MDedge Dermatology

THE DIAGNOSIS: Mpox Virus

The histopathologic features of mpox virus infection may vary depending on the stage of evolution; findings include ballooning degeneration with multinucleated keratinocytes, acanthosis, spongiosis, a neutrophil-rich inflammatory infiltrate, and eosinophilic intracytoplasmic (Guarnieri) inclusion bodies (quiz image inset [arrows]). Prominent neutrophil exocytosis also has been described and may be a characteristic feature in the pustular stage.^1,2 A pattern of interface dermatitis also has been observed on histopathology.³ In our patient, the diagnosis of mpox initially was made by clinical and histopathologic correlation and exclusion of other entities in the differential diagnosis. The diagnosis subsequently was confirmed by real-time polymerase chain reaction. The patient received treatment with tecovirimat, but lesions progressed over the following 6 weeks. He subsequently died due to sepsis and multiorgan failure secondary to AIDS.

Mpox is a zoonotic, double-stranded DNA virus of the genus Orthopoxvirus in the family Poxviridae.⁴ It is transmitted to humans via direct contact with infected animals, most commonly small mammals such as monkeys, squirrels, and rodents. Mpox also may be transmitted between humans through direct contact with bodily fluids, skin and mucosal lesions, respiratory droplets, or fomites. Mpox infection typically begins with a nonspecific flulike prodrome after a 5- to 21-day incubation period, followed by skin lesions of variable morphology affecting any region of the body. Clinically, mpox lesions have been reported to evolve through macular, papular, and vesiculopustular phases, followed by resolution with crusting. Lesions may occur anywhere on the body but frequently manifest on the face then spread centrifugally across the body, with various phases observed simultaneously.⁵ A worldwide outbreak in 2022 involved larger numbers of cases in nonendemic areas, primarily due to skin-to-skin contact, with predominant anal and genital localization of the lesions as well as fewer prodromal symptoms.⁶

The differential diagnosis of crusted and umbilicated papules includes disseminated herpesvirus infection, molluscum contagiosum, disseminated cryptococcosis, and histoplasmosis. Additional causative organisms to consider include Penicillium, Mycobacterium tuberculosis and nontuberculous mycobacteria, as well as Sporothrix schenckii.

Herpesvirus infections may have similar clinical and histopathologic findings to mpox. Histopathologically, herpes simplex virus (HSV) and varicella zoster virus (VZV) are essentially identical; both demonstrate ballooning and reticular epidermal degeneration, chromatin condensation, nuclear degeneration, multinucleated keratinocytes with steel-gray nuclei, and prominent epidermal acantholysis with an inflammatory infiltrate (Figure 1). However, involvement of folliculosebaceous units may favor a diagnosis of VZV. Immunohistochemical staining can further differentiate between HSV and VZV.⁷ While mpox may have features that overlap with both HSV and VZV, including ballooning degeneration and multinucleated keratinocytes with nuclear degeneration, acantholysis is a less commonly reported feature of mpox, and mpox virus infection is characterized by intracytoplasmic (Guarnieri) inclusion bodies rather than the intranuclear inclusion bodies of HSV and VZV.^2,5 The presence of Guarnieri bodies in mpox may further help to distinguish mpox from HSV infection on routine histology.

Molluscum contagiosum infection typically manifests as multiple umbilicated papules at sites of inoculation. Large lesions may be seen in the setting of immunosuppression; however, they usually do not progress to vesicular, pustular, or crusted morphologies. Histopathology demonstrates a cup-shaped invagination of the epidermis into the dermis and proliferative rete ridges that descend downward and encircle the dermis with large eosinophilic intracytoplasmic inclusion (Henderson-Patterson) bodies (Figure 2).⁸

Disseminated cryptococcus infection is caused by the invasive fungus Cryptococcus neoformans and is characterized by meningitis along with fever, malaise, headache, neck stiffness, photophobia, nausea, vomiting, pneumonia with cough and dyspnea, and skin rash, most commonly in immunocompromised individuals.⁹ Skin lesions are a sign of disseminated infection and can manifest as umbilicated or molluscumlike lesions. Histopathology of cryptococcosis demonstrates a granulomatous dermal infiltrate with neutrophils and pleomorphic yeasts measuring 4 µm to 6 µm with refringent capsules.¹⁰ Staining with Grocott methenamine silver and/or mucicarmine for yeast capsules can help to identify organisms (Figure 3).

Cutaneous histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus that can lead to pulmonary, cutaneous, and disseminated disease, often in immunocompromised patients.¹¹ Cutaneous disease may manifest with molluscumlike or verrucous papules and plaques. Histopathologic examination reveals diffuse suppurative and granulomatous infiltrates with foamy histiocytes and multinucleated giant cells, containing intracellular and extracellular yeasts measuring 1µm to 5µm, surrounded by a clear halo visible with Grocott methenamine silver stain (Figure 4).

Spreading cutaneous lesions in an immunocompromised individual may be the presentation of multiple infectious etiologies. With the recent rise in mpox cases occurring in nonendemic areas, clinicians should be aware of the spectrum of clinical findings that may occur. Notably, more than one infection may be present in severely immunocompromised individuals, as seen in our patient with chronic orolabial HSV-2 and acute mpox infection. Thorough clinical, histopathologic, and laboratory investigations are necessary for timely diagnosis, appropriate treatment, and exclusion of other life-threatening conditions.

THE DIAGNOSIS: Mpox Virus

The histopathologic features of mpox virus infection may vary depending on the stage of evolution; findings include ballooning degeneration with multinucleated keratinocytes, acanthosis, spongiosis, a neutrophil-rich inflammatory infiltrate, and eosinophilic intracytoplasmic (Guarnieri) inclusion bodies (quiz image inset [arrows]). Prominent neutrophil exocytosis also has been described and may be a characteristic feature in the pustular stage.^1,2 A pattern of interface dermatitis also has been observed on histopathology.³ In our patient, the diagnosis of mpox initially was made by clinical and histopathologic correlation and exclusion of other entities in the differential diagnosis. The diagnosis subsequently was confirmed by real-time polymerase chain reaction. The patient received treatment with tecovirimat, but lesions progressed over the following 6 weeks. He subsequently died due to sepsis and multiorgan failure secondary to AIDS.

Mpox is a zoonotic, double-stranded DNA virus of the genus Orthopoxvirus in the family Poxviridae.⁴ It is transmitted to humans via direct contact with infected animals, most commonly small mammals such as monkeys, squirrels, and rodents. Mpox also may be transmitted between humans through direct contact with bodily fluids, skin and mucosal lesions, respiratory droplets, or fomites. Mpox infection typically begins with a nonspecific flulike prodrome after a 5- to 21-day incubation period, followed by skin lesions of variable morphology affecting any region of the body. Clinically, mpox lesions have been reported to evolve through macular, papular, and vesiculopustular phases, followed by resolution with crusting. Lesions may occur anywhere on the body but frequently manifest on the face then spread centrifugally across the body, with various phases observed simultaneously.⁵ A worldwide outbreak in 2022 involved larger numbers of cases in nonendemic areas, primarily due to skin-to-skin contact, with predominant anal and genital localization of the lesions as well as fewer prodromal symptoms.⁶

The differential diagnosis of crusted and umbilicated papules includes disseminated herpesvirus infection, molluscum contagiosum, disseminated cryptococcosis, and histoplasmosis. Additional causative organisms to consider include Penicillium, Mycobacterium tuberculosis and nontuberculous mycobacteria, as well as Sporothrix schenckii.

Herpesvirus infections may have similar clinical and histopathologic findings to mpox. Histopathologically, herpes simplex virus (HSV) and varicella zoster virus (VZV) are essentially identical; both demonstrate ballooning and reticular epidermal degeneration, chromatin condensation, nuclear degeneration, multinucleated keratinocytes with steel-gray nuclei, and prominent epidermal acantholysis with an inflammatory infiltrate (Figure 1). However, involvement of folliculosebaceous units may favor a diagnosis of VZV. Immunohistochemical staining can further differentiate between HSV and VZV.⁷ While mpox may have features that overlap with both HSV and VZV, including ballooning degeneration and multinucleated keratinocytes with nuclear degeneration, acantholysis is a less commonly reported feature of mpox, and mpox virus infection is characterized by intracytoplasmic (Guarnieri) inclusion bodies rather than the intranuclear inclusion bodies of HSV and VZV.^2,5 The presence of Guarnieri bodies in mpox may further help to distinguish mpox from HSV infection on routine histology.

Molluscum contagiosum infection typically manifests as multiple umbilicated papules at sites of inoculation. Large lesions may be seen in the setting of immunosuppression; however, they usually do not progress to vesicular, pustular, or crusted morphologies. Histopathology demonstrates a cup-shaped invagination of the epidermis into the dermis and proliferative rete ridges that descend downward and encircle the dermis with large eosinophilic intracytoplasmic inclusion (Henderson-Patterson) bodies (Figure 2).⁸

Disseminated cryptococcus infection is caused by the invasive fungus Cryptococcus neoformans and is characterized by meningitis along with fever, malaise, headache, neck stiffness, photophobia, nausea, vomiting, pneumonia with cough and dyspnea, and skin rash, most commonly in immunocompromised individuals.⁹ Skin lesions are a sign of disseminated infection and can manifest as umbilicated or molluscumlike lesions. Histopathology of cryptococcosis demonstrates a granulomatous dermal infiltrate with neutrophils and pleomorphic yeasts measuring 4 µm to 6 µm with refringent capsules.¹⁰ Staining with Grocott methenamine silver and/or mucicarmine for yeast capsules can help to identify organisms (Figure 3).

Cutaneous histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus that can lead to pulmonary, cutaneous, and disseminated disease, often in immunocompromised patients.¹¹ Cutaneous disease may manifest with molluscumlike or verrucous papules and plaques. Histopathologic examination reveals diffuse suppurative and granulomatous infiltrates with foamy histiocytes and multinucleated giant cells, containing intracellular and extracellular yeasts measuring 1µm to 5µm, surrounded by a clear halo visible with Grocott methenamine silver stain (Figure 4).

Spreading cutaneous lesions in an immunocompromised individual may be the presentation of multiple infectious etiologies. With the recent rise in mpox cases occurring in nonendemic areas, clinicians should be aware of the spectrum of clinical findings that may occur. Notably, more than one infection may be present in severely immunocompromised individuals, as seen in our patient with chronic orolabial HSV-2 and acute mpox infection. Thorough clinical, histopathologic, and laboratory investigations are necessary for timely diagnosis, appropriate treatment, and exclusion of other life-threatening conditions.

THE DIAGNOSIS: Mpox Virus

The histopathologic features of mpox virus infection may vary depending on the stage of evolution; findings include ballooning degeneration with multinucleated keratinocytes, acanthosis, spongiosis, a neutrophil-rich inflammatory infiltrate, and eosinophilic intracytoplasmic (Guarnieri) inclusion bodies (quiz image inset [arrows]). Prominent neutrophil exocytosis also has been described and may be a characteristic feature in the pustular stage.^1,2 A pattern of interface dermatitis also has been observed on histopathology.³ In our patient, the diagnosis of mpox initially was made by clinical and histopathologic correlation and exclusion of other entities in the differential diagnosis. The diagnosis subsequently was confirmed by real-time polymerase chain reaction. The patient received treatment with tecovirimat, but lesions progressed over the following 6 weeks. He subsequently died due to sepsis and multiorgan failure secondary to AIDS.

Mpox is a zoonotic, double-stranded DNA virus of the genus Orthopoxvirus in the family Poxviridae.⁴ It is transmitted to humans via direct contact with infected animals, most commonly small mammals such as monkeys, squirrels, and rodents. Mpox also may be transmitted between humans through direct contact with bodily fluids, skin and mucosal lesions, respiratory droplets, or fomites. Mpox infection typically begins with a nonspecific flulike prodrome after a 5- to 21-day incubation period, followed by skin lesions of variable morphology affecting any region of the body. Clinically, mpox lesions have been reported to evolve through macular, papular, and vesiculopustular phases, followed by resolution with crusting. Lesions may occur anywhere on the body but frequently manifest on the face then spread centrifugally across the body, with various phases observed simultaneously.⁵ A worldwide outbreak in 2022 involved larger numbers of cases in nonendemic areas, primarily due to skin-to-skin contact, with predominant anal and genital localization of the lesions as well as fewer prodromal symptoms.⁶

The differential diagnosis of crusted and umbilicated papules includes disseminated herpesvirus infection, molluscum contagiosum, disseminated cryptococcosis, and histoplasmosis. Additional causative organisms to consider include Penicillium, Mycobacterium tuberculosis and nontuberculous mycobacteria, as well as Sporothrix schenckii.

Herpesvirus infections may have similar clinical and histopathologic findings to mpox. Histopathologically, herpes simplex virus (HSV) and varicella zoster virus (VZV) are essentially identical; both demonstrate ballooning and reticular epidermal degeneration, chromatin condensation, nuclear degeneration, multinucleated keratinocytes with steel-gray nuclei, and prominent epidermal acantholysis with an inflammatory infiltrate (Figure 1). However, involvement of folliculosebaceous units may favor a diagnosis of VZV. Immunohistochemical staining can further differentiate between HSV and VZV.⁷ While mpox may have features that overlap with both HSV and VZV, including ballooning degeneration and multinucleated keratinocytes with nuclear degeneration, acantholysis is a less commonly reported feature of mpox, and mpox virus infection is characterized by intracytoplasmic (Guarnieri) inclusion bodies rather than the intranuclear inclusion bodies of HSV and VZV.^2,5 The presence of Guarnieri bodies in mpox may further help to distinguish mpox from HSV infection on routine histology.

Molluscum contagiosum infection typically manifests as multiple umbilicated papules at sites of inoculation. Large lesions may be seen in the setting of immunosuppression; however, they usually do not progress to vesicular, pustular, or crusted morphologies. Histopathology demonstrates a cup-shaped invagination of the epidermis into the dermis and proliferative rete ridges that descend downward and encircle the dermis with large eosinophilic intracytoplasmic inclusion (Henderson-Patterson) bodies (Figure 2).⁸

Disseminated cryptococcus infection is caused by the invasive fungus Cryptococcus neoformans and is characterized by meningitis along with fever, malaise, headache, neck stiffness, photophobia, nausea, vomiting, pneumonia with cough and dyspnea, and skin rash, most commonly in immunocompromised individuals.⁹ Skin lesions are a sign of disseminated infection and can manifest as umbilicated or molluscumlike lesions. Histopathology of cryptococcosis demonstrates a granulomatous dermal infiltrate with neutrophils and pleomorphic yeasts measuring 4 µm to 6 µm with refringent capsules.¹⁰ Staining with Grocott methenamine silver and/or mucicarmine for yeast capsules can help to identify organisms (Figure 3).

Cutaneous histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus that can lead to pulmonary, cutaneous, and disseminated disease, often in immunocompromised patients.¹¹ Cutaneous disease may manifest with molluscumlike or verrucous papules and plaques. Histopathologic examination reveals diffuse suppurative and granulomatous infiltrates with foamy histiocytes and multinucleated giant cells, containing intracellular and extracellular yeasts measuring 1µm to 5µm, surrounded by a clear halo visible with Grocott methenamine silver stain (Figure 4).

Spreading cutaneous lesions in an immunocompromised individual may be the presentation of multiple infectious etiologies. With the recent rise in mpox cases occurring in nonendemic areas, clinicians should be aware of the spectrum of clinical findings that may occur. Notably, more than one infection may be present in severely immunocompromised individuals, as seen in our patient with chronic orolabial HSV-2 and acute mpox infection. Thorough clinical, histopathologic, and laboratory investigations are necessary for timely diagnosis, appropriate treatment, and exclusion of other life-threatening conditions.

To the Editor:

The popularity of the social media platform TikTok, which is known for its short-form videos, has surged in recent years. Viral videos demonstrating skin care routines reach millions of viewers,¹ showcasing specific products, detailing beauty regimens, and setting fads that many users eagerly follow. These trends often influence consumer behavior—in 2023, viral videos using the tag #TikTokMadeMeBuy lead to a 14% growth in the sale of skin care products.² However, they also encourage purchasing decisions that may escalate environmental waste through plastic packaging and single-use products. In this study, we analyzed videos on TikTok to assess the environmental impact of trending skin care routines. By examining the types of products promoted, their packaging, and the frequency with which they appear in viral content, we aimed to investigate how these trends, which may be imitated by users, impact the environment.

A search of TikTok videos using #skincareroutine was conducted on June 21, 2024. Sponsored content, non–English language videos, videos without demonstrated skin care routines, and videos showing makeup routines were excluded from our analysis. Data collected from each video included username, date posted, number of likes, total number of skin care products used, number of single-use skin care products used, average amount of product used, number of skin care applicators used, and number of single-use applicators used. Single-use items, defined as those intended for one-time use and subsequent disposal, were identified visually by packaging, manufacturer intent, and common consumer usage patterns. The amount of product used per application was graded on a scale of 1 to 3 (1=pea-sized amount or less; 2=single full pump/spray; 3=multiple pumps/sprays). Videos were categorized as personal (ie, skin care routine walk-throughs by the creator) or autonomous sensory meridian response (ASMR)(focused on product sounds and aesthetics).³ A Mann-Whitney U test was utilized to statistically compare the 2 groups. Statistical analysis was performed using Microsoft Excel (α=0.05). 

A total of 50 videos met the inclusion criteria and were included in the analysis. The average number of likes per video was 499,696.15, with skin care routines featuring an average of 6.4 unique products (Table). There was a weak positive correlation (r=0.1809) between the number of skin care products used and the number of likes. A total of 320 products were used across the videos, 23 of which were single-use (7.2%).On average, single-use skin care items were used 0.46 times per routine, comprising a mean 7.99% of total products per video. The average score for the amount of product used per application was 2.18. There was no difference in personal vs ASMR videos with regard to the total number of skin care products used or the average amount of product used per application (P>.05). Thirty-three (70.2%) of the 47 applicators used across all videos were single-use. An average of 0.94 applicators per routine were utilized, with a mean 68.83% being single-use applicators. Common single-use products were toner wipes and eye patches, and single-use applicators included cotton pads and plastic spatulas. 

