes. Still, many patients who exhibit acrylate-induced contact dermatitis, with or without an associated id reaction, will not attest to a history of adverse reactions; they simply may not recognize acrylate as the inciting agent. Practitioners across a range of specialties outside of dermatology—surgeons, emergency physicians, and primary care providers—should be prepared to both recognize contact dermatitis and id reaction arising from the use of 2-CA and implement a basic treatment plan that will bring the patient relief without compromising wound closure.

To the Editor:

In 1998, 2-octyl-cyanoacrylate (2-CA) tissue adhesive gained US Food and Drug Administration approval for topical application to easily hold closed approximated skin edges from surgical excisions and simple trauma-induced lacerations.¹ It has since been employed for a number of off-label indications, including sutureless circumcision,² skin graft fixation,³ pericatheter leakage,⁴ and intracorporeal use to control air leaks during lung resection.⁵ Animal investigations additionally have attempted to elucidate potential future uses of 2-CA for procedures such as inguinal hernia repair,⁶ bowel anastomosis,⁷ incisional hernia repair with mesh,⁸ and microvascular anastomosis.⁹ Compared to sutures, 2-CA offers ease and rapidity of application, a water-resistant barrier, and equivalent cosmetic results, as well as eliminates the need for suture removal.¹⁰ As 2-CA is used with increasing frequency across a variety of settings, there arises a greater need to be mindful of the potential complications of its use, such as irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), and cutaneous id reaction.

A 14-year-old adolescent boy with no notable medical history and no known allergies underwent a minimally invasive Nuss procedure¹¹ (performed by P.L.G.) for the repair of severe pectus excavatum. Two 4-cm incisions were made—one in each lateral chest wall at the approximately eighth intercostal space—to facilitate the introduction of the Nuss bar. The surgical wounds were closed with 2 layers of running polyglactin 910 suture before 2-CA was applied topically to the incision sites. The surgery was well tolerated, and the patient’s wounds healed without incident. When the patient was evaluated for Nuss bar removal 3 years later, incision sites were noted to be well healed, and he exhibited no other skin lesions. The original incision sites (bilateral chest walls) were utilized to facilitate surgical Nuss bar removal. The wounds were closed in 4 layers and 2-CA was again applied topically to the incision sites. There were no intraoperative complications; no devices, drains, or tissue implants were left in the patient at the conclusion of the procedure.

One week later, via text message and digital photographs, the patient reported intense pruritus at the bilateral chest wall incision sites, which were now surrounded by symmetric 1-cm erythematous plaques and associated sparse erythematous satellite papules (Figure 1). The patient denied any fevers, pain, swelling, or purulent discharge from the wounds. He was started on hydrocortisone cream 1% twice daily as well as oral diphenhydramine 25 mg at bedtime with initial good effect.

Three days later, the patient sent digital photographs of a morphologically similar–appearing rash that had progressed beyond the lateral chest walls to include the central chest and bilateral upper and lower extremities (Figure 2). He continued to deny any local or systemic signs of infection. Dermatology was consulted, and a diagnosis of ACD with cutaneous id reaction was made. The patient’s medication regimen was modified to include triamcinolone acetonide cream 0.1% applied twice daily to the rash away from the wounds, clobetasol propionate ointment 0.05% applied twice daily to the rash at the wound sites, oral levocetirizine 5 mg once daily, and oral hydroxyzine 25 to 50 mg every 6 hours as needed for pruritus. Additional recommendations included the use of a fragrance-free soap and application of an over-the-counter anti-itch lotion containing menthol and camphor applied as needed. Within 24 hours of starting this modified treatment regimen, the patient began to notice an improvement in symptoms, with full resolution over the course of the ensuing 2 weeks. The patient was counseled to inform his physicians—present and future—of his allergy to 2-CA.