Our findings indicated a prevalence of multiple products and large amount of product used in trending skin care routines, suggesting a shift toward multistep skin care. This implies a high rate of product consumption that may accelerate the carbon footprint associated with skin care products,³ which could contribute to climate change and environmental degradation. Consumers also may feel compelled to purchase and discard numerous partially used products in order to keep up with the latest trends, exacerbating the environmental impact. Furthermore, the utilization of single-use products and applicators contributes to increased plastic waste, pollution, and resource depletion. Single-use items often are difficult to recycle due to their mixed materials and small size,^4,5 and therefore they can accumulate in landfills and oceans. This impact can be mitigated by switching to reusable applicators, refillable packaging, and biodegradable materials. 

The substantial average number of likes per video indicates high engagement with skin care content among TikTok users. The continued popularity of complex multi­step skin care routines, despite a weak correlation between the number of skin care products used and the number of likes per video, likely stems from factors such as aesthetic appeal, ASMR effects, and creators’ established followings, which may drive user engagement to contribute to unsustainable consumption patterns. Factors such as presentation style, aesthetics, or creators’ pre-existing online following may have a major impact on how well a video performs on TikTok. The similarity between personal and ASMR videos, particularly in the number of products used and the amount applied, suggests that both formats employ common approaches to meet audience expectations and align with promotional trends, relying more on sensory and aesthetic strategies than substantive differences in skin care routines.

Our use of only one tag in our search as well as the subjective quantity scale limits the generalizability of these findings to broader TikTok skin care content.

Overall, our study underscores the role of brands and social media influencers in skin care education and promotion of sustainable practices. The extensive number of products used and generous application of each product in skin care routines demonstrated in TikTok videos may mislead viewers into believing that using more product improves outcomes, when often, less is more. We recommend that dermatologists counsel patients about informed skin care regimens that prioritize individual needs over social media fads.

To the Editor:

The popularity of the social media platform TikTok, which is known for its short-form videos, has surged in recent years. Viral videos demonstrating skin care routines reach millions of viewers,¹ showcasing specific products, detailing beauty regimens, and setting fads that many users eagerly follow. These trends often influence consumer behavior—in 2023, viral videos using the tag #TikTokMadeMeBuy lead to a 14% growth in the sale of skin care products.² However, they also encourage purchasing decisions that may escalate environmental waste through plastic packaging and single-use products. In this study, we analyzed videos on TikTok to assess the environmental impact of trending skin care routines. By examining the types of products promoted, their packaging, and the frequency with which they appear in viral content, we aimed to investigate how these trends, which may be imitated by users, impact the environment.

A search of TikTok videos using #skincareroutine was conducted on June 21, 2024. Sponsored content, non–English language videos, videos without demonstrated skin care routines, and videos showing makeup routines were excluded from our analysis. Data collected from each video included username, date posted, number of likes, total number of skin care products used, number of single-use skin care products used, average amount of product used, number of skin care applicators used, and number of single-use applicators used. Single-use items, defined as those intended for one-time use and subsequent disposal, were identified visually by packaging, manufacturer intent, and common consumer usage patterns. The amount of product used per application was graded on a scale of 1 to 3 (1=pea-sized amount or less; 2=single full pump/spray; 3=multiple pumps/sprays). Videos were categorized as personal (ie, skin care routine walk-throughs by the creator) or autonomous sensory meridian response (ASMR)(focused on product sounds and aesthetics).³ A Mann-Whitney U test was utilized to statistically compare the 2 groups. Statistical analysis was performed using Microsoft Excel (α=0.05). 

A total of 50 videos met the inclusion criteria and were included in the analysis. The average number of likes per video was 499,696.15, with skin care routines featuring an average of 6.4 unique products (Table). There was a weak positive correlation (r=0.1809) between the number of skin care products used and the number of likes. A total of 320 products were used across the videos, 23 of which were single-use (7.2%).On average, single-use skin care items were used 0.46 times per routine, comprising a mean 7.99% of total products per video. The average score for the amount of product used per application was 2.18. There was no difference in personal vs ASMR videos with regard to the total number of skin care products used or the average amount of product used per application (P>.05). Thirty-three (70.2%) of the 47 applicators used across all videos were single-use. An average of 0.94 applicators per routine were utilized, with a mean 68.83% being single-use applicators. Common single-use products were toner wipes and eye patches, and single-use applicators included cotton pads and plastic spatulas. 

Our findings indicated a prevalence of multiple products and large amount of product used in trending skin care routines, suggesting a shift toward multistep skin care. This implies a high rate of product consumption that may accelerate the carbon footprint associated with skin care products,³ which could contribute to climate change and environmental degradation. Consumers also may feel compelled to purchase and discard numerous partially used products in order to keep up with the latest trends, exacerbating the environmental impact. Furthermore, the utilization of single-use products and applicators contributes to increased plastic waste, pollution, and resource depletion. Single-use items often are difficult to recycle due to their mixed materials and small size,^4,5 and therefore they can accumulate in landfills and oceans. This impact can be mitigated by switching to reusable applicators, refillable packaging, and biodegradable materials. 

The substantial average number of likes per video indicates high engagement with skin care content among TikTok users. The continued popularity of complex multi­step skin care routines, despite a weak correlation between the number of skin care products used and the number of likes per video, likely stems from factors such as aesthetic appeal, ASMR effects, and creators’ established followings, which may drive user engagement to contribute to unsustainable consumption patterns. Factors such as presentation style, aesthetics, or creators’ pre-existing online following may have a major impact on how well a video performs on TikTok. The similarity between personal and ASMR videos, particularly in the number of products used and the amount applied, suggests that both formats employ common approaches to meet audience expectations and align with promotional trends, relying more on sensory and aesthetic strategies than substantive differences in skin care routines.

Our use of only one tag in our search as well as the subjective quantity scale limits the generalizability of these findings to broader TikTok skin care content.

Overall, our study underscores the role of brands and social media influencers in skin care education and promotion of sustainable practices. The extensive number of products used and generous application of each product in skin care routines demonstrated in TikTok videos may mislead viewers into believing that using more product improves outcomes, when often, less is more. We recommend that dermatologists counsel patients about informed skin care regimens that prioritize individual needs over social media fads.

To the Editor:

The popularity of the social media platform TikTok, which is known for its short-form videos, has surged in recent years. Viral videos demonstrating skin care routines reach millions of viewers,¹ showcasing specific products, detailing beauty regimens, and setting fads that many users eagerly follow. These trends often influence consumer behavior—in 2023, viral videos using the tag #TikTokMadeMeBuy lead to a 14% growth in the sale of skin care products.² However, they also encourage purchasing decisions that may escalate environmental waste through plastic packaging and single-use products. In this study, we analyzed videos on TikTok to assess the environmental impact of trending skin care routines. By examining the types of products promoted, their packaging, and the frequency with which they appear in viral content, we aimed to investigate how these trends, which may be imitated by users, impact the environment.

A search of TikTok videos using #skincareroutine was conducted on June 21, 2024. Sponsored content, non–English language videos, videos without demonstrated skin care routines, and videos showing makeup routines were excluded from our analysis. Data collected from each video included username, date posted, number of likes, total number of skin care products used, number of single-use skin care products used, average amount of product used, number of skin care applicators used, and number of single-use applicators used. Single-use items, defined as those intended for one-time use and subsequent disposal, were identified visually by packaging, manufacturer intent, and common consumer usage patterns. The amount of product used per application was graded on a scale of 1 to 3 (1=pea-sized amount or less; 2=single full pump/spray; 3=multiple pumps/sprays). Videos were categorized as personal (ie, skin care routine walk-throughs by the creator) or autonomous sensory meridian response (ASMR)(focused on product sounds and aesthetics).³ A Mann-Whitney U test was utilized to statistically compare the 2 groups. Statistical analysis was performed using Microsoft Excel (α=0.05). 

A total of 50 videos met the inclusion criteria and were included in the analysis. The average number of likes per video was 499,696.15, with skin care routines featuring an average of 6.4 unique products (Table). There was a weak positive correlation (r=0.1809) between the number of skin care products used and the number of likes. A total of 320 products were used across the videos, 23 of which were single-use (7.2%).On average, single-use skin care items were used 0.46 times per routine, comprising a mean 7.99% of total products per video. The average score for the amount of product used per application was 2.18. There was no difference in personal vs ASMR videos with regard to the total number of skin care products used or the average amount of product used per application (P>.05). Thirty-three (70.2%) of the 47 applicators used across all videos were single-use. An average of 0.94 applicators per routine were utilized, with a mean 68.83% being single-use applicators. Common single-use products were toner wipes and eye patches, and single-use applicators included cotton pads and plastic spatulas. 

Our findings indicated a prevalence of multiple products and large amount of product used in trending skin care routines, suggesting a shift toward multistep skin care. This implies a high rate of product consumption that may accelerate the carbon footprint associated with skin care products,³ which could contribute to climate change and environmental degradation. Consumers also may feel compelled to purchase and discard numerous partially used products in order to keep up with the latest trends, exacerbating the environmental impact. Furthermore, the utilization of single-use products and applicators contributes to increased plastic waste, pollution, and resource depletion. Single-use items often are difficult to recycle due to their mixed materials and small size,^4,5 and therefore they can accumulate in landfills and oceans. This impact can be mitigated by switching to reusable applicators, refillable packaging, and biodegradable materials. 

The substantial average number of likes per video indicates high engagement with skin care content among TikTok users. The continued popularity of complex multi­step skin care routines, despite a weak correlation between the number of skin care products used and the number of likes per video, likely stems from factors such as aesthetic appeal, ASMR effects, and creators’ established followings, which may drive user engagement to contribute to unsustainable consumption patterns. Factors such as presentation style, aesthetics, or creators’ pre-existing online following may have a major impact on how well a video performs on TikTok. The similarity between personal and ASMR videos, particularly in the number of products used and the amount applied, suggests that both formats employ common approaches to meet audience expectations and align with promotional trends, relying more on sensory and aesthetic strategies than substantive differences in skin care routines.

Our use of only one tag in our search as well as the subjective quantity scale limits the generalizability of these findings to broader TikTok skin care content.

Overall, our study underscores the role of brands and social media influencers in skin care education and promotion of sustainable practices. The extensive number of products used and generous application of each product in skin care routines demonstrated in TikTok videos may mislead viewers into believing that using more product improves outcomes, when often, less is more. We recommend that dermatologists counsel patients about informed skin care regimens that prioritize individual needs over social media fads.

Implantation mycoses such as chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma are a diverse group of fungal diseases that occur when a break in the skin allows the entry of the causative fungus. These diseases disproportionately affect individuals in low- and middle-income countries causing substantial disability, decreased quality of life, and severe social stigma.^1-3 Timely diagnosis and appropriate treatment are critical.

Chromoblastomycosis and mycetoma are designated as neglected tropical diseases, but research to improve their management is sparse, even compared to other neglected tropical diseases.^4,5 Since there are no global diagnostic and treatment guidelines to date, we outline steps to diagnose and manage chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma.

Chromoblastomycosis

Chromoblastomycosis is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Chromoblastomycosis is distinguished from subcutaneous phaeohyphomycosis by microscopically visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).⁶ In phaeohyphomycosis, short hyphae and pseudohyphae plus some single cells typically are seen.

Epidemiology—Globally, the distribution and burden of chromoblastomycosis are relatively unknown. Infections are more common in tropical and subtropical areas but can be acquired anywhere. A literature review conducted in 2021 identified 7740 cases of chromo­blastomycosis, mostly reported in South America, Africa, Central America and Mexico, and Asia.⁷ Most of the patients were male, and the median age was 52 years. One study found an incidence of 14.7 per 1,000,000 patients in the United States for both chromoblastomycosis and phaeohyphomycotic abscesses (which included both skin and brain abscesses).⁸ Most patients were aged 65 years or older, with a higher incidence in males. Geographically, the incidence was highest in the Northeast followed by the South; patients in rural areas also had higher incidence of disease.⁸

Causative Organisms—Causative species cannot reliably distinguish between chromoblastomycosis and subcutaneous phaeohyphomycosis, as some species overlap. Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa most commonly cause chromoblastomycosis.^9,10

Clinical Manifestations—Chromoblastomycosis initially manifests as a solitary erythematous macule at a site of trauma (often not recalled by the patient) that can evolve to a smooth pink papule and may progress to 1 of 5 morphologies: nodular, verrucous, tumorous, cicatricial, or plaque.⁶ Patients may present with more than one morphology, particularly in long-standing or advanced disease. Lesions commonly manifest on the arms and legs in otherwise healthy individuals in environments (eg, rural, agricultural) that have more opportunities for injury and exposure to the causative fungi. Affected individuals often have small black specks on the lesion surface that are visible with the naked eye.⁶

Diagnosis—Common differential diagnoses include cutaneous blastomycosis, fixed sporotrichosis, warty tuberculosis nocardiosis, cutaneous leishmaniasis, human papillomavirus (HPV) infection, podoconiosis, lymphatic filariasis, cutaneous tuberculosis, and psoriasis.⁶ Squamous cell carcinoma is both a differential diagnosis as well as a potential complication of the disease.¹¹

Potassium hydroxide preparation with skin scapings or a biopsy from the lesion has high sensitivity and quick turnaround times. There often is a background histopathologic reaction of pseudoepitheliomatous hyperplasia. Examining samples taken from areas with the visible small black dots on the skin surface can increase the likelihood of detecting fungal elements (Figure 1). Clinicians also may choose to obtain a 6- to 8-mm deep skin biopsy from the lesion and splice it in half, with one sample sent for histopathology and the other for culture (Figure 2). Skin scrapings can be sent for culture instead. In the case of verrucous lesions, biopsy is preferred if feasible. 

Treatment should not be delayed while awaiting the culture results if infection is otherwise confirmed by direct microscopy or histopathology. The treatment approach remains similar regardless of the causative species. If the culture results are positive, the causative genus can be identified by the microscopic morphology; however, molecular diagnostic tools are needed for accurate species identification.^12,13

Antifungal Susceptibility Testing—For most dematiaceous fungi, interpreting minimum inhibitory concentrations (MICs) is challenging due to a lack of data from multicenter studies. One report examined sequential isolates of Fonsecaea pedrosoi and demonstrated both high MIC values and clinical resistance to itraconazole in some cases, likely from treatment pressure.¹⁴ Clinical Laboratory Standards Institute–approved epidemiologic cutoff values (ECVs) are established for F pedrosoi for commonly used antifungals including itraconazole (0.5 µg/mL), terbinafine (0.25 µg/mL), and posaconazole (0.5 µg/mL).¹⁵ Clinicians may choose to obtain sequential isolates for any causative fungi in recalcitrant disease to monitor for increases in MIC.

Management—In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. If antifungals are needed, itraconazole is the most commonly prescribed agent, typically at a dose of 100 to 200 mg twice daily. Terbinafine also has been used first-line at a dose of 250 to 500 mg per day. Voriconazole and posaconazole also may be suitable options for first-line or for refractory disease treatment. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy usually is several months, but many patients require years of therapy until resolution of lesions. 

Clinicians can consider combination therapy with an antifungal and a topical immunomodulator such as imiquimod (applied topically 3 times per week); this combination can be considered in refractory disease and even upon initial diagnosis, especially in severe disease.^17,18 Nonpharmacologic interventions such as cryotherapy, heat, and light-based therapies have been used, but outcome data are scarce.^19-23

Subcutaneous Phaeohyphomycosis

Subcutaneous phaeohyphomycosis also is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Subcutaneous phaeohyphomycosis is distinguished from chromoblastomycosis by short hyphae and hyphal fragments usually seen microscopically instead of visualizing thick-walled, single, or multicellular clusters of pigmented fungal cells.⁶

Epidemiology—Globally, the burden and distribution of phaeohyphomycosis, including its cutaneous manifestations, are not well understood. Infections are more common in tropical and subtropical areas but can be acquired anywhere. Phaeohyphomycosis is a generic term used to describe infections caused by pigmented hyphal fungi that can manifest on the skin (subcutaneous phaeohyphomycosis) but also can affect deep structures including the brain (systemic phaeohyphomycosis).²⁴

Causative Organisms—Alternaria, Bipolaris, Cladosporium, Curvularia, Exophiala, and Exserohilum species most commonly cause subcutaneous phaeohyphomycosis. Alternaria infections manifesting with skin lesions often are referred to as cutaneous alternariosis.²⁵

Clinical Manifestations—The most common skin manifestation of phaeohyphomycosis is a subcutaneous cyst (cystic phaeohyphomycosis)(Figure 2). Subcutaneous phaeohyphomycosis also may manifest with nodules or plaques (Figure 3). Phaeohyphomycosis appears to occur more commonly in individuals who are immunosuppressed, those in whom T-cell function is affected, in congenital immunodeficiency states (eg, individuals with CARD9 mutations).²⁶

Diagnosis—Culture is the gold standard for confirming phaeohyphomycosis.²⁷ For cystic phaeohyphomycosis, clinicians can consider aspiration of the cyst for direct microscopic examination and culture. Histopathology may be utilized but can have lower sensitivity in showing dematiaceous hyphae and granulomatous inflammation; using the Masson-Fontana stain for melanin can be helpful. Molecular diagnostic tools including metagenomics applied directly to the tissue may be useful but are likely to have lower sensitivity than culture and require specialist diagnostic facilities.

Management—The approaches to managing chromoblastomycosis and subcutaneous phaeohyphomycosis are similar, though the preferred agents often differ. In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. In localized forms, itraconazole usually is used, but in those cases associated with immunodeficiency states, voriconazole may be necessary. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy may be substantially longer for chromoblastomycosis (months to years) compared to subcutaneous phaeohyphomycosis (weeks to months), although in immunocompromised individuals treatment may be even more prolonged.

Mycetoma

Mycetoma is caused by one of several different types of fungi (eumycetoma) and bacteria (actinomycetoma) that lead to progressively debilitating yet painless subcutaneous tumorlike lesions. The lesions usually manifest on the arms and legs but can occur anywhere.

Epidemiology—Little is known about the true global burden of mycetoma, but it occurs more frequently in low-income communities in rural areas.²⁸ A retrospective review identified 19,494 cases published from 1876 to 2019, with cases reported in 102 countries.²⁹ The countries with the highest numbers of cases are Sudan and Mexico, where there is more information on the distribution of the disease. Cases often are reported in what is known as the mycetoma belt (between latitudes 15° south and 30° north) but are increasingly identified outside this region.²⁸ Young men aged 20 to 40 years are most commonly affected.

In the United States, mycetoma is uncommon, but clinicians can encounter locally acquired and travel-associated cases; hence, taking a good travel history is essential. One study specifically evaluating eumycetoma found a prevalence of 5.2 per 1,000,000 patients.⁸ Women and those aged 65 years or older had a higher incidence. Incidence was similar across US regions, but a higher incidence was reported in nonrural areas.⁸

Causative Organisms—More than 60 different species of fungi can cause eumycetoma; most cases are caused by Madurella mycetomatis, Trematosphaeria grisea (formerly Madurella grisea); Pseudallescheria boydii species complex, and Falciformispora (formerly Leptosphaeria) senegalensis.³⁰ Actinomycetoma commonly is caused by Nocardia species (Nocardia brasiliensis, Nocardia asteroides, Nocardia otitidiscaviarum, Nocardia transvalensis, Nocardia harenae, and Nocardia takedensis), Streptomyces somaliensis, and Actinomadura species (Actinomadura madurae, Actinomadura pelletieri).³¹

Clinical Manifestations—Mycetoma is a chronic granulomatous disease with a progressive inflammatory reaction (Figures 4 and 5). Over the course of years, mycetoma progresses from small nodules to large, bone-invasive, mutilating lesions. Mycetoma manifests as a triad of painless firm subcutaneous masses, formation of multiple sinuses within the masses, and a purulent or seropurulent discharge containing sandlike visible particles (grains) that can be white, yellow, red, or black.²⁸ Lesions usually are painless in early disease and are slowly progressive. Large lesion size, bone destruction, secondary bacterial infections, and actinomycetoma may lead to higher likelihood of pain.³²

Diagnosis—Other conditions that could manifest with the same triad seen in mycetoma such as botryomycosis should be included in the differential. Other differential diagnoses include foreign body granuloma, filariasis, mycobacterial infection, skeletal tuberculosis, and yaws. 

Proper treatment requires an accurate diagnosis that distinguishes actinomycetoma from eumycetoma.³³ Culturing of grains obtained from deep lesion aspirates enables identification of the causative organism (Figure 6). The color of the grains may provide clues to their etiology: black grains are caused by fungus, red grains by a bacterium (A pelletieri), and pale (yellow or white) grains can be caused by either one.³¹Nocardia mycetoma grains are very small and usually cannot be appreciated with the naked eye. Histopathology of deep biopsy specimens (biopsy needle or surgical biopsy) stained with hematoxylin and eosin can diagnose actinomycetoma and eumycetoma. Punch biopsies often are not helpful, as the inflammatory mass is too deeply located. Deep surgical biopsy is preferred; however, species identification cannot be made without culture. Molecular tests for certain causative organisms of mycetoma have been developed but are not readily available.^34,35 Currently, no serologic tests can diagnose mycetoma reliably. Ultrasonography can be used to diagnose mycetoma and, with appropriate training, distinguish between actinomycetoma and eumycetoma; it also can be combined with needle aspiration for taking grain samples.³⁶

Treatment—Treatment of mycetoma depends on identification of the causal etiology and requires long-term and expensive drug regimens. It is not possible to determine the causative organism clinically. Actinomycetoma generally responds to medical treatment, and surgery rarely is needed. The current first-line treatment is co-trimoxazole (trimethoprim/sulfamethoxazole) in combination with amoxicillin and clavulanate acid or co-trimoxazole and amikacin for refractory disease; linezolid also may be a promising option for refractory disease.³⁷

Eumycetoma is less responsive to medical therapies, and recurrence is common. Current recommended therapy is itraconazole for 9 to 12 months; however, cure rates ranging from 26% to 75% in combination with surgery have been reported, and fungi often can still be cultured from lesions posttreatment.^38,39 Surgical excision often is used following 6 months of treatment with itraconazole to obtain better outcomes. Amputation may be required if the combination of antifungals and surgical excision fails. Fosravuconazole has shown promise in one clinical trial, but it is not approved in most countries, including the United States.³⁹

Final Thoughts

Chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma can cause devastating disease. Patients with these conditions often are unable to carry out daily activities and experience stigma and discrimination. Limited diagnostic and treatment options hamper the ability of clinicians to respond appropriately to suspect and confirmed disease. Effectively examining the skin is the starting point for diagnosing and managing these diseases and can help clinicians to care for patients and prevent severe disease.

Implantation mycoses such as chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma are a diverse group of fungal diseases that occur when a break in the skin allows the entry of the causative fungus. These diseases disproportionately affect individuals in low- and middle-income countries causing substantial disability, decreased quality of life, and severe social stigma.^1-3 Timely diagnosis and appropriate treatment are critical.

Chromoblastomycosis and mycetoma are designated as neglected tropical diseases, but research to improve their management is sparse, even compared to other neglected tropical diseases.^4,5 Since there are no global diagnostic and treatment guidelines to date, we outline steps to diagnose and manage chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma.

Chromoblastomycosis

Chromoblastomycosis is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Chromoblastomycosis is distinguished from subcutaneous phaeohyphomycosis by microscopically visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).⁶ In phaeohyphomycosis, short hyphae and pseudohyphae plus some single cells typically are seen.

Epidemiology—Globally, the distribution and burden of chromoblastomycosis are relatively unknown. Infections are more common in tropical and subtropical areas but can be acquired anywhere. A literature review conducted in 2021 identified 7740 cases of chromo­blastomycosis, mostly reported in South America, Africa, Central America and Mexico, and Asia.⁷ Most of the patients were male, and the median age was 52 years. One study found an incidence of 14.7 per 1,000,000 patients in the United States for both chromoblastomycosis and phaeohyphomycotic abscesses (which included both skin and brain abscesses).⁸ Most patients were aged 65 years or older, with a higher incidence in males. Geographically, the incidence was highest in the Northeast followed by the South; patients in rural areas also had higher incidence of disease.⁸

Causative Organisms—Causative species cannot reliably distinguish between chromoblastomycosis and subcutaneous phaeohyphomycosis, as some species overlap. Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa most commonly cause chromoblastomycosis.^9,10

Clinical Manifestations—Chromoblastomycosis initially manifests as a solitary erythematous macule at a site of trauma (often not recalled by the patient) that can evolve to a smooth pink papule and may progress to 1 of 5 morphologies: nodular, verrucous, tumorous, cicatricial, or plaque.⁶ Patients may present with more than one morphology, particularly in long-standing or advanced disease. Lesions commonly manifest on the arms and legs in otherwise healthy individuals in environments (eg, rural, agricultural) that have more opportunities for injury and exposure to the causative fungi. Affected individuals often have small black specks on the lesion surface that are visible with the naked eye.⁶

Diagnosis—Common differential diagnoses include cutaneous blastomycosis, fixed sporotrichosis, warty tuberculosis nocardiosis, cutaneous leishmaniasis, human papillomavirus (HPV) infection, podoconiosis, lymphatic filariasis, cutaneous tuberculosis, and psoriasis.⁶ Squamous cell carcinoma is both a differential diagnosis as well as a potential complication of the disease.¹¹

Potassium hydroxide preparation with skin scapings or a biopsy from the lesion has high sensitivity and quick turnaround times. There often is a background histopathologic reaction of pseudoepitheliomatous hyperplasia. Examining samples taken from areas with the visible small black dots on the skin surface can increase the likelihood of detecting fungal elements (Figure 1). Clinicians also may choose to obtain a 6- to 8-mm deep skin biopsy from the lesion and splice it in half, with one sample sent for histopathology and the other for culture (Figure 2). Skin scrapings can be sent for culture instead. In the case of verrucous lesions, biopsy is preferred if feasible. 

Treatment should not be delayed while awaiting the culture results if infection is otherwise confirmed by direct microscopy or histopathology. The treatment approach remains similar regardless of the causative species. If the culture results are positive, the causative genus can be identified by the microscopic morphology; however, molecular diagnostic tools are needed for accurate species identification.^12,13

Antifungal Susceptibility Testing—For most dematiaceous fungi, interpreting minimum inhibitory concentrations (MICs) is challenging due to a lack of data from multicenter studies. One report examined sequential isolates of Fonsecaea pedrosoi and demonstrated both high MIC values and clinical resistance to itraconazole in some cases, likely from treatment pressure.¹⁴ Clinical Laboratory Standards Institute–approved epidemiologic cutoff values (ECVs) are established for F pedrosoi for commonly used antifungals including itraconazole (0.5 µg/mL), terbinafine (0.25 µg/mL), and posaconazole (0.5 µg/mL).¹⁵ Clinicians may choose to obtain sequential isolates for any causative fungi in recalcitrant disease to monitor for increases in MIC.

Management—In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. If antifungals are needed, itraconazole is the most commonly prescribed agent, typically at a dose of 100 to 200 mg twice daily. Terbinafine also has been used first-line at a dose of 250 to 500 mg per day. Voriconazole and posaconazole also may be suitable options for first-line or for refractory disease treatment. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy usually is several months, but many patients require years of therapy until resolution of lesions. 

Clinicians can consider combination therapy with an antifungal and a topical immunomodulator such as imiquimod (applied topically 3 times per week); this combination can be considered in refractory disease and even upon initial diagnosis, especially in severe disease.^17,18 Nonpharmacologic interventions such as cryotherapy, heat, and light-based therapies have been used, but outcome data are scarce.^19-23

Subcutaneous Phaeohyphomycosis

Subcutaneous phaeohyphomycosis also is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Subcutaneous phaeohyphomycosis is distinguished from chromoblastomycosis by short hyphae and hyphal fragments usually seen microscopically instead of visualizing thick-walled, single, or multicellular clusters of pigmented fungal cells.⁶

Epidemiology—Globally, the burden and distribution of phaeohyphomycosis, including its cutaneous manifestations, are not well understood. Infections are more common in tropical and subtropical areas but can be acquired anywhere. Phaeohyphomycosis is a generic term used to describe infections caused by pigmented hyphal fungi that can manifest on the skin (subcutaneous phaeohyphomycosis) but also can affect deep structures including the brain (systemic phaeohyphomycosis).²⁴

Causative Organisms—Alternaria, Bipolaris, Cladosporium, Curvularia, Exophiala, and Exserohilum species most commonly cause subcutaneous phaeohyphomycosis. Alternaria infections manifesting with skin lesions often are referred to as cutaneous alternariosis.²⁵

Clinical Manifestations—The most common skin manifestation of phaeohyphomycosis is a subcutaneous cyst (cystic phaeohyphomycosis)(Figure 2). Subcutaneous phaeohyphomycosis also may manifest with nodules or plaques (Figure 3). Phaeohyphomycosis appears to occur more commonly in individuals who are immunosuppressed, those in whom T-cell function is affected, in congenital immunodeficiency states (eg, individuals with CARD9 mutations).²⁶

Diagnosis—Culture is the gold standard for confirming phaeohyphomycosis.²⁷ For cystic phaeohyphomycosis, clinicians can consider aspiration of the cyst for direct microscopic examination and culture. Histopathology may be utilized but can have lower sensitivity in showing dematiaceous hyphae and granulomatous inflammation; using the Masson-Fontana stain for melanin can be helpful. Molecular diagnostic tools including metagenomics applied directly to the tissue may be useful but are likely to have lower sensitivity than culture and require specialist diagnostic facilities.

Management—The approaches to managing chromoblastomycosis and subcutaneous phaeohyphomycosis are similar, though the preferred agents often differ. In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. In localized forms, itraconazole usually is used, but in those cases associated with immunodeficiency states, voriconazole may be necessary. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy may be substantially longer for chromoblastomycosis (months to years) compared to subcutaneous phaeohyphomycosis (weeks to months), although in immunocompromised individuals treatment may be even more prolonged.

Mycetoma

Mycetoma is caused by one of several different types of fungi (eumycetoma) and bacteria (actinomycetoma) that lead to progressively debilitating yet painless subcutaneous tumorlike lesions. The lesions usually manifest on the arms and legs but can occur anywhere.

Epidemiology—Little is known about the true global burden of mycetoma, but it occurs more frequently in low-income communities in rural areas.²⁸ A retrospective review identified 19,494 cases published from 1876 to 2019, with cases reported in 102 countries.²⁹ The countries with the highest numbers of cases are Sudan and Mexico, where there is more information on the distribution of the disease. Cases often are reported in what is known as the mycetoma belt (between latitudes 15° south and 30° north) but are increasingly identified outside this region.²⁸ Young men aged 20 to 40 years are most commonly affected.

In the United States, mycetoma is uncommon, but clinicians can encounter locally acquired and travel-associated cases; hence, taking a good travel history is essential. One study specifically evaluating eumycetoma found a prevalence of 5.2 per 1,000,000 patients.⁸ Women and those aged 65 years or older had a higher incidence. Incidence was similar across US regions, but a higher incidence was reported in nonrural areas.⁸

Causative Organisms—More than 60 different species of fungi can cause eumycetoma; most cases are caused by Madurella mycetomatis, Trematosphaeria grisea (formerly Madurella grisea); Pseudallescheria boydii species complex, and Falciformispora (formerly Leptosphaeria) senegalensis.³⁰ Actinomycetoma commonly is caused by Nocardia species (Nocardia brasiliensis, Nocardia asteroides, Nocardia otitidiscaviarum, Nocardia transvalensis, Nocardia harenae, and Nocardia takedensis), Streptomyces somaliensis, and Actinomadura species (Actinomadura madurae, Actinomadura pelletieri).³¹

Clinical Manifestations—Mycetoma is a chronic granulomatous disease with a progressive inflammatory reaction (Figures 4 and 5). Over the course of years, mycetoma progresses from small nodules to large, bone-invasive, mutilating lesions. Mycetoma manifests as a triad of painless firm subcutaneous masses, formation of multiple sinuses within the masses, and a purulent or seropurulent discharge containing sandlike visible particles (grains) that can be white, yellow, red, or black.²⁸ Lesions usually are painless in early disease and are slowly progressive. Large lesion size, bone destruction, secondary bacterial infections, and actinomycetoma may lead to higher likelihood of pain.³²

Diagnosis—Other conditions that could manifest with the same triad seen in mycetoma such as botryomycosis should be included in the differential. Other differential diagnoses include foreign body granuloma, filariasis, mycobacterial infection, skeletal tuberculosis, and yaws. 

Proper treatment requires an accurate diagnosis that distinguishes actinomycetoma from eumycetoma.³³ Culturing of grains obtained from deep lesion aspirates enables identification of the causative organism (Figure 6). The color of the grains may provide clues to their etiology: black grains are caused by fungus, red grains by a bacterium (A pelletieri), and pale (yellow or white) grains can be caused by either one.³¹Nocardia mycetoma grains are very small and usually cannot be appreciated with the naked eye. Histopathology of deep biopsy specimens (biopsy needle or surgical biopsy) stained with hematoxylin and eosin can diagnose actinomycetoma and eumycetoma. Punch biopsies often are not helpful, as the inflammatory mass is too deeply located. Deep surgical biopsy is preferred; however, species identification cannot be made without culture. Molecular tests for certain causative organisms of mycetoma have been developed but are not readily available.^34,35 Currently, no serologic tests can diagnose mycetoma reliably. Ultrasonography can be used to diagnose mycetoma and, with appropriate training, distinguish between actinomycetoma and eumycetoma; it also can be combined with needle aspiration for taking grain samples.³⁶

Treatment—Treatment of mycetoma depends on identification of the causal etiology and requires long-term and expensive drug regimens. It is not possible to determine the causative organism clinically. Actinomycetoma generally responds to medical treatment, and surgery rarely is needed. The current first-line treatment is co-trimoxazole (trimethoprim/sulfamethoxazole) in combination with amoxicillin and clavulanate acid or co-trimoxazole and amikacin for refractory disease; linezolid also may be a promising option for refractory disease.³⁷

Eumycetoma is less responsive to medical therapies, and recurrence is common. Current recommended therapy is itraconazole for 9 to 12 months; however, cure rates ranging from 26% to 75% in combination with surgery have been reported, and fungi often can still be cultured from lesions posttreatment.^38,39 Surgical excision often is used following 6 months of treatment with itraconazole to obtain better outcomes. Amputation may be required if the combination of antifungals and surgical excision fails. Fosravuconazole has shown promise in one clinical trial, but it is not approved in most countries, including the United States.³⁹

Final Thoughts

Chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma can cause devastating disease. Patients with these conditions often are unable to carry out daily activities and experience stigma and discrimination. Limited diagnostic and treatment options hamper the ability of clinicians to respond appropriately to suspect and confirmed disease. Effectively examining the skin is the starting point for diagnosing and managing these diseases and can help clinicians to care for patients and prevent severe disease.

Implantation mycoses such as chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma are a diverse group of fungal diseases that occur when a break in the skin allows the entry of the causative fungus. These diseases disproportionately affect individuals in low- and middle-income countries causing substantial disability, decreased quality of life, and severe social stigma.^1-3 Timely diagnosis and appropriate treatment are critical.

Chromoblastomycosis and mycetoma are designated as neglected tropical diseases, but research to improve their management is sparse, even compared to other neglected tropical diseases.^4,5 Since there are no global diagnostic and treatment guidelines to date, we outline steps to diagnose and manage chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma.