 

Contact dermatitis associated with the use of 2-CA has been described in the literature.^12-15 We report progression to an id reaction, which is characterized by the diffuse symmetric spread of a cutaneous eruption at a site distant from the primary localized dermatitis that develops within a few days of the primary lesion and exhibits the same morphologic and histopathologic findings.^16,17 In our patient, pruritic erythematous papules and plaques symmetrically distributed on the arms, legs, and chest appeared 3 days after he first reported a similar eruption at the 2-CA application sites. It is theorized that id reactions develop when the sensitization phase of a type IV hypersensitivity reaction generates a population of T cells that not only recognizes a hapten but also recognizes keratinocyte-derived epitopes.¹⁶ A hapten is a small molecule (<500 Da) that is capable of penetrating the stratum corneum and binding skin components. A contact allergen is a hapten that has bound epidermal proteins to create a new antigenic determinant.¹⁸ The secondary dermatitis that characterizes id reactions results from an abnormal autoimmune response. Id reactions associated with exposure to adhesive material are rare.¹⁹

Allergic contact dermatitis is a type IV hypersensitivity reaction that appears after initial sensitization to an allergen followed by re-exposure. Our patient presented with symmetric erythematous plaques at the surgical incision sites 1 week after 2-CA had been applied. During this interval, sensitization to the inciting allergen occurred. The allergen is taken up by antigen-presenting cells, which then migrate to lymph nodes where they encounter naïve T lymphocytes that subsequently undergo clonal expansion to produce a cohort of T cells that are capable of recognizing the allergen. If subsequent exposure to the specific allergen takes place, an elicitation phase occurs in which primed T cells are incited to release mediators of inflammation that engender the manifestations of ACD within 24 to 72 hours.^18,20 Sensitization may be promoted by skin barrier impairments such as dermatitis or a frank wound.^12,20 In most cases, the patient is unaware that sensitization has occurred, though a primary ACD within 5 to 15 days after initial exposure to the inciting allergen rarely may be observed.¹⁸ Although our patient had 2-CA applied to his surgical wounds at 14 years of age, it was unlikely that sensitization took place at that time, as it was 1 week rather than 1 to 3 days before he experienced the cutaneous eruption associated with his second 2-CA exposure at 17 years of age.

Cyanoacrylate tissue adhesive also may cause ICD resulting from histotoxic degradation products such as formaldehyde and cyanoacetate that are capable of compromising cutaneous barrier function. Keratinocytes that have had their membranes disturbed release proinflammatory cytokines, which recruit cells of the innate immune system as well as T lymphocytes to the site of insult to facilitate the inflammatory response. The manifestations of ICD include erythema, edema, and local necrosis that can compromise wound healing.²⁰ The speed at which a given cyanoacrylate adhesive degrades is proportional to the length of its carbon side chain. Those with shorter side chains—ethyl and methyl cyanoacrylate—degrade more rapidly into formaldehyde and cyanoacetate; 2-CA possesses a longer side chain and therefore degrades more slowly, which should, in theory, lessen its potential to cause ICD.²⁰ Because it may take 7 to 14 days before 2-CA will spontaneously peel from the application site, however, its potential to evoke ICD nevertheless exists.

Treatment of ICD entails removing the irritant while concurrently working to restore the skin’s barrier with emollients. Although topical corticosteroids often are reflexively prescribed to treat rashes, some believe that their use should be avoided in cases of ICD, as their inhibitory effects on epidermal lipid synthesis may further impair the skin’s barrier.²¹ For cases of ACD, with or without an accompanying id reaction, topical corticosteroids are the mainstay of therapy. It is customary to start with a higher-potency topical steroid such as clobetasol and taper to lower-potency steroids as the patient’s condition improves. Steroid ointments are petroleum based and are capable of causing 2-CA to separate from the skin.¹⁰ As a result, they should be used with care when being applied to an area where 2-CA is maintaining dermal closure. Systemic corticosteroids may be warranted in cases with involvement of more than 20% of the body surface area and should start to provide relief within 12 to 24 hours.²² Oral antihistamines and cold water compresses can be added to help address pruritus and discomfort in both ACD and ICD.

Instances of contact dermatitis caused by 2-CA are rare, and progression to an id reaction is rarer still. Physicians should be aware of the possibility of encountering a patient that manifests one or both of these complications whenever 2-CA is employed for skin closure. Physicians who employ 2-CA for skin closure should first ask patients about prior cutaneous reactions to cyanoacrylates including 2-CA and other commonly encountered acrylate-containing products including adhesive wound dressings, dental cements and prostheses, superglue, artificial nails, and adhesives for wigs and false eyelashes. Still, many patients who exhibit acrylate-induced contact dermatitis, with or without an associated id reaction, will not attest to a history of adverse reactions; they simply may not recognize acrylate as the inciting agent. Practitioners across a range of specialties outside of dermatology—surgeons, emergency physicians, and primary care providers—should be prepared to both recognize contact dermatitis and id reaction arising from the use of 2-CA and implement a basic treatment plan that will bring the patient relief without compromising wound closure.

To the Editor:

In 1998, 2-octyl-cyanoacrylate (2-CA) tissue adhesive gained US Food and Drug Administration approval for topical application to easily hold closed approximated skin edges from surgical excisions and simple trauma-induced lacerations.¹ It has since been employed for a number of off-label indications, including sutureless circumcision,² skin graft fixation,³ pericatheter leakage,⁴ and intracorporeal use to control air leaks during lung resection.⁵ Animal investigations additionally have attempted to elucidate potential future uses of 2-CA for procedures such as inguinal hernia repair,⁶ bowel anastomosis,⁷ incisional hernia repair with mesh,⁸ and microvascular anastomosis.⁹ Compared to sutures, 2-CA offers ease and rapidity of application, a water-resistant barrier, and equivalent cosmetic results, as well as eliminates the need for suture removal.¹⁰ As 2-CA is used with increasing frequency across a variety of settings, there arises a greater need to be mindful of the potential complications of its use, such as irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), and cutaneous id reaction.

A 14-year-old adolescent boy with no notable medical history and no known allergies underwent a minimally invasive Nuss procedure¹¹ (performed by P.L.G.) for the repair of severe pectus excavatum. Two 4-cm incisions were made—one in each lateral chest wall at the approximately eighth intercostal space—to facilitate the introduction of the Nuss bar. The surgical wounds were closed with 2 layers of running polyglactin 910 suture before 2-CA was applied topically to the incision sites. The surgery was well tolerated, and the patient’s wounds healed without incident. When the patient was evaluated for Nuss bar removal 3 years later, incision sites were noted to be well healed, and he exhibited no other skin lesions. The original incision sites (bilateral chest walls) were utilized to facilitate surgical Nuss bar removal. The wounds were closed in 4 layers and 2-CA was again applied topically to the incision sites. There were no intraoperative complications; no devices, drains, or tissue implants were left in the patient at the conclusion of the procedure.

One week later, via text message and digital photographs, the patient reported intense pruritus at the bilateral chest wall incision sites, which were now surrounded by symmetric 1-cm erythematous plaques and associated sparse erythematous satellite papules (Figure 1). The patient denied any fevers, pain, swelling, or purulent discharge from the wounds. He was started on hydrocortisone cream 1% twice daily as well as oral diphenhydramine 25 mg at bedtime with initial good effect.

Three days later, the patient sent digital photographs of a morphologically similar–appearing rash that had progressed beyond the lateral chest walls to include the central chest and bilateral upper and lower extremities (Figure 2). He continued to deny any local or systemic signs of infection. Dermatology was consulted, and a diagnosis of ACD with cutaneous id reaction was made. The patient’s medication regimen was modified to include triamcinolone acetonide cream 0.1% applied twice daily to the rash away from the wounds, clobetasol propionate ointment 0.05% applied twice daily to the rash at the wound sites, oral levocetirizine 5 mg once daily, and oral hydroxyzine 25 to 50 mg every 6 hours as needed for pruritus. Additional recommendations included the use of a fragrance-free soap and application of an over-the-counter anti-itch lotion containing menthol and camphor applied as needed. Within 24 hours of starting this modified treatment regimen, the patient began to notice an improvement in symptoms, with full resolution over the course of the ensuing 2 weeks. The patient was counseled to inform his physicians—present and future—of his allergy to 2-CA.

 

Contact dermatitis associated with the use of 2-CA has been described in the literature.^12-15 We report progression to an id reaction, which is characterized by the diffuse symmetric spread of a cutaneous eruption at a site distant from the primary localized dermatitis that develops within a few days of the primary lesion and exhibits the same morphologic and histopathologic findings.^16,17 In our patient, pruritic erythematous papules and plaques symmetrically distributed on the arms, legs, and chest appeared 3 days after he first reported a similar eruption at the 2-CA application sites. It is theorized that id reactions develop when the sensitization phase of a type IV hypersensitivity reaction generates a population of T cells that not only recognizes a hapten but also recognizes keratinocyte-derived epitopes.¹⁶ A hapten is a small molecule (<500 Da) that is capable of penetrating the stratum corneum and binding skin components. A contact allergen is a hapten that has bound epidermal proteins to create a new antigenic determinant.¹⁸ The secondary dermatitis that characterizes id reactions results from an abnormal autoimmune response. Id reactions associated with exposure to adhesive material are rare.¹⁹