Chromoblastomycosis

Chromoblastomycosis is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Chromoblastomycosis is distinguished from subcutaneous phaeohyphomycosis by microscopically visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).⁶ In phaeohyphomycosis, short hyphae and pseudohyphae plus some single cells typically are seen.

Epidemiology—Globally, the distribution and burden of chromoblastomycosis are relatively unknown. Infections are more common in tropical and subtropical areas but can be acquired anywhere. A literature review conducted in 2021 identified 7740 cases of chromo­blastomycosis, mostly reported in South America, Africa, Central America and Mexico, and Asia.⁷ Most of the patients were male, and the median age was 52 years. One study found an incidence of 14.7 per 1,000,000 patients in the United States for both chromoblastomycosis and phaeohyphomycotic abscesses (which included both skin and brain abscesses).⁸ Most patients were aged 65 years or older, with a higher incidence in males. Geographically, the incidence was highest in the Northeast followed by the South; patients in rural areas also had higher incidence of disease.⁸

Causative Organisms—Causative species cannot reliably distinguish between chromoblastomycosis and subcutaneous phaeohyphomycosis, as some species overlap. Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa most commonly cause chromoblastomycosis.^9,10

Clinical Manifestations—Chromoblastomycosis initially manifests as a solitary erythematous macule at a site of trauma (often not recalled by the patient) that can evolve to a smooth pink papule and may progress to 1 of 5 morphologies: nodular, verrucous, tumorous, cicatricial, or plaque.⁶ Patients may present with more than one morphology, particularly in long-standing or advanced disease. Lesions commonly manifest on the arms and legs in otherwise healthy individuals in environments (eg, rural, agricultural) that have more opportunities for injury and exposure to the causative fungi. Affected individuals often have small black specks on the lesion surface that are visible with the naked eye.⁶

Diagnosis—Common differential diagnoses include cutaneous blastomycosis, fixed sporotrichosis, warty tuberculosis nocardiosis, cutaneous leishmaniasis, human papillomavirus (HPV) infection, podoconiosis, lymphatic filariasis, cutaneous tuberculosis, and psoriasis.⁶ Squamous cell carcinoma is both a differential diagnosis as well as a potential complication of the disease.¹¹

Potassium hydroxide preparation with skin scapings or a biopsy from the lesion has high sensitivity and quick turnaround times. There often is a background histopathologic reaction of pseudoepitheliomatous hyperplasia. Examining samples taken from areas with the visible small black dots on the skin surface can increase the likelihood of detecting fungal elements (Figure 1). Clinicians also may choose to obtain a 6- to 8-mm deep skin biopsy from the lesion and splice it in half, with one sample sent for histopathology and the other for culture (Figure 2). Skin scrapings can be sent for culture instead. In the case of verrucous lesions, biopsy is preferred if feasible. 

Treatment should not be delayed while awaiting the culture results if infection is otherwise confirmed by direct microscopy or histopathology. The treatment approach remains similar regardless of the causative species. If the culture results are positive, the causative genus can be identified by the microscopic morphology; however, molecular diagnostic tools are needed for accurate species identification.^12,13

Antifungal Susceptibility Testing—For most dematiaceous fungi, interpreting minimum inhibitory concentrations (MICs) is challenging due to a lack of data from multicenter studies. One report examined sequential isolates of Fonsecaea pedrosoi and demonstrated both high MIC values and clinical resistance to itraconazole in some cases, likely from treatment pressure.¹⁴ Clinical Laboratory Standards Institute–approved epidemiologic cutoff values (ECVs) are established for F pedrosoi for commonly used antifungals including itraconazole (0.5 µg/mL), terbinafine (0.25 µg/mL), and posaconazole (0.5 µg/mL).¹⁵ Clinicians may choose to obtain sequential isolates for any causative fungi in recalcitrant disease to monitor for increases in MIC.

Management—In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. If antifungals are needed, itraconazole is the most commonly prescribed agent, typically at a dose of 100 to 200 mg twice daily. Terbinafine also has been used first-line at a dose of 250 to 500 mg per day. Voriconazole and posaconazole also may be suitable options for first-line or for refractory disease treatment. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy usually is several months, but many patients require years of therapy until resolution of lesions. 

Clinicians can consider combination therapy with an antifungal and a topical immunomodulator such as imiquimod (applied topically 3 times per week); this combination can be considered in refractory disease and even upon initial diagnosis, especially in severe disease.^17,18 Nonpharmacologic interventions such as cryotherapy, heat, and light-based therapies have been used, but outcome data are scarce.^19-23

Subcutaneous Phaeohyphomycosis

Subcutaneous phaeohyphomycosis also is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Subcutaneous phaeohyphomycosis is distinguished from chromoblastomycosis by short hyphae and hyphal fragments usually seen microscopically instead of visualizing thick-walled, single, or multicellular clusters of pigmented fungal cells.⁶

Epidemiology—Globally, the burden and distribution of phaeohyphomycosis, including its cutaneous manifestations, are not well understood. Infections are more common in tropical and subtropical areas but can be acquired anywhere. Phaeohyphomycosis is a generic term used to describe infections caused by pigmented hyphal fungi that can manifest on the skin (subcutaneous phaeohyphomycosis) but also can affect deep structures including the brain (systemic phaeohyphomycosis).²⁴

Causative Organisms—Alternaria, Bipolaris, Cladosporium, Curvularia, Exophiala, and Exserohilum species most commonly cause subcutaneous phaeohyphomycosis. Alternaria infections manifesting with skin lesions often are referred to as cutaneous alternariosis.²⁵

Clinical Manifestations—The most common skin manifestation of phaeohyphomycosis is a subcutaneous cyst (cystic phaeohyphomycosis)(Figure 2). Subcutaneous phaeohyphomycosis also may manifest with nodules or plaques (Figure 3). Phaeohyphomycosis appears to occur more commonly in individuals who are immunosuppressed, those in whom T-cell function is affected, in congenital immunodeficiency states (eg, individuals with CARD9 mutations).²⁶

Diagnosis—Culture is the gold standard for confirming phaeohyphomycosis.²⁷ For cystic phaeohyphomycosis, clinicians can consider aspiration of the cyst for direct microscopic examination and culture. Histopathology may be utilized but can have lower sensitivity in showing dematiaceous hyphae and granulomatous inflammation; using the Masson-Fontana stain for melanin can be helpful. Molecular diagnostic tools including metagenomics applied directly to the tissue may be useful but are likely to have lower sensitivity than culture and require specialist diagnostic facilities.

Management—The approaches to managing chromoblastomycosis and subcutaneous phaeohyphomycosis are similar, though the preferred agents often differ. In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. In localized forms, itraconazole usually is used, but in those cases associated with immunodeficiency states, voriconazole may be necessary. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy may be substantially longer for chromoblastomycosis (months to years) compared to subcutaneous phaeohyphomycosis (weeks to months), although in immunocompromised individuals treatment may be even more prolonged.

Mycetoma

Mycetoma is caused by one of several different types of fungi (eumycetoma) and bacteria (actinomycetoma) that lead to progressively debilitating yet painless subcutaneous tumorlike lesions. The lesions usually manifest on the arms and legs but can occur anywhere.

Epidemiology—Little is known about the true global burden of mycetoma, but it occurs more frequently in low-income communities in rural areas.²⁸ A retrospective review identified 19,494 cases published from 1876 to 2019, with cases reported in 102 countries.²⁹ The countries with the highest numbers of cases are Sudan and Mexico, where there is more information on the distribution of the disease. Cases often are reported in what is known as the mycetoma belt (between latitudes 15° south and 30° north) but are increasingly identified outside this region.²⁸ Young men aged 20 to 40 years are most commonly affected.

In the United States, mycetoma is uncommon, but clinicians can encounter locally acquired and travel-associated cases; hence, taking a good travel history is essential. One study specifically evaluating eumycetoma found a prevalence of 5.2 per 1,000,000 patients.⁸ Women and those aged 65 years or older had a higher incidence. Incidence was similar across US regions, but a higher incidence was reported in nonrural areas.⁸

Causative Organisms—More than 60 different species of fungi can cause eumycetoma; most cases are caused by Madurella mycetomatis, Trematosphaeria grisea (formerly Madurella grisea); Pseudallescheria boydii species complex, and Falciformispora (formerly Leptosphaeria) senegalensis.³⁰ Actinomycetoma commonly is caused by Nocardia species (Nocardia brasiliensis, Nocardia asteroides, Nocardia otitidiscaviarum, Nocardia transvalensis, Nocardia harenae, and Nocardia takedensis), Streptomyces somaliensis, and Actinomadura species (Actinomadura madurae, Actinomadura pelletieri).³¹

Clinical Manifestations—Mycetoma is a chronic granulomatous disease with a progressive inflammatory reaction (Figures 4 and 5). Over the course of years, mycetoma progresses from small nodules to large, bone-invasive, mutilating lesions. Mycetoma manifests as a triad of painless firm subcutaneous masses, formation of multiple sinuses within the masses, and a purulent or seropurulent discharge containing sandlike visible particles (grains) that can be white, yellow, red, or black.²⁸ Lesions usually are painless in early disease and are slowly progressive. Large lesion size, bone destruction, secondary bacterial infections, and actinomycetoma may lead to higher likelihood of pain.³²

Diagnosis—Other conditions that could manifest with the same triad seen in mycetoma such as botryomycosis should be included in the differential. Other differential diagnoses include foreign body granuloma, filariasis, mycobacterial infection, skeletal tuberculosis, and yaws. 

Proper treatment requires an accurate diagnosis that distinguishes actinomycetoma from eumycetoma.³³ Culturing of grains obtained from deep lesion aspirates enables identification of the causative organism (Figure 6). The color of the grains may provide clues to their etiology: black grains are caused by fungus, red grains by a bacterium (A pelletieri), and pale (yellow or white) grains can be caused by either one.³¹Nocardia mycetoma grains are very small and usually cannot be appreciated with the naked eye. Histopathology of deep biopsy specimens (biopsy needle or surgical biopsy) stained with hematoxylin and eosin can diagnose actinomycetoma and eumycetoma. Punch biopsies often are not helpful, as the inflammatory mass is too deeply located. Deep surgical biopsy is preferred; however, species identification cannot be made without culture. Molecular tests for certain causative organisms of mycetoma have been developed but are not readily available.^34,35 Currently, no serologic tests can diagnose mycetoma reliably. Ultrasonography can be used to diagnose mycetoma and, with appropriate training, distinguish between actinomycetoma and eumycetoma; it also can be combined with needle aspiration for taking grain samples.³⁶

Treatment—Treatment of mycetoma depends on identification of the causal etiology and requires long-term and expensive drug regimens. It is not possible to determine the causative organism clinically. Actinomycetoma generally responds to medical treatment, and surgery rarely is needed. The current first-line treatment is co-trimoxazole (trimethoprim/sulfamethoxazole) in combination with amoxicillin and clavulanate acid or co-trimoxazole and amikacin for refractory disease; linezolid also may be a promising option for refractory disease.³⁷

Eumycetoma is less responsive to medical therapies, and recurrence is common. Current recommended therapy is itraconazole for 9 to 12 months; however, cure rates ranging from 26% to 75% in combination with surgery have been reported, and fungi often can still be cultured from lesions posttreatment.^38,39 Surgical excision often is used following 6 months of treatment with itraconazole to obtain better outcomes. Amputation may be required if the combination of antifungals and surgical excision fails. Fosravuconazole has shown promise in one clinical trial, but it is not approved in most countries, including the United States.³⁹

Final Thoughts

Chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma can cause devastating disease. Patients with these conditions often are unable to carry out daily activities and experience stigma and discrimination. Limited diagnostic and treatment options hamper the ability of clinicians to respond appropriately to suspect and confirmed disease. Effectively examining the skin is the starting point for diagnosing and managing these diseases and can help clinicians to care for patients and prevent severe disease.

Prurigo nodularis (PN) is a chronic, severely pruritic neuroimmunologic skin disorder characterized by multiple firm hyperkeratotic nodules and intense pruritus, often leading to considerable impairment in quality of life and increased rates of depression and anxiety.¹ It is considered difficult to treat due to its complex pathogenesis, the severity and chronicity of pruritus, and the limited efficacy of conventional therapies.^2,3 The disease is driven by a self-perpetuating itch-scratch cycle, underpinned by dysregulation of both immune and neural pathways including type 2 (interleukin [IL] 4, IL-13, IL-31), Th17, and Th22 cytokines as well as neuropeptides and altered cutaneous nerve architecture.^1,3 This results in persistent severe pruritus and nodular lesions that are highly refractory to standard treatments.¹ Conventional therapies (eg, locally acting agents, phototherapy, and systemic immunomodulators and neuromodulators) have varied efficacy and notable adverse effect profiles.³ While the approval of targeted biologics has transformed the therapeutic landscape, several other treatment options also are being explored in clinical trials. Herein, we review all recently approved therapies as well as emerging treatments currently under investigation.

Dupilumab

Dupilumab, the first therapy for PN approved by the US Food and Drug Administration (FDA) in 2022—is a monoclonal antibody that inhibits signaling of IL-4 and IL-13, key drivers of type 2 inflammation implicated in PN pathogenesis.^4,5 In 2 pivotal phase 3 randomized controlled trials (LIBERTY-PN PRIME and PRIME2),⁵ dupilumab demonstrated notable efficacy in adults with moderate to severe PN. A reduction of 4 points or more on the Worst Itch Numeric Rating Scale (WI-NRS) was achieved by 60.0% (45/75) of patients treated with dupilumab at week 24 compared with 18.4% (14/76) receiving placebo in the PRIME trial. In PRIME2, the same outcome was achieved by 37.2% (29/78) of patients receiving dupilumab at week 12 compared with 22.0% (18/82) of patients receiving placebo.⁵ Dupilumab also led to a greater proportion of patients achieving a substantial reduction in nodule count (≤5 nodules) and improved quality of life compared with placebo.^5,6 The safety profile of dupilumab for treatment of PN was favorable and consistent with prior experience in atopic dermatitis; conjunctivitis was the most common adverse event.^5,6

Nemolizumab

Nemolizumab, an IL-31 receptor A antagonist, is the most recent agent approved by the FDA for PN in 2024.⁷ In the OLYMPIA 1 and OLYMPIA 2 phase 3 trials,⁸ nemolizumab produced a clinically meaningful reduction in itch (defined as a ≥4-point improvement in the Peak Pruritus Numerical Rating Scale score) in 56.3% (103/183) of patients at week 16 compared with 20.9% (19/91) receiving placebo. Additionally, 37.7% (69/183) of patients receiving nemolizumab achieved clear or almost clear skin (Investigator’s Global Assessment score of 0 or 1 with a ≥2-point reduction) vs 11.0% with placebo (both P<.001). Benefits were observed as early as week 4, including rapid improvements in itch, sleep disturbance, and nodule count.⁸ Nemolizumab also improved quality of life and reduced symptoms of anxiety and depression. The safety profile was favorable, with headache and atopic dermatitis the most common adverse events; serious adverse events were infrequent and similar between groups.⁸

Abrocitinib

Abrocitinib, an oral selective Janus kinase 1 inhibitor, is an investigational therapy for PN and currently has not been approved by the FDA for this indication. In a phase 2 open-label trial, abrocitinib 200 mg daily for 12 weeks led to a 78.3% reduction in weekly Peak Pruritus Numerical Rating Scale scores in PN, with 80.0% (8/10) of patients achieving a clinically meaningful improvement of 4 points or higher. Nodule counts and quality of life also improved, with an onset of itch relief as early as week 2. The safety profile was favorable, with acneform eruptions the most common adverse event and no serious adverse events reported⁹; however, these results are based on small, nonrandomized studies and require confirmation in larger randomized controlled trials before abrocitinib can be considered a standard therapy for PN.

Cryosim-1

Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing ion channel found in unmyelinated sensory neurons within the dorsal root and trigeminal ­ganglia.¹⁰ It is activated by cool temperatures (15-28 °C) and compounds such as menthol, leading to calcium influx and a cooling sensation. In a randomized, double-blind, vehicle-controlled trial, researchers investigated the efficacy of cryosim-1 (a synthetic TRPM8 agonist) in treating PN.¹⁰ Thirty patients were enrolled, with 18 (60.0%) receiving cryosim-1 and 12 (40.0%) receiving placebo over 8 weeks. By week 8, cryosim-1 significantly reduced itch severity (mean numerical rating scale score postapplication, 2.8 vs 4.3; P=.031) and improved sleep disturbances (2.2 vs 4.2; P=.031) compared to placebo. Patients reported higher satisfaction with itch relief, and no adverse effects were observed. The study concluded that cryosim-1 is a safe, effective topical therapy for PN, likely working by interrupting the itch-scratch cycle and potentially modulating inflammatory pathways involved in chronic itch.¹⁰

Nalbuphine

Nalbuphine is a κ opioid receptor agonist and μ opioid receptor antagonist that has been investigated for the treatment of PN.¹¹ In a phase 2 randomized controlled trial, oral nalbuphine extended release (NAL-ER) 162 mg twice daily provided measurable antipruritic efficacy, with 44.4% (8/18) of patients achieving at least a 30% reduction in 7-day WI-NRS at week 10 compared with 36.4% (8/22) in the placebo group. Among those who completed the study, 66.7% (8/12) of patients receiving NAL-ER 162 mg achieved significant itch reduction vs 40% (8/20) receiving placebo (P=.03). At least a 50% reduction in WI-NRS was achieved by 33.3% (6/18) of patients receiving NAL-ER 162 mg twice daily. Extended open-label treatment was associated with further improvements in itch and lesion activity. Adverse events were mostly mild to moderate (eg, nausea, dizziness, headache, and fatigue) and occurred during dose titration. Physiologic opioid withdrawal symptoms were limited and resolved within a few days of discontinuing the medication.¹¹

Final Thoughts

In conclusion, PN remains one of the most challenging chronic dermatologic conditions to manage and is driven by a complex interplay of neuroimmune mechanisms and resistance to many conventional therapies. The approval of dupilumab and nemolizumab has marked a pivotal shift in the therapeutic landscape, offering hope to patients who previously had limited options^5,8; however, the burden of PN remains substantial, and many patients continue to experience relentless itch, poor sleep, and reduced quality of life.¹ Emerging therapies such as TRPM8 agonists, Janus kinase inhibitors, and opioid modulators represent promising additions to the treatment options, targeting novel pathways beyond traditional immunosuppression.^9-11

Prurigo nodularis (PN) is a chronic, severely pruritic neuroimmunologic skin disorder characterized by multiple firm hyperkeratotic nodules and intense pruritus, often leading to considerable impairment in quality of life and increased rates of depression and anxiety.¹ It is considered difficult to treat due to its complex pathogenesis, the severity and chronicity of pruritus, and the limited efficacy of conventional therapies.^2,3 The disease is driven by a self-perpetuating itch-scratch cycle, underpinned by dysregulation of both immune and neural pathways including type 2 (interleukin [IL] 4, IL-13, IL-31), Th17, and Th22 cytokines as well as neuropeptides and altered cutaneous nerve architecture.^1,3 This results in persistent severe pruritus and nodular lesions that are highly refractory to standard treatments.¹ Conventional therapies (eg, locally acting agents, phototherapy, and systemic immunomodulators and neuromodulators) have varied efficacy and notable adverse effect profiles.³ While the approval of targeted biologics has transformed the therapeutic landscape, several other treatment options also are being explored in clinical trials. Herein, we review all recently approved therapies as well as emerging treatments currently under investigation.

Dupilumab

Dupilumab, the first therapy for PN approved by the US Food and Drug Administration (FDA) in 2022—is a monoclonal antibody that inhibits signaling of IL-4 and IL-13, key drivers of type 2 inflammation implicated in PN pathogenesis.^4,5 In 2 pivotal phase 3 randomized controlled trials (LIBERTY-PN PRIME and PRIME2),⁵ dupilumab demonstrated notable efficacy in adults with moderate to severe PN. A reduction of 4 points or more on the Worst Itch Numeric Rating Scale (WI-NRS) was achieved by 60.0% (45/75) of patients treated with dupilumab at week 24 compared with 18.4% (14/76) receiving placebo in the PRIME trial. In PRIME2, the same outcome was achieved by 37.2% (29/78) of patients receiving dupilumab at week 12 compared with 22.0% (18/82) of patients receiving placebo.⁵ Dupilumab also led to a greater proportion of patients achieving a substantial reduction in nodule count (≤5 nodules) and improved quality of life compared with placebo.^5,6 The safety profile of dupilumab for treatment of PN was favorable and consistent with prior experience in atopic dermatitis; conjunctivitis was the most common adverse event.^5,6

Nemolizumab

Nemolizumab, an IL-31 receptor A antagonist, is the most recent agent approved by the FDA for PN in 2024.⁷ In the OLYMPIA 1 and OLYMPIA 2 phase 3 trials,⁸ nemolizumab produced a clinically meaningful reduction in itch (defined as a ≥4-point improvement in the Peak Pruritus Numerical Rating Scale score) in 56.3% (103/183) of patients at week 16 compared with 20.9% (19/91) receiving placebo. Additionally, 37.7% (69/183) of patients receiving nemolizumab achieved clear or almost clear skin (Investigator’s Global Assessment score of 0 or 1 with a ≥2-point reduction) vs 11.0% with placebo (both P<.001). Benefits were observed as early as week 4, including rapid improvements in itch, sleep disturbance, and nodule count.⁸ Nemolizumab also improved quality of life and reduced symptoms of anxiety and depression. The safety profile was favorable, with headache and atopic dermatitis the most common adverse events; serious adverse events were infrequent and similar between groups.⁸

Abrocitinib

Abrocitinib, an oral selective Janus kinase 1 inhibitor, is an investigational therapy for PN and currently has not been approved by the FDA for this indication. In a phase 2 open-label trial, abrocitinib 200 mg daily for 12 weeks led to a 78.3% reduction in weekly Peak Pruritus Numerical Rating Scale scores in PN, with 80.0% (8/10) of patients achieving a clinically meaningful improvement of 4 points or higher. Nodule counts and quality of life also improved, with an onset of itch relief as early as week 2. The safety profile was favorable, with acneform eruptions the most common adverse event and no serious adverse events reported⁹; however, these results are based on small, nonrandomized studies and require confirmation in larger randomized controlled trials before abrocitinib can be considered a standard therapy for PN.

Cryosim-1

Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing ion channel found in unmyelinated sensory neurons within the dorsal root and trigeminal ­ganglia.¹⁰ It is activated by cool temperatures (15-28 °C) and compounds such as menthol, leading to calcium influx and a cooling sensation. In a randomized, double-blind, vehicle-controlled trial, researchers investigated the efficacy of cryosim-1 (a synthetic TRPM8 agonist) in treating PN.¹⁰ Thirty patients were enrolled, with 18 (60.0%) receiving cryosim-1 and 12 (40.0%) receiving placebo over 8 weeks. By week 8, cryosim-1 significantly reduced itch severity (mean numerical rating scale score postapplication, 2.8 vs 4.3; P=.031) and improved sleep disturbances (2.2 vs 4.2; P=.031) compared to placebo. Patients reported higher satisfaction with itch relief, and no adverse effects were observed. The study concluded that cryosim-1 is a safe, effective topical therapy for PN, likely working by interrupting the itch-scratch cycle and potentially modulating inflammatory pathways involved in chronic itch.¹⁰

Nalbuphine

Nalbuphine is a κ opioid receptor agonist and μ opioid receptor antagonist that has been investigated for the treatment of PN.¹¹ In a phase 2 randomized controlled trial, oral nalbuphine extended release (NAL-ER) 162 mg twice daily provided measurable antipruritic efficacy, with 44.4% (8/18) of patients achieving at least a 30% reduction in 7-day WI-NRS at week 10 compared with 36.4% (8/22) in the placebo group. Among those who completed the study, 66.7% (8/12) of patients receiving NAL-ER 162 mg achieved significant itch reduction vs 40% (8/20) receiving placebo (P=.03). At least a 50% reduction in WI-NRS was achieved by 33.3% (6/18) of patients receiving NAL-ER 162 mg twice daily. Extended open-label treatment was associated with further improvements in itch and lesion activity. Adverse events were mostly mild to moderate (eg, nausea, dizziness, headache, and fatigue) and occurred during dose titration. Physiologic opioid withdrawal symptoms were limited and resolved within a few days of discontinuing the medication.¹¹

Final Thoughts

In conclusion, PN remains one of the most challenging chronic dermatologic conditions to manage and is driven by a complex interplay of neuroimmune mechanisms and resistance to many conventional therapies. The approval of dupilumab and nemolizumab has marked a pivotal shift in the therapeutic landscape, offering hope to patients who previously had limited options^5,8; however, the burden of PN remains substantial, and many patients continue to experience relentless itch, poor sleep, and reduced quality of life.¹ Emerging therapies such as TRPM8 agonists, Janus kinase inhibitors, and opioid modulators represent promising additions to the treatment options, targeting novel pathways beyond traditional immunosuppression.^9-11

Prurigo nodularis (PN) is a chronic, severely pruritic neuroimmunologic skin disorder characterized by multiple firm hyperkeratotic nodules and intense pruritus, often leading to considerable impairment in quality of life and increased rates of depression and anxiety.¹ It is considered difficult to treat due to its complex pathogenesis, the severity and chronicity of pruritus, and the limited efficacy of conventional therapies.^2,3 The disease is driven by a self-perpetuating itch-scratch cycle, underpinned by dysregulation of both immune and neural pathways including type 2 (interleukin [IL] 4, IL-13, IL-31), Th17, and Th22 cytokines as well as neuropeptides and altered cutaneous nerve architecture.^1,3 This results in persistent severe pruritus and nodular lesions that are highly refractory to standard treatments.¹ Conventional therapies (eg, locally acting agents, phototherapy, and systemic immunomodulators and neuromodulators) have varied efficacy and notable adverse effect profiles.³ While the approval of targeted biologics has transformed the therapeutic landscape, several other treatment options also are being explored in clinical trials. Herein, we review all recently approved therapies as well as emerging treatments currently under investigation.

Dupilumab

Dupilumab, the first therapy for PN approved by the US Food and Drug Administration (FDA) in 2022—is a monoclonal antibody that inhibits signaling of IL-4 and IL-13, key drivers of type 2 inflammation implicated in PN pathogenesis.^4,5 In 2 pivotal phase 3 randomized controlled trials (LIBERTY-PN PRIME and PRIME2),⁵ dupilumab demonstrated notable efficacy in adults with moderate to severe PN. A reduction of 4 points or more on the Worst Itch Numeric Rating Scale (WI-NRS) was achieved by 60.0% (45/75) of patients treated with dupilumab at week 24 compared with 18.4% (14/76) receiving placebo in the PRIME trial. In PRIME2, the same outcome was achieved by 37.2% (29/78) of patients receiving dupilumab at week 12 compared with 22.0% (18/82) of patients receiving placebo.⁵ Dupilumab also led to a greater proportion of patients achieving a substantial reduction in nodule count (≤5 nodules) and improved quality of life compared with placebo.^5,6 The safety profile of dupilumab for treatment of PN was favorable and consistent with prior experience in atopic dermatitis; conjunctivitis was the most common adverse event.^5,6

Nemolizumab

Nemolizumab, an IL-31 receptor A antagonist, is the most recent agent approved by the FDA for PN in 2024.⁷ In the OLYMPIA 1 and OLYMPIA 2 phase 3 trials,⁸ nemolizumab produced a clinically meaningful reduction in itch (defined as a ≥4-point improvement in the Peak Pruritus Numerical Rating Scale score) in 56.3% (103/183) of patients at week 16 compared with 20.9% (19/91) receiving placebo. Additionally, 37.7% (69/183) of patients receiving nemolizumab achieved clear or almost clear skin (Investigator’s Global Assessment score of 0 or 1 with a ≥2-point reduction) vs 11.0% with placebo (both P<.001). Benefits were observed as early as week 4, including rapid improvements in itch, sleep disturbance, and nodule count.⁸ Nemolizumab also improved quality of life and reduced symptoms of anxiety and depression. The safety profile was favorable, with headache and atopic dermatitis the most common adverse events; serious adverse events were infrequent and similar between groups.⁸

Abrocitinib

Abrocitinib, an oral selective Janus kinase 1 inhibitor, is an investigational therapy for PN and currently has not been approved by the FDA for this indication. In a phase 2 open-label trial, abrocitinib 200 mg daily for 12 weeks led to a 78.3% reduction in weekly Peak Pruritus Numerical Rating Scale scores in PN, with 80.0% (8/10) of patients achieving a clinically meaningful improvement of 4 points or higher. Nodule counts and quality of life also improved, with an onset of itch relief as early as week 2. The safety profile was favorable, with acneform eruptions the most common adverse event and no serious adverse events reported⁹; however, these results are based on small, nonrandomized studies and require confirmation in larger randomized controlled trials before abrocitinib can be considered a standard therapy for PN.

Cryosim-1

Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing ion channel found in unmyelinated sensory neurons within the dorsal root and trigeminal ­ganglia.¹⁰ It is activated by cool temperatures (15-28 °C) and compounds such as menthol, leading to calcium influx and a cooling sensation. In a randomized, double-blind, vehicle-controlled trial, researchers investigated the efficacy of cryosim-1 (a synthetic TRPM8 agonist) in treating PN.¹⁰ Thirty patients were enrolled, with 18 (60.0%) receiving cryosim-1 and 12 (40.0%) receiving placebo over 8 weeks. By week 8, cryosim-1 significantly reduced itch severity (mean numerical rating scale score postapplication, 2.8 vs 4.3; P=.031) and improved sleep disturbances (2.2 vs 4.2; P=.031) compared to placebo. Patients reported higher satisfaction with itch relief, and no adverse effects were observed. The study concluded that cryosim-1 is a safe, effective topical therapy for PN, likely working by interrupting the itch-scratch cycle and potentially modulating inflammatory pathways involved in chronic itch.¹⁰

Nalbuphine

Nalbuphine is a κ opioid receptor agonist and μ opioid receptor antagonist that has been investigated for the treatment of PN.¹¹ In a phase 2 randomized controlled trial, oral nalbuphine extended release (NAL-ER) 162 mg twice daily provided measurable antipruritic efficacy, with 44.4% (8/18) of patients achieving at least a 30% reduction in 7-day WI-NRS at week 10 compared with 36.4% (8/22) in the placebo group. Among those who completed the study, 66.7% (8/12) of patients receiving NAL-ER 162 mg achieved significant itch reduction vs 40% (8/20) receiving placebo (P=.03). At least a 50% reduction in WI-NRS was achieved by 33.3% (6/18) of patients receiving NAL-ER 162 mg twice daily. Extended open-label treatment was associated with further improvements in itch and lesion activity. Adverse events were mostly mild to moderate (eg, nausea, dizziness, headache, and fatigue) and occurred during dose titration. Physiologic opioid withdrawal symptoms were limited and resolved within a few days of discontinuing the medication.¹¹

Final Thoughts

In conclusion, PN remains one of the most challenging chronic dermatologic conditions to manage and is driven by a complex interplay of neuroimmune mechanisms and resistance to many conventional therapies. The approval of dupilumab and nemolizumab has marked a pivotal shift in the therapeutic landscape, offering hope to patients who previously had limited options^5,8; however, the burden of PN remains substantial, and many patients continue to experience relentless itch, poor sleep, and reduced quality of life.¹ Emerging therapies such as TRPM8 agonists, Janus kinase inhibitors, and opioid modulators represent promising additions to the treatment options, targeting novel pathways beyond traditional immunosuppression.^9-11

There are 3 uncommon types of mechanobullous skin diseases caused by relative reduction or complete loss of functional type VII collagen, which is the main component of anchoring fibrils in the lamina densa of the basement membrane zone (BMZ) of the skin and mucous membrane epithelium.¹ The function of the anchoring fibrils is to maintain adherence of the basement membrane of the epithelium to the connective tissue of the papillary dermis and submucosa.¹ The mechanism of action of the loss of type VII collagen function is via autoimmunity in epidermolysis bullosa acquisita (EBA)² and bullous systemic lupus erythematosus (BSLE).³ In the heritable family of 4 epidermolysis bullosa (EB) variants, only one of the subtypes—dystrophic EB (DEB)—is caused by various recessive and dominant mutations of the type VII collagen gene (COL7A1).⁴ The other 3 diseases in the family—EB simplex, junctional EB, and Kindler syndrome—are caused by diverse mutations that corrupt the integrity of keratinocytes and the BMZ.^5,6 This article provides an overview of these 3 subtypes to help differentiate them from DEB.

Epidermolysis Bullosa

Epidermolysis bullosa consists of a heterogeneous family of 4 major genetic mechanobullous diseases that affect the skin and mucous membranes with more than 30 subtypes.¹ Dystrophic EB is caused by mutations in the COL7A1 gene, which encodes for the α-1 chain of collagen type VII. Classically, EB is divided into 4 main variants based on the location of the cleavage plane or split occurring in the epithelium, which in turn helps to predict the severity of the illness.

Epidermolysis bullosa may be inherited in an ­autosomal-dominant or autosomal-recessive fashion, or it may occur as a spontaneous mutation. All sexes and races are affected equally. Patients present at birth or in early childhood with fragile skin and mucous membranes that may develop blisters, erosions, and ulcerations after minor trauma.⁷ These lesions are marked by slow healing and scar formation and often are associated with itching and pain.

Dystrophic Epidermolysis Bullosa

Dystrophic EB accounts for approximately 25%⁶ of all EB cases in the United States and may be inherited as either a dominant or recessive trait. Hundreds of different pathogenic mutations have been discovered in the COL7A1 gene in the subtypes of DEB.^4,8 Dominant DEB tends to cause milder disease because the patients retain one normal COL7A1 allele and produce some type VII collagen (Figure 1), whereas patients with recessive DEB lack type VII collagen completely.⁹ The cleavage plane is between the lamina densa and the superficial dermis or submucosa. Severity is variable and ranges from ­localization to the hands and feet to severe generalized blistering and painful ulcerations depending on which of the many possible gene mutations have been inherited. Sequelae include mitten deformities, malalignment and tooth decay, and the development of early aggressive squamous cell carcinomas, which may be fatal. The most severe cases of recessive DEB also may have internal organ involvement.

Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex is the most common variant, comprising approximately 70%of EB cases in the United States.⁶ Epidermolysis bullosa simplex usually is inherited as autosomal-dominant mutations in the keratin 5 or keratin 14 genes,¹⁰ not COL7A1. Skin blistering results from cleavage within the basal cell layer where the keratin genes are primarily expressed. Blisters tend to occur in acral areas such as hands and feet and may heal without scarring in the localized form of epidermolysis bullosa simplex (Figure 2).

Junctional Epidermolysis Bullosa and Kindler Syndrome

Junctional epidermolysis bullosa (JEB) and Kindler syndrome¹¹ are the rarest of the autosomal-recessive EB ­variants.⁶ The plane of cleavage in JEB is through the lamina lucida of the BMZ. Junctional epidermolysis bullosa is caused by mutations of the genes that encode for the 3 chains of laminin 332 protein and type XVII collagen,^5,12 not to be confused with type VII collagen. As with DEB, there is a wide range of severity in JEB, from localized effects on the eyes, oral cavity, and tooth enamel to widespread blistering and skin cancers. In JEB cases involving newborns, nonhealing wounds on the face, buttocks, fingers, and toes may be seen, with devastating complications in the oral cavity, esophagus, and larynx. Life expectancy is limited to 2 years or less.⁶ There have only been approximately 40,013 cases of Kindler syndrome reported worldwide⁶ and there is clinical overlap with DEB. Patients also may demonstrate poikiloderma and photosensitivity. Kindler syndrome is caused by mutations in the FERMT1 gene which encodes for kindlin-1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix.^5,11 Loss of function produces variable cleavage planes around the dermoepidermal junction.

Clinical management of all EB variants, especially the severe recessive types, traditionally has been limited to the prevention of trauma to the skin and mucous membranes and supportive care, including dressing changes to erosions and ulcerations, antibiotic ointments as needed, and amelioration of pain and pruritus. Bone marrow and pluripotential stem cell transplants have been attempted.¹² Complications of EB, such as deformities of the hands and feet caused by excessive scarring, esophageal strictures, poor dentition, and squamous cell carcinomas, must be addressed by a multidisciplinary team of specialists, including plastic surgery, gastroenterology, dentistry/oral surgery, ophthalmology, and dermatology/Mohs surgery. 

Until recently, there were no medications approved by the US Food and Drug Administration (FDA) specifically indicated for EB. In 2023, topical gene therapy was approved by the FDA for both recessive and dominant forms of DEB. Normal COL7A1 sequences are delivered by an attenuated herpes simplex virus 1 vector (beremagene geperpavec) in a gel applied directly to the wounds of patients with DEB. In a clinical trial, matching wounds on 31 patients (62 wounds total) were treated with the active agent or placebo gel. After 6 months, complete wound closure was observed in 67% (21/31) of those treated with the active agent and 22% (7/31) of those treated with placebo (P=.002).¹⁴ In a single case report, a patient with recessive DEB and cicatrizing conjunctivitis (Figure 3) was given ophthalmic beremagene geperpavec after surgery and had improved visual acuity.¹⁵ A topical gel consisting of birch triterpenes to promote healing of partial-thickness wounds also was approved for patients with DEB and JEB by the FDA and the European Commission. In a study of 223 patients, 41% of those using active gel and 29% of those using placebo gel achieved the primary end point of percentage of target wounds that had first complete closure at 45 days.¹⁶ 

The most recent FDA approval for DEB involves transferring the functional COL7A1 gene to the patient’s skin cells, then expanding the gene-corrected cells into sheets of keratinocytes that can be surgically applied to the chronic wound sites. In a phase 3 trial of prademagene zamikeracel (pz-cel), 11 patients with 86 matched wounds were randomized to receive pz-cel (50%) or standard wound care (50%). After 24 weeks, 35 wounds treated with pz-cel were at least 50% healed compared to 7 control wounds.¹⁷ The results for healing and reduction of pain were statistically significant (P<.0001 and P<.0002, respectively).¹⁷ Recombinant collagen VII as replacement therapy also is under study to be given by intravenous infusion to increase tissue collagen VII where it is lacking. This treatment has shown early biologic and therapeutic effects.^9,18 Larger long-term follow-up studies are necessary to confirm persistence of the gene-corrected skin cells, the functionality of the replacement collagen VII, and the potential risk for the development of autoantibodies to type VII collagen.

Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita is a rare autoimmune subepithelial bullous disease that primarily affects middle-aged adults but also has been reported in children.¹⁹ Epidermolysis bullosa acquisita is caused by circulating pathogenic IgG autoantibodies that target and bind to type VII collagen in the anchoring fibrils,^20-22 thereby disrupting the attachment of the epithelium to its underlying connective tissue.

The 2 major clinical manifestations of EBA include a mechanobullous disease resembling inherited forms of DEB (Figure 4) and an inflammatory bullous pemphigoid (BP)–like disease,²³ as well as a combination of both types of skin lesions (Figure 5). The skin and mucous membranes of the oral cavity, esophagus, eyes, and urogenital areas are affected in both types; scarring may cause functional disabilities. In the mechanobullous type of EBA, it is common for blisters and erosions to develop in trauma-prone areas such as the hands, feet, elbows, and knees. The blisters tend to heal with scarring and milia formation as might be seen in porphyria cutanea tarda or cicatricial pemphigoid, which are in the differential diagnosis. Dystrophy of the fingernails or complete nail loss may be observed, resembling DEB. In the BP-like presentation, tense blisters arise upon inflamed or urticarial skin and mucous membranes, which may then become generalized. 

Histopathology in both forms of EBA demonstrates subepithelial separation as clefts or blisters. The mechanobullous type shows a sparse inflammatory infiltrate compared to large collections of neutrophils and eosinophils in the blister cavity and in the superficial dermis in the BP-like cases. The final diagnosis rests on the results of immunopathology testing.²⁴ Direct immunofluorescence of perilesional skin and mucosa shows a linear-granular band of IgG and C3 and other conjugates along the BMZ. Deposits of IgA alone in EBA occur in only about 2.4% of cases and are observed more often when there is mucous membrane involvement.² Indirect immunofluorescence of sera against salt-split skin substrates detects immunoreactants in the floor of the blister rather than in the roof, as would be seen in BP. Highly specific and sensitive enzyme-linked immunosorbent assay (ELISA) kits now are commercially available and can detect autoantibodies against the N-terminal domain of type VII collagen in more than 90% of cases of EBA.²⁵ 

Inflammatory bowel disease (IBD), particularly Crohn disease (CD), precedes the onset of EBA in approximately 25% of cases.^26,27 Ulcerative colitis is much less common. Type VII collagen is normally present in the basement membrane of intestinal epithelium. In a survey of patients with IBD, 68% of those with CD and 13% of those with ulcerative colitis had circulating anti–type VII collagen antibodies detected by ELISA without having symptoms of EBA.²⁸ A case report of a patient with both well-proven EBA and CD highlighted the clinical difficulty of controlling EBA: treatment with prednisolone and sulfasalazine improved the CD but had little effect on the skin blisters.²⁹ A variety of malignancies have been reported in association with EBA, including cancers of the uterine cervix,³⁰ thyroid, and pancreas,³¹ lymphoma, and chronic lymphatic leukemia. Some of these cases have met the criteria for classification as paraneoplastic, whereas others may have been coincidental. 

Treatment for chronic EBA generally has been limited.^2,24 Putative antineutrophil drugs such as dapsone and colchicine combined with systemic corticosteroids may be useful in milder or juvenile cases, which tend to have a better prognosis than adult cases.¹⁹ In more severe EBA, systemic corticosteroids and/or immunosuppressive drugs such as azathioprine,²³ cyclophosphamide,²³ mycophenolate mofetil,³¹ methotrexate,²³ cyclosporine,³³ and infliximab²³ have been used. More recently, rituximab infusion monotherapy³³ and rituximab combined with intravenous immunoglobulin or adjuvant immunoadsorption of the pathogenic autoantibodies have induced remission of refractory EBA.³² Adjuvant immunoadsorption therapy is not widely available. Multispecialty care often is required, especially ophthalmology for conjunctival involvement and gastroenterology for potential esophageal stenosis and the early detection and treatment of IBD.

Bullous Systemic Lupus Erythematosus

Bullous systemic lupus erythematosus is a rare and specific autoimmune skin complication that mostly is seen in patients with an established diagnosis of systemic lupus erythematosus (SLE) who are experiencing a disease flare. Although more common in women, it has been reported in all sexes and races as well as in children. Vesicles and bullae may arise on sun-exposed (Figure 6) and sun-protected areas of skin.

Histopathology shows subepidermal separation with collections of neutrophils and nuclear fragments in the blister cavity. The differential diagnosis of BSLE includes EBA, BP, dermatitis herpetiformis, and linear IgA bullous dermatosis. Direct immunofluorescence testing shows linear-granular deposits of IgG and/or IgM and IgA along the BMZ.³⁴ When utilizing the indirect immunofluorescence split-skin assay, the autoantibody to type VII collagen would be detected in the floor of the blister if the serum titer was sufficiently high.³ Proposed criteria for the diagnosis of BSLE have been published: 1) diagnosis of SLE now based on the 2019 European League Against Rheumatism/American College of Rheumatology classification³⁵; 2) vesicles and bullae arising upon but not limited to sun-exposed skin; 3) histopathology featuring neutrophil-rich subepithelial bullae; 4) positive indirect immunofluorescence for circulating BMZ antibodies using separated human skin as substrate; 5) and direct immunofluorescence showing IgG and/or IgM and often IgA at the BMZ.³⁶ Using ELISA to detect circulating antibodies against type VII collagen²⁴ should now be added to the criteria. The new criteria for SLE³⁴ do not include BSLE, perhaps because it occurs in less than 1% of patients with SLE.³⁷ 

Further investigation by Gammon et al³ confirmed that the autoantibodies in BSLE are identical to those found in EBA (ie, directed against type VII collagen in the lamina densa). Bullous systemic lupus erythematosus is not considered to be the coexistence of EBA with SLE but rather a specific entity wherein type VII collagen autoantibodies are expressed in the autoimmune spectrum of SLE. It is especially important to make the diagnosis of BSLE because it is predictive of more serious systemic complications of SLE (eg, hematologic and renal disease is found in up to 90% of cases).³⁸ 

The natural course of BSLE is variable. Treatments include systemic corticosteroids, dapsone, and immunosuppressive drugs such as azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide, especially in cases with nephritis.³⁷ There may be spontaneous resolution of the rash as the inflammatory activity of SLE subsides. Rituximab has been used effectively in several refractory cases of BSLE that failed to respond to all other conventional treatments.³⁹

Conclusion

Anchoring fibrils are composed primarily of type VII collagen. Their role is to maintain the attachment of epithelium to the upper dermis and submucosa. The reduction or complete loss of type VII collagen caused by mutations of the COL7A1 gene results in dominant DEB or recessive DEB, respectively. Two distinct non-heritable immunobullous diseases, EBA and BSLE, are caused by autoantibodies that target type VII collagen. A comparison of the 4 type VII collagen disorders can be found in the Table.

There are 3 uncommon types of mechanobullous skin diseases caused by relative reduction or complete loss of functional type VII collagen, which is the main component of anchoring fibrils in the lamina densa of the basement membrane zone (BMZ) of the skin and mucous membrane epithelium.¹ The function of the anchoring fibrils is to maintain adherence of the basement membrane of the epithelium to the connective tissue of the papillary dermis and submucosa.¹ The mechanism of action of the loss of type VII collagen function is via autoimmunity in epidermolysis bullosa acquisita (EBA)² and bullous systemic lupus erythematosus (BSLE).³ In the heritable family of 4 epidermolysis bullosa (EB) variants, only one of the subtypes—dystrophic EB (DEB)—is caused by various recessive and dominant mutations of the type VII collagen gene (COL7A1).⁴ The other 3 diseases in the family—EB simplex, junctional EB, and Kindler syndrome—are caused by diverse mutations that corrupt the integrity of keratinocytes and the BMZ.^5,6 This article provides an overview of these 3 subtypes to help differentiate them from DEB.

Epidermolysis Bullosa

Epidermolysis bullosa consists of a heterogeneous family of 4 major genetic mechanobullous diseases that affect the skin and mucous membranes with more than 30 subtypes.¹ Dystrophic EB is caused by mutations in the COL7A1 gene, which encodes for the α-1 chain of collagen type VII. Classically, EB is divided into 4 main variants based on the location of the cleavage plane or split occurring in the epithelium, which in turn helps to predict the severity of the illness.

Epidermolysis bullosa may be inherited in an ­autosomal-dominant or autosomal-recessive fashion, or it may occur as a spontaneous mutation. All sexes and races are affected equally. Patients present at birth or in early childhood with fragile skin and mucous membranes that may develop blisters, erosions, and ulcerations after minor trauma.⁷ These lesions are marked by slow healing and scar formation and often are associated with itching and pain.

Dystrophic Epidermolysis Bullosa

Dystrophic EB accounts for approximately 25%⁶ of all EB cases in the United States and may be inherited as either a dominant or recessive trait. Hundreds of different pathogenic mutations have been discovered in the COL7A1 gene in the subtypes of DEB.^4,8 Dominant DEB tends to cause milder disease because the patients retain one normal COL7A1 allele and produce some type VII collagen (Figure 1), whereas patients with recessive DEB lack type VII collagen completely.⁹ The cleavage plane is between the lamina densa and the superficial dermis or submucosa. Severity is variable and ranges from ­localization to the hands and feet to severe generalized blistering and painful ulcerations depending on which of the many possible gene mutations have been inherited. Sequelae include mitten deformities, malalignment and tooth decay, and the development of early aggressive squamous cell carcinomas, which may be fatal. The most severe cases of recessive DEB also may have internal organ involvement.

Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex is the most common variant, comprising approximately 70%of EB cases in the United States.⁶ Epidermolysis bullosa simplex usually is inherited as autosomal-dominant mutations in the keratin 5 or keratin 14 genes,¹⁰ not COL7A1. Skin blistering results from cleavage within the basal cell layer where the keratin genes are primarily expressed. Blisters tend to occur in acral areas such as hands and feet and may heal without scarring in the localized form of epidermolysis bullosa simplex (Figure 2).

Junctional Epidermolysis Bullosa and Kindler Syndrome

Junctional epidermolysis bullosa (JEB) and Kindler syndrome¹¹ are the rarest of the autosomal-recessive EB ­variants.⁶ The plane of cleavage in JEB is through the lamina lucida of the BMZ. Junctional epidermolysis bullosa is caused by mutations of the genes that encode for the 3 chains of laminin 332 protein and type XVII collagen,^5,12 not to be confused with type VII collagen. As with DEB, there is a wide range of severity in JEB, from localized effects on the eyes, oral cavity, and tooth enamel to widespread blistering and skin cancers. In JEB cases involving newborns, nonhealing wounds on the face, buttocks, fingers, and toes may be seen, with devastating complications in the oral cavity, esophagus, and larynx. Life expectancy is limited to 2 years or less.⁶ There have only been approximately 40,013 cases of Kindler syndrome reported worldwide⁶ and there is clinical overlap with DEB. Patients also may demonstrate poikiloderma and photosensitivity. Kindler syndrome is caused by mutations in the FERMT1 gene which encodes for kindlin-1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix.^5,11 Loss of function produces variable cleavage planes around the dermoepidermal junction.

Clinical management of all EB variants, especially the severe recessive types, traditionally has been limited to the prevention of trauma to the skin and mucous membranes and supportive care, including dressing changes to erosions and ulcerations, antibiotic ointments as needed, and amelioration of pain and pruritus. Bone marrow and pluripotential stem cell transplants have been attempted.¹² Complications of EB, such as deformities of the hands and feet caused by excessive scarring, esophageal strictures, poor dentition, and squamous cell carcinomas, must be addressed by a multidisciplinary team of specialists, including plastic surgery, gastroenterology, dentistry/oral surgery, ophthalmology, and dermatology/Mohs surgery. 

Until recently, there were no medications approved by the US Food and Drug Administration (FDA) specifically indicated for EB. In 2023, topical gene therapy was approved by the FDA for both recessive and dominant forms of DEB. Normal COL7A1 sequences are delivered by an attenuated herpes simplex virus 1 vector (beremagene geperpavec) in a gel applied directly to the wounds of patients with DEB. In a clinical trial, matching wounds on 31 patients (62 wounds total) were treated with the active agent or placebo gel. After 6 months, complete wound closure was observed in 67% (21/31) of those treated with the active agent and 22% (7/31) of those treated with placebo (P=.002).¹⁴ In a single case report, a patient with recessive DEB and cicatrizing conjunctivitis (Figure 3) was given ophthalmic beremagene geperpavec after surgery and had improved visual acuity.¹⁵ A topical gel consisting of birch triterpenes to promote healing of partial-thickness wounds also was approved for patients with DEB and JEB by the FDA and the European Commission. In a study of 223 patients, 41% of those using active gel and 29% of those using placebo gel achieved the primary end point of percentage of target wounds that had first complete closure at 45 days.¹⁶ 

The most recent FDA approval for DEB involves transferring the functional COL7A1 gene to the patient’s skin cells, then expanding the gene-corrected cells into sheets of keratinocytes that can be surgically applied to the chronic wound sites. In a phase 3 trial of prademagene zamikeracel (pz-cel), 11 patients with 86 matched wounds were randomized to receive pz-cel (50%) or standard wound care (50%). After 24 weeks, 35 wounds treated with pz-cel were at least 50% healed compared to 7 control wounds.¹⁷ The results for healing and reduction of pain were statistically significant (P<.0001 and P<.0002, respectively).¹⁷ Recombinant collagen VII as replacement therapy also is under study to be given by intravenous infusion to increase tissue collagen VII where it is lacking. This treatment has shown early biologic and therapeutic effects.^9,18 Larger long-term follow-up studies are necessary to confirm persistence of the gene-corrected skin cells, the functionality of the replacement collagen VII, and the potential risk for the development of autoantibodies to type VII collagen.

Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita is a rare autoimmune subepithelial bullous disease that primarily affects middle-aged adults but also has been reported in children.¹⁹ Epidermolysis bullosa acquisita is caused by circulating pathogenic IgG autoantibodies that target and bind to type VII collagen in the anchoring fibrils,^20-22 thereby disrupting the attachment of the epithelium to its underlying connective tissue.

The 2 major clinical manifestations of EBA include a mechanobullous disease resembling inherited forms of DEB (Figure 4) and an inflammatory bullous pemphigoid (BP)–like disease,²³ as well as a combination of both types of skin lesions (Figure 5). The skin and mucous membranes of the oral cavity, esophagus, eyes, and urogenital areas are affected in both types; scarring may cause functional disabilities. In the mechanobullous type of EBA, it is common for blisters and erosions to develop in trauma-prone areas such as the hands, feet, elbows, and knees. The blisters tend to heal with scarring and milia formation as might be seen in porphyria cutanea tarda or cicatricial pemphigoid, which are in the differential diagnosis. Dystrophy of the fingernails or complete nail loss may be observed, resembling DEB. In the BP-like presentation, tense blisters arise upon inflamed or urticarial skin and mucous membranes, which may then become generalized. 

Histopathology in both forms of EBA demonstrates subepithelial separation as clefts or blisters. The mechanobullous type shows a sparse inflammatory infiltrate compared to large collections of neutrophils and eosinophils in the blister cavity and in the superficial dermis in the BP-like cases. The final diagnosis rests on the results of immunopathology testing.²⁴ Direct immunofluorescence of perilesional skin and mucosa shows a linear-granular band of IgG and C3 and other conjugates along the BMZ. Deposits of IgA alone in EBA occur in only about 2.4% of cases and are observed more often when there is mucous membrane involvement.² Indirect immunofluorescence of sera against salt-split skin substrates detects immunoreactants in the floor of the blister rather than in the roof, as would be seen in BP. Highly specific and sensitive enzyme-linked immunosorbent assay (ELISA) kits now are commercially available and can detect autoantibodies against the N-terminal domain of type VII collagen in more than 90% of cases of EBA.²⁵ 

Inflammatory bowel disease (IBD), particularly Crohn disease (CD), precedes the onset of EBA in approximately 25% of cases.^26,27 Ulcerative colitis is much less common. Type VII collagen is normally present in the basement membrane of intestinal epithelium. In a survey of patients with IBD, 68% of those with CD and 13% of those with ulcerative colitis had circulating anti–type VII collagen antibodies detected by ELISA without having symptoms of EBA.²⁸ A case report of a patient with both well-proven EBA and CD highlighted the clinical difficulty of controlling EBA: treatment with prednisolone and sulfasalazine improved the CD but had little effect on the skin blisters.²⁹ A variety of malignancies have been reported in association with EBA, including cancers of the uterine cervix,³⁰ thyroid, and pancreas,³¹ lymphoma, and chronic lymphatic leukemia. Some of these cases have met the criteria for classification as paraneoplastic, whereas others may have been coincidental. 

Treatment for chronic EBA generally has been limited.^2,24 Putative antineutrophil drugs such as dapsone and colchicine combined with systemic corticosteroids may be useful in milder or juvenile cases, which tend to have a better prognosis than adult cases.¹⁹ In more severe EBA, systemic corticosteroids and/or immunosuppressive drugs such as azathioprine,²³ cyclophosphamide,²³ mycophenolate mofetil,³¹ methotrexate,²³ cyclosporine,³³ and infliximab²³ have been used. More recently, rituximab infusion monotherapy³³ and rituximab combined with intravenous immunoglobulin or adjuvant immunoadsorption of the pathogenic autoantibodies have induced remission of refractory EBA.³² Adjuvant immunoadsorption therapy is not widely available. Multispecialty care often is required, especially ophthalmology for conjunctival involvement and gastroenterology for potential esophageal stenosis and the early detection and treatment of IBD.

Bullous Systemic Lupus Erythematosus

Bullous systemic lupus erythematosus is a rare and specific autoimmune skin complication that mostly is seen in patients with an established diagnosis of systemic lupus erythematosus (SLE) who are experiencing a disease flare. Although more common in women, it has been reported in all sexes and races as well as in children. Vesicles and bullae may arise on sun-exposed (Figure 6) and sun-protected areas of skin.

Histopathology shows subepidermal separation with collections of neutrophils and nuclear fragments in the blister cavity. The differential diagnosis of BSLE includes EBA, BP, dermatitis herpetiformis, and linear IgA bullous dermatosis. Direct immunofluorescence testing shows linear-granular deposits of IgG and/or IgM and IgA along the BMZ.³⁴ When utilizing the indirect immunofluorescence split-skin assay, the autoantibody to type VII collagen would be detected in the floor of the blister if the serum titer was sufficiently high.³ Proposed criteria for the diagnosis of BSLE have been published: 1) diagnosis of SLE now based on the 2019 European League Against Rheumatism/American College of Rheumatology classification³⁵; 2) vesicles and bullae arising upon but not limited to sun-exposed skin; 3) histopathology featuring neutrophil-rich subepithelial bullae; 4) positive indirect immunofluorescence for circulating BMZ antibodies using separated human skin as substrate; 5) and direct immunofluorescence showing IgG and/or IgM and often IgA at the BMZ.³⁶ Using ELISA to detect circulating antibodies against type VII collagen²⁴ should now be added to the criteria. The new criteria for SLE³⁴ do not include BSLE, perhaps because it occurs in less than 1% of patients with SLE.³⁷ 

Further investigation by Gammon et al³ confirmed that the autoantibodies in BSLE are identical to those found in EBA (ie, directed against type VII collagen in the lamina densa). Bullous systemic lupus erythematosus is not considered to be the coexistence of EBA with SLE but rather a specific entity wherein type VII collagen autoantibodies are expressed in the autoimmune spectrum of SLE. It is especially important to make the diagnosis of BSLE because it is predictive of more serious systemic complications of SLE (eg, hematologic and renal disease is found in up to 90% of cases).³⁸ 

The natural course of BSLE is variable. Treatments include systemic corticosteroids, dapsone, and immunosuppressive drugs such as azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide, especially in cases with nephritis.³⁷ There may be spontaneous resolution of the rash as the inflammatory activity of SLE subsides. Rituximab has been used effectively in several refractory cases of BSLE that failed to respond to all other conventional treatments.³⁹

Conclusion

Anchoring fibrils are composed primarily of type VII collagen. Their role is to maintain the attachment of epithelium to the upper dermis and submucosa. The reduction or complete loss of type VII collagen caused by mutations of the COL7A1 gene results in dominant DEB or recessive DEB, respectively. Two distinct non-heritable immunobullous diseases, EBA and BSLE, are caused by autoantibodies that target type VII collagen. A comparison of the 4 type VII collagen disorders can be found in the Table.

There are 3 uncommon types of mechanobullous skin diseases caused by relative reduction or complete loss of functional type VII collagen, which is the main component of anchoring fibrils in the lamina densa of the basement membrane zone (BMZ) of the skin and mucous membrane epithelium.¹ The function of the anchoring fibrils is to maintain adherence of the basement membrane of the epithelium to the connective tissue of the papillary dermis and submucosa.¹ The mechanism of action of the loss of type VII collagen function is via autoimmunity in epidermolysis bullosa acquisita (EBA)² and bullous systemic lupus erythematosus (BSLE).³ In the heritable family of 4 epidermolysis bullosa (EB) variants, only one of the subtypes—dystrophic EB (DEB)—is caused by various recessive and dominant mutations of the type VII collagen gene (COL7A1).⁴ The other 3 diseases in the family—EB simplex, junctional EB, and Kindler syndrome—are caused by diverse mutations that corrupt the integrity of keratinocytes and the BMZ.^5,6 This article provides an overview of these 3 subtypes to help differentiate them from DEB.

Epidermolysis Bullosa

Epidermolysis bullosa consists of a heterogeneous family of 4 major genetic mechanobullous diseases that affect the skin and mucous membranes with more than 30 subtypes.¹ Dystrophic EB is caused by mutations in the COL7A1 gene, which encodes for the α-1 chain of collagen type VII. Classically, EB is divided into 4 main variants based on the location of the cleavage plane or split occurring in the epithelium, which in turn helps to predict the severity of the illness.

Epidermolysis bullosa may be inherited in an ­autosomal-dominant or autosomal-recessive fashion, or it may occur as a spontaneous mutation. All sexes and races are affected equally. Patients present at birth or in early childhood with fragile skin and mucous membranes that may develop blisters, erosions, and ulcerations after minor trauma.⁷ These lesions are marked by slow healing and scar formation and often are associated with itching and pain.

Dystrophic Epidermolysis Bullosa

Dystrophic EB accounts for approximately 25%⁶ of all EB cases in the United States and may be inherited as either a dominant or recessive trait. Hundreds of different pathogenic mutations have been discovered in the COL7A1 gene in the subtypes of DEB.^4,8 Dominant DEB tends to cause milder disease because the patients retain one normal COL7A1 allele and produce some type VII collagen (Figure 1), whereas patients with recessive DEB lack type VII collagen completely.⁹ The cleavage plane is between the lamina densa and the superficial dermis or submucosa. Severity is variable and ranges from ­localization to the hands and feet to severe generalized blistering and painful ulcerations depending on which of the many possible gene mutations have been inherited. Sequelae include mitten deformities, malalignment and tooth decay, and the development of early aggressive squamous cell carcinomas, which may be fatal. The most severe cases of recessive DEB also may have internal organ involvement.

Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex is the most common variant, comprising approximately 70%of EB cases in the United States.⁶ Epidermolysis bullosa simplex usually is inherited as autosomal-dominant mutations in the keratin 5 or keratin 14 genes,¹⁰ not COL7A1. Skin blistering results from cleavage within the basal cell layer where the keratin genes are primarily expressed. Blisters tend to occur in acral areas such as hands and feet and may heal without scarring in the localized form of epidermolysis bullosa simplex (Figure 2).

Junctional Epidermolysis Bullosa and Kindler Syndrome

Junctional epidermolysis bullosa (JEB) and Kindler syndrome¹¹ are the rarest of the autosomal-recessive EB ­variants.⁶ The plane of cleavage in JEB is through the lamina lucida of the BMZ. Junctional epidermolysis bullosa is caused by mutations of the genes that encode for the 3 chains of laminin 332 protein and type XVII collagen,^5,12 not to be confused with type VII collagen. As with DEB, there is a wide range of severity in JEB, from localized effects on the eyes, oral cavity, and tooth enamel to widespread blistering and skin cancers. In JEB cases involving newborns, nonhealing wounds on the face, buttocks, fingers, and toes may be seen, with devastating complications in the oral cavity, esophagus, and larynx. Life expectancy is limited to 2 years or less.⁶ There have only been approximately 40,013 cases of Kindler syndrome reported worldwide⁶ and there is clinical overlap with DEB. Patients also may demonstrate poikiloderma and photosensitivity. Kindler syndrome is caused by mutations in the FERMT1 gene which encodes for kindlin-1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix.^5,11 Loss of function produces variable cleavage planes around the dermoepidermal junction.

Clinical management of all EB variants, especially the severe recessive types, traditionally has been limited to the prevention of trauma to the skin and mucous membranes and supportive care, including dressing changes to erosions and ulcerations, antibiotic ointments as needed, and amelioration of pain and pruritus. Bone marrow and pluripotential stem cell transplants have been attempted.¹² Complications of EB, such as deformities of the hands and feet caused by excessive scarring, esophageal strictures, poor dentition, and squamous cell carcinomas, must be addressed by a multidisciplinary team of specialists, including plastic surgery, gastroenterology, dentistry/oral surgery, ophthalmology, and dermatology/Mohs surgery. 

Until recently, there were no medications approved by the US Food and Drug Administration (FDA) specifically indicated for EB. In 2023, topical gene therapy was approved by the FDA for both recessive and dominant forms of DEB. Normal COL7A1 sequences are delivered by an attenuated herpes simplex virus 1 vector (beremagene geperpavec) in a gel applied directly to the wounds of patients with DEB. In a clinical trial, matching wounds on 31 patients (62 wounds total) were treated with the active agent or placebo gel. After 6 months, complete wound closure was observed in 67% (21/31) of those treated with the active agent and 22% (7/31) of those treated with placebo (P=.002).¹⁴ In a single case report, a patient with recessive DEB and cicatrizing conjunctivitis (Figure 3) was given ophthalmic beremagene geperpavec after surgery and had improved visual acuity.¹⁵ A topical gel consisting of birch triterpenes to promote healing of partial-thickness wounds also was approved for patients with DEB and JEB by the FDA and the European Commission. In a study of 223 patients, 41% of those using active gel and 29% of those using placebo gel achieved the primary end point of percentage of target wounds that had first complete closure at 45 days.¹⁶ 

The most recent FDA approval for DEB involves transferring the functional COL7A1 gene to the patient’s skin cells, then expanding the gene-corrected cells into sheets of keratinocytes that can be surgically applied to the chronic wound sites. In a phase 3 trial of prademagene zamikeracel (pz-cel), 11 patients with 86 matched wounds were randomized to receive pz-cel (50%) or standard wound care (50%). After 24 weeks, 35 wounds treated with pz-cel were at least 50% healed compared to 7 control wounds.¹⁷ The results for healing and reduction of pain were statistically significant (P<.0001 and P<.0002, respectively).¹⁷ Recombinant collagen VII as replacement therapy also is under study to be given by intravenous infusion to increase tissue collagen VII where it is lacking. This treatment has shown early biologic and therapeutic effects.^9,18 Larger long-term follow-up studies are necessary to confirm persistence of the gene-corrected skin cells, the functionality of the replacement collagen VII, and the potential risk for the development of autoantibodies to type VII collagen.

Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita is a rare autoimmune subepithelial bullous disease that primarily affects middle-aged adults but also has been reported in children.¹⁹ Epidermolysis bullosa acquisita is caused by circulating pathogenic IgG autoantibodies that target and bind to type VII collagen in the anchoring fibrils,^20-22 thereby disrupting the attachment of the epithelium to its underlying connective tissue.

The 2 major clinical manifestations of EBA include a mechanobullous disease resembling inherited forms of DEB (Figure 4) and an inflammatory bullous pemphigoid (BP)–like disease,²³ as well as a combination of both types of skin lesions (Figure 5). The skin and mucous membranes of the oral cavity, esophagus, eyes, and urogenital areas are affected in both types; scarring may cause functional disabilities. In the mechanobullous type of EBA, it is common for blisters and erosions to develop in trauma-prone areas such as the hands, feet, elbows, and knees. The blisters tend to heal with scarring and milia formation as might be seen in porphyria cutanea tarda or cicatricial pemphigoid, which are in the differential diagnosis. Dystrophy of the fingernails or complete nail loss may be observed, resembling DEB. In the BP-like presentation, tense blisters arise upon inflamed or urticarial skin and mucous membranes, which may then become generalized. 

Histopathology in both forms of EBA demonstrates subepithelial separation as clefts or blisters. The mechanobullous type shows a sparse inflammatory infiltrate compared to large collections of neutrophils and eosinophils in the blister cavity and in the superficial dermis in the BP-like cases. The final diagnosis rests on the results of immunopathology testing.²⁴ Direct immunofluorescence of perilesional skin and mucosa shows a linear-granular band of IgG and C3 and other conjugates along the BMZ. Deposits of IgA alone in EBA occur in only about 2.4% of cases and are observed more often when there is mucous membrane involvement.² Indirect immunofluorescence of sera against salt-split skin substrates detects immunoreactants in the floor of the blister rather than in the roof, as would be seen in BP. Highly specific and sensitive enzyme-linked immunosorbent assay (ELISA) kits now are commercially available and can detect autoantibodies against the N-terminal domain of type VII collagen in more than 90% of cases of EBA.²⁵ 

Inflammatory bowel disease (IBD), particularly Crohn disease (CD), precedes the onset of EBA in approximately 25% of cases.^26,27 Ulcerative colitis is much less common. Type VII collagen is normally present in the basement membrane of intestinal epithelium. In a survey of patients with IBD, 68% of those with CD and 13% of those with ulcerative colitis had circulating anti–type VII collagen antibodies detected by ELISA without having symptoms of EBA.²⁸ A case report of a patient with both well-proven EBA and CD highlighted the clinical difficulty of controlling EBA: treatment with prednisolone and sulfasalazine improved the CD but had little effect on the skin blisters.²⁹ A variety of malignancies have been reported in association with EBA, including cancers of the uterine cervix,³⁰ thyroid, and pancreas,³¹ lymphoma, and chronic lymphatic leukemia. Some of these cases have met the criteria for classification as paraneoplastic, whereas others may have been coincidental. 

Treatment for chronic EBA generally has been limited.^2,24 Putative antineutrophil drugs such as dapsone and colchicine combined with systemic corticosteroids may be useful in milder or juvenile cases, which tend to have a better prognosis than adult cases.¹⁹ In more severe EBA, systemic corticosteroids and/or immunosuppressive drugs such as azathioprine,²³ cyclophosphamide,²³ mycophenolate mofetil,³¹ methotrexate,²³ cyclosporine,³³ and infliximab²³ have been used. More recently, rituximab infusion monotherapy³³ and rituximab combined with intravenous immunoglobulin or adjuvant immunoadsorption of the pathogenic autoantibodies have induced remission of refractory EBA.³² Adjuvant immunoadsorption therapy is not widely available. Multispecialty care often is required, especially ophthalmology for conjunctival involvement and gastroenterology for potential esophageal stenosis and the early detection and treatment of IBD.

Bullous Systemic Lupus Erythematosus

Bullous systemic lupus erythematosus is a rare and specific autoimmune skin complication that mostly is seen in patients with an established diagnosis of systemic lupus erythematosus (SLE) who are experiencing a disease flare. Although more common in women, it has been reported in all sexes and races as well as in children. Vesicles and bullae may arise on sun-exposed (Figure 6) and sun-protected areas of skin.

Histopathology shows subepidermal separation with collections of neutrophils and nuclear fragments in the blister cavity. The differential diagnosis of BSLE includes EBA, BP, dermatitis herpetiformis, and linear IgA bullous dermatosis. Direct immunofluorescence testing shows linear-granular deposits of IgG and/or IgM and IgA along the BMZ.³⁴ When utilizing the indirect immunofluorescence split-skin assay, the autoantibody to type VII collagen would be detected in the floor of the blister if the serum titer was sufficiently high.³ Proposed criteria for the diagnosis of BSLE have been published: 1) diagnosis of SLE now based on the 2019 European League Against Rheumatism/American College of Rheumatology classification³⁵; 2) vesicles and bullae arising upon but not limited to sun-exposed skin; 3) histopathology featuring neutrophil-rich subepithelial bullae; 4) positive indirect immunofluorescence for circulating BMZ antibodies using separated human skin as substrate; 5) and direct immunofluorescence showing IgG and/or IgM and often IgA at the BMZ.³⁶ Using ELISA to detect circulating antibodies against type VII collagen²⁴ should now be added to the criteria. The new criteria for SLE³⁴ do not include BSLE, perhaps because it occurs in less than 1% of patients with SLE.³⁷ 

Further investigation by Gammon et al³ confirmed that the autoantibodies in BSLE are identical to those found in EBA (ie, directed against type VII collagen in the lamina densa). Bullous systemic lupus erythematosus is not considered to be the coexistence of EBA with SLE but rather a specific entity wherein type VII collagen autoantibodies are expressed in the autoimmune spectrum of SLE. It is especially important to make the diagnosis of BSLE because it is predictive of more serious systemic complications of SLE (eg, hematologic and renal disease is found in up to 90% of cases).³⁸ 

The natural course of BSLE is variable. Treatments include systemic corticosteroids, dapsone, and immunosuppressive drugs such as azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide, especially in cases with nephritis.³⁷ There may be spontaneous resolution of the rash as the inflammatory activity of SLE subsides. Rituximab has been used effectively in several refractory cases of BSLE that failed to respond to all other conventional treatments.³⁹

Conclusion

Anchoring fibrils are composed primarily of type VII collagen. Their role is to maintain the attachment of epithelium to the upper dermis and submucosa. The reduction or complete loss of type VII collagen caused by mutations of the COL7A1 gene results in dominant DEB or recessive DEB, respectively. Two distinct non-heritable immunobullous diseases, EBA and BSLE, are caused by autoantibodies that target type VII collagen. A comparison of the 4 type VII collagen disorders can be found in the Table.

Humans possess the ability to recognize and distinguish a large range of odors that can be utilized in a wide range of applications. For example, sommeliers can classify more than 88 smells specific to the roughly 800 volatile organic compounds (VOCs) in wine. Thorough physical examination is essential in dermatology, and although sight and touch play the most important diagnostic roles, the sense of smell often is overlooked. Dermatologists are rigorously trained on the many visual aspects of skin disease and have a plethora of terms to describe these features while there is minimal characterization of odors. Research on odors and the role of olfaction in dermatologic practice is limited.^1,2 We conducted a literature review of PubMed and Google Scholar for peer-reviewed articles discussing the role of odors in dermatologic diseases. Keywords included odor + dermatology, smell + dermatology, cutaneous odor, odor + diagnosis, and disease odor. Relevant studies were identified by screening their abstracts, followed by a full-text review. A total of 38 articles written in English that presented information on the odor associated with dermatologic diseases were included. Articles that were unrelated to the topic or written in a language other than English were excluded.

Common Skin Odors

The human body emits odorants—small VOCs—in various forms (skin/sweat, breath, urine, reproductive fluids). Human odor originates from the oxidation and bacterial metabolism of sweat and sebum on the skin.³ While many odors are physiologic and not cause for concern, others can signal underlying dermatologic pathologies.⁴ Odor-producing conditions can be categorized broadly into infectious diseases, disorders of keratinization and acantholysis, metabolic disorders, and organ dysfunction (Table). Infectious causes include bacterial infections and chronic wounds, which commonly emit characteristic offensive odors. For example, coryneform infections produce methanethiol, causing a cheesy odor of putrid fruit, and pseudomonal pyoderma infections emit a grape juice–like or mousy odor.

Bacterial and Fungal Infections

Bacterial and fungal infections often have distinct smells. Coryneform infections emit an odor of sweaty feet, pseudomonal infections emit a grape juice–like or mousy odor, and trichomycosis infections (caused by Corynebacterium tenuis) present with malodor.⁵ Pseudomonas can infect pyoderma gangrenosum lesions, producing a characteristic malodor.⁵ These smells can be clues for infectious etiology and guide further workup.

Pitted keratolysis, a malodorous pitted rash characterized by infection of the stratum corneum by Kytococcus sedentarius, Dermatophilus congolensis, or Corynebacterium species, is associated with a rotten smell. Its pungent odor, clinical location, and characteristic appearance often are enough to make a diagnosis. The amount of bacteria maintained in the stratum corneum is correlated with the extent of the lesion. Controlling excessive moisture in footwear, aluminum chloride, and topical microbial agents work together to eliminate the skin eruption.⁶ 

Hidradenitis suppurativa, a chronic inflammatory disease of apocrine gland–containing skin, can manifest with abscesses, draining sinuses, and nodules that produce a foul-smelling, purulent discharge. The disease can be debilitating, largely impacting patients’ quality of life, making early diagnosis and treatment critical.^7,8 Therapy is dependent on disease severity and includes topical antibiotics, systemic therapies, and biologics.⁸ 

Patients with atopic dermatitis often experience bacterial superinfection with Staphylococcus aureus. A case report described a patient who developed a fishy odor in this setting that resolved with antibiotic treatment, implicating S aureus in the etiology of the smell.⁹ 

A seminal fluid odor has been reported in cases of Pasteurella wound infection. In such cases, Pasteurella multocida subspecies septica was identified in the wounds caused by a dog scratch and a cat bite. The seminal fluid–like odor was apparent hours after the inciting incident and resolved after treatment with antibiotics.¹⁰ 

Fungal infections frequently emit musty or moldy odors. Tinea pedis (athlete’s foot) is the most prevalent cutaneous fungal infection. The presence of tinea pedis is associated with an intense foul-smelling odor, itching, fissuring, scaling, or maceration of the interdigital regions. The rash and odor resolve with use of topical antifungal agents.^11,12 Seborrheic dermatitis, a prevalent and chronic dermatosis, is characterized by yellow greasy scaling on an erythematous base. In severe cases, a greasy crust with an offensive odor can cover the entire scalp.¹³ The specific cause of this odor is unclear, but it is thought that sebum production and the immunological response to specific Malassezia yeast species may play a role.¹⁴

Genetic and Metabolic Disorders

An array of disorders of keratinization and acantholysis can manifest with distinctive smells that dermatologists frequently encounter. For example, Darier disease, characterized by keratotic papules progressing to crusted plaques, has a signature foul-smelling odor associated with cutaneous bacterial colonization.¹⁵ Similarly, Hailey-Hailey disease, an autosomal-dominant disorder with crusted erosions in skinfold areas, produces a distinct foul smell.¹⁶ Disorders such as pemphigus vulgaris and pemphigus foliaceus emit a peculiar fishy odor that can be helpful in making a diagnosis.¹⁷ Additionally, bullous ichthyosiform erythroderma, keratitis-ichthyosis-deafness syndrome, mal de Meleda, and Papillon-Lefèvre syndrome are all associated with malodor.⁵

Certain metabolic disorders can manifest and present initially with identifiable odors. Trimethylaminuria is a psychologically disabling disease known for its rotting fishy smell due to high amounts of trimethylamine appearing in affected individuals’ sweat, urine, and breath. Previously considered to be very rare, Messenger et al¹⁸ reported the disorder is likely underdiagnosed in those with idiopathic malodor production. Detection and treatment can greatly improve patient quality of life.

Phenylketonuria is an autosomal-recessive inborn error of phenylalanine metabolism that produces a musty body and urine odor as well as other neurologic and dermatologic symptoms.^19,20 Patients can present with eczematous rashes, fair skin, and blue eyes. Phenylacetic acid produces the characteristic odor in the bodily fluids, and the disease is treated with a phenylalanine-free diet.²¹ 

Maple syrup urine disease is a disorder of the oxidative decarboxylation of valine, leucine, and isoleucine (branched-chain amino acids) characterized by urine that smells sweet, resembling maple syrup, in afflicted individuals. The odor also can be present in other bodily secretions, such as sweat. Patients present early in infancy with poor feeding and vomiting as well as neurologic symptoms, eventually leading to intellectual disability. These individuals must avoid the branched-chain amino acids in their diets.²¹ 

Other metabolic storage disorders linked with specific odors are methionine adenosyltransferase deficiency (boiled cabbage), hypermethioninemia (fishy, boiled cabbage), isovaleric acidemia (sweaty feet), methionine malabsorption syndrome (pungent malodor), and dimethylglycine dehydrogenase deficiency (fishy).^5,21,22

In diabetic ketoacidosis, a life-threatening complication of diabetes, the excess of ketone bodies produced causes patients to have a distinct fruity breath and urine odor, as well as fatigue, polyuria, polydipsia, nausea, and vomiting.²² Although patients with type 1 diabetes typically comprise the cohort of patients presenting with diabetic ketoacidosis, patients with type 2 diabetes can exhibit cutaneous manifestations such as infection, xerosis, and inflammatory skin diseases.^23,24 

Organ Dysfunction

A peculiar body odor can be a sign of organ dysfunction. Renal dysfunction may present with both an odor and dermatologic manifestations. Patients with end-stage renal disease can have an ammonialike uremic breath odor as the result of excessive nitrogenous waste products and increased concentrations of urea in their saliva.^4,22 These patients also can exhibit pruritus, xerosis, pigmentation changes, nail changes, other dermatoses, and rarely uremic frost with white urate crystals present on the skin.^25,26 

Liver failure has been associated with an ammonialike musty breath odor termed fetor hepaticus. Shimamoto et al²⁷ reported notably higher levels of breath ammonia levels in patients with hepatic encephalopathy, indicating that excess ammonia is responsible for the odor. Fetor hepaticus has unique characteristics that can permit a diagnosis of liver disease, though it has been reported in cases in which a liver injury could not be identified.²⁸ 

Aging patients typically have a distinctive smell. Haze et al²⁹ analyzed the body odor of patients aged 26 to 75 years and discovered the compound 2-nonenal—an unsaturated aldehyde with a smell described as greasy and grassy—was found only in patients older than 40 years. The researchers’ analysis of skin-surface lipids also revealed that the presence of ω7 unsaturated fatty acids and lipid peroxides increased with age. They concluded that 2-nonenal is generated from the oxidative degradation of ω7 unsaturated fatty acids by lipid peroxides, suggesting that 2-nonenal may be a cause of the odor of old age.²⁹

Cutaneous Malignancies 

Research shows that the profiles of the body’s continuously released VOCs change in the presence of malignancy. Some studies suggest that melanoma may have a unique odor. Willis et al³⁰ reported that after a 13-month training period, a dog was able to correctly identify melanoma and distinguish it from basal cell carcinoma, benign nevi, and healthy skin based on olfaction alone. Additional cases have been reported in which dogs have been able to identify melanoma based on smell, suggesting that canine olfactory detection of melanoma could possibly aid in the diagnosis of skin cancer, which warrants further investigation.^31,32 There is limited evidence on the specific odors of other cutaneous malignancies, such as basal cell carcinoma and squamous cell carcinoma. 

Bacterial superinfection of cutaneous malignancy can secrete pungent odors. An offensive rotting odor has been associated with necrotic malignant ulcers of the vagina. This malodor likely is a result of the formation of putrescine, cadaverine, short-chain fatty acids (isovaleric and butyric acids) and sulfur-containing compounds by bacteria.³³ Recognition of similar smells may aid in management of these infections.

Diagnostic Techniques

Evaluating human skin odor is challenging, as the components of VOCs are complicated and typically found at trace levels. Studies indicate that gas chromatography–mass spectrometry is the most effective way to analyze human odor. This method separates, quantifies, and analyzes VOCs from samples containing odors.³⁴ Gas chromatography–mass spectrometry, however, has limitations, as the time for analysis is lengthy, the equipment is large, and the process is expensive.³ Research supports the usefulness and validity of quantitative gas chromatography–olfactometry to detect odorants and evaluate odor activity of VOCs in various samples.³⁵ With this technique, human assessors act in place of more conventional detectors, such as mass spectrometers. This method has been used to evaluate odorants in human urine with the goal of increasing understanding of metabolization and excretion processes.³⁶ However, gas chromatography–olfactometry typically is used in the analysis of food and drink, and future research should be aimed at applying this method to medicine. 

Zheng et al³ proposed a wearable electronic nose as a tool to identify human odor to emulate the odor recognition of a canine’s nose. They developed a sensor array based on the composites of carbon nanotubes and polymers able to examine and identify odors in the air. Study participants wore the electronic nose on the arm with the sensory array facing the armpits while they walked on a treadmill. Although many issues regarding odor measurement were not addressed in this study, the research suggests further studies are warranted to improve analysis of odor.³

Clinical Cases

Patient 1—Arseculeratne et al³⁷ described a 41-year-old man who presented with a fishy odor that others had noticed since the age of 13 years but that the patient could not smell himself. Based on his presentation, he was worked up for trimethylaminuria and found to have elevated levels of urinary trimethylamine (TMA) with a raised TMA/TMA-oxidase ratio. These findings were consistent with a diagnosis of primary trimethylaminuria, and the patient was referred to a dietician for counseling on foods that contain low amounts of choline and lecithin. Initially his urinary TMA level fell but then rose again, indicating possible relaxation of his diet. He then took a 10-day course of metronidazole, which helped reduce some of the malodor. The authors reported that the most impactful therapy for the patient was being able to discuss the disorder with his friends and family members.³⁷ This case highlighted the importance of confirming the diagnosis and early initiation of dietary and pharmacologic interventions in patients with trimethylaminuria. In patients reporting a persistent fishy body odor, trimethylaminuria should be on the differential.

Patient 2—In 1999, Schissel et al⁶ described a 20-year-old active-duty soldier who presented to the dermatology department with smelly trench foot and tinea pedis. The soldier reported having this malodorous pitted rash for more than 10 years. He also reported occasional interdigital burning and itching and noted no improvement despite using various topical antifungals. Physical examination revealed an “overpowering pungent odor” when the patient removed his shoes. He had many tender, white, and wet plaques with scalloped borders coalescing into shallow pits on the plantar surface of the feet and great toes. Potassium hydroxide preparation of the great toe plaques and interdigital web spaces were positive for fungal elements, and bacterial cultures isolated moderate coagulase-negative staphylococcal and Corynebacterium species. Additionally, fungal cultures identified Acremonium species. The patient was started on clotrimazole cream twice daily, clindamycin solution twice daily, and topical ammonium chloride nightly. Two weeks later, the patient reported resolution of symptoms, including the malodor.⁶ In pitted keratolysis, warm and wet environments within boots or shoes allow for the growth of bacteria and fungi. The extent of the lesions is related to the amount of bacteria within the stratum corneum. The diagnosis often is made based on odor, location, and appearance of the rash alone. The most common organisms implicated as causal agents in the condition are Kytococcus sedentarius, Dermatophilus congolensis, and species of Corynebacterium and Actinomyces. It is thought that these organisms release proteolytic enzymes that degrade the horny layer, releasing a mixture of thiols, thioesters, and sulfides, which cause the pungent odor. Familiarity with the characteristic odor aids in prompt diagnosis and treatment, which will ultimately heal the skin eruption. 

Patient 3—Srivastava et al³² described a 43-year-old woman who presented with a nevus on the back since childhood. She noticed that it had changed and grown over the past few years and reported that her dog would often sniff the lesion and try to scratch and bite the lesion. This reaction from her dog led the patient to seek out evaluation from a dermatologist. The patient had no personal history of skin cancer, bad sunburns, tanning bed use, or use of immunosuppressants. She reported that her father had a history of basal cell carcinoma. Physical examination revealed a 1.2×1.5-cm brown patch with an ulcerated nodule located on the lower aspect of the lesion. The patient underwent a wide local excision and sentinel lymph node biopsy with pathology showing a 4-mm-thick melanoma with positive lymph nodes. She then underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. Following the surgery, the patient’s dog would sniff the back and calmly rest his head in her lap. She has not had a recurrence and credits her dog for saving her life.³² Canine olfaction may play a role in detecting skin cancers, as evidenced by this case. Patients and dermatologists should pay attention to the behavior of dogs toward skin lesions. Harnessing this sense into a method to noninvasively screen for melanoma in humans should be further investigated.

Patient 4—Matthews et al³⁸ described a 32-year-old woman who presented to an emergency eye clinic with a white “lump” on the left upper eyelid of 6 months’ duration. Physical examination revealed 3 nodular and cystic lesions oozing a thick yellow-white discharge. Cultures were taken, and the patient was started on chloramphenicol ointment once daily to the skin. At follow-up, the lesions had not changed, and the cultures were negative. The patient reported an intermittent malodorous discharge and noted multiple similar lesions on her body. Excisional biopsy demonstrated histologic findings including dyskeratosis, papillomatosis, and suprabasal acantholysis associated with focal underlying chronic inflammatory infiltrate. She was referred to a dermatologist and was diagnosed with Darier disease. She was started on clobetasone butyrate when necessary and adapalene nocte. Understanding the smell associated with Darier disease in conjunction with the cutaneous findings may aid in earlier diagnosis, improving outcomes for affected patients.³⁸ 

Conclusion

The sense of smell may be an overlooked diagnostic tool that dermatologists innately possess. Odors detected when examining patients should be considered, as these odors may help guide a diagnosis. Early diagnosis and treatment are important in many dermatologic diseases, so it is imperative to consider all diagnostic clues. Although physician olfaction may aid in diagnosis, its utility remains challenging, as there is a lack of consensus and terminology regarding odor in disease. A limitation of training to identify disease-specific odors is the requirement of engaging in often unpleasant odors. Methods to objectively measure odor are expensive and still in the early stages of development. Further research and exploration of olfactory-based diagnostic techniques is warranted to potentially improve dermatologic diagnosis. 

Humans possess the ability to recognize and distinguish a large range of odors that can be utilized in a wide range of applications. For example, sommeliers can classify more than 88 smells specific to the roughly 800 volatile organic compounds (VOCs) in wine. Thorough physical examination is essential in dermatology, and although sight and touch play the most important diagnostic roles, the sense of smell often is overlooked. Dermatologists are rigorously trained on the many visual aspects of skin disease and have a plethora of terms to describe these features while there is minimal characterization of odors. Research on odors and the role of olfaction in dermatologic practice is limited.^1,2 We conducted a literature review of PubMed and Google Scholar for peer-reviewed articles discussing the role of odors in dermatologic diseases. Keywords included odor + dermatology, smell + dermatology, cutaneous odor, odor + diagnosis, and disease odor. Relevant studies were identified by screening their abstracts, followed by a full-text review. A total of 38 articles written in English that presented information on the odor associated with dermatologic diseases were included. Articles that were unrelated to the topic or written in a language other than English were excluded.

Common Skin Odors

The human body emits odorants—small VOCs—in various forms (skin/sweat, breath, urine, reproductive fluids). Human odor originates from the oxidation and bacterial