Allergic contact dermatitis is a type IV hypersensitivity reaction that appears after initial sensitization to an allergen followed by re-exposure. Our patient presented with symmetric erythematous plaques at the surgical incision sites 1 week after 2-CA had been applied. During this interval, sensitization to the inciting allergen occurred. The allergen is taken up by antigen-presenting cells, which then migrate to lymph nodes where they encounter naïve T lymphocytes that subsequently undergo clonal expansion to produce a cohort of T cells that are capable of recognizing the allergen. If subsequent exposure to the specific allergen takes place, an elicitation phase occurs in which primed T cells are incited to release mediators of inflammation that engender the manifestations of ACD within 24 to 72 hours.^18,20 Sensitization may be promoted by skin barrier impairments such as dermatitis or a frank wound.^12,20 In most cases, the patient is unaware that sensitization has occurred, though a primary ACD within 5 to 15 days after initial exposure to the inciting allergen rarely may be observed.¹⁸ Although our patient had 2-CA applied to his surgical wounds at 14 years of age, it was unlikely that sensitization took place at that time, as it was 1 week rather than 1 to 3 days before he experienced the cutaneous eruption associated with his second 2-CA exposure at 17 years of age.

Cyanoacrylate tissue adhesive also may cause ICD resulting from histotoxic degradation products such as formaldehyde and cyanoacetate that are capable of compromising cutaneous barrier function. Keratinocytes that have had their membranes disturbed release proinflammatory cytokines, which recruit cells of the innate immune system as well as T lymphocytes to the site of insult to facilitate the inflammatory response. The manifestations of ICD include erythema, edema, and local necrosis that can compromise wound healing.²⁰ The speed at which a given cyanoacrylate adhesive degrades is proportional to the length of its carbon side chain. Those with shorter side chains—ethyl and methyl cyanoacrylate—degrade more rapidly into formaldehyde and cyanoacetate; 2-CA possesses a longer side chain and therefore degrades more slowly, which should, in theory, lessen its potential to cause ICD.²⁰ Because it may take 7 to 14 days before 2-CA will spontaneously peel from the application site, however, its potential to evoke ICD nevertheless exists.

Treatment of ICD entails removing the irritant while concurrently working to restore the skin’s barrier with emollients. Although topical corticosteroids often are reflexively prescribed to treat rashes, some believe that their use should be avoided in cases of ICD, as their inhibitory effects on epidermal lipid synthesis may further impair the skin’s barrier.²¹ For cases of ACD, with or without an accompanying id reaction, topical corticosteroids are the mainstay of therapy. It is customary to start with a higher-potency topical steroid such as clobetasol and taper to lower-potency steroids as the patient’s condition improves. Steroid ointments are petroleum based and are capable of causing 2-CA to separate from the skin.¹⁰ As a result, they should be used with care when being applied to an area where 2-CA is maintaining dermal closure. Systemic corticosteroids may be warranted in cases with involvement of more than 20% of the body surface area and should start to provide relief within 12 to 24 hours.²² Oral antihistamines and cold water compresses can be added to help address pruritus and discomfort in both ACD and ICD.

Instances of contact dermatitis caused by 2-CA are rare, and progression to an id reaction is rarer still. Physicians should be aware of the possibility of encountering a patient that manifests one or both of these complications whenever 2-CA is employed for skin closure. Physicians who employ 2-CA for skin closure should first ask patients about prior cutaneous reactions to cyanoacrylates including 2-CA and other commonly encountered acrylate-containing products including adhesive wound dressings, dental cements and prostheses, superglue, artificial nails, and adhesives for wigs and false eyelashes. Still, many patients who exhibit acrylate-induced contact dermatitis, with or without an associated id reaction, will not attest to a history of adverse reactions; they simply may not recognize acrylate as the inciting agent. Practitioners across a range of specialties outside of dermatology—surgeons, emergency physicians, and primary care providers—should be prepared to both recognize contact dermatitis and id reaction arising from the use of 2-CA and implement a basic treatment plan that will bring the patient relief without compromising wound closure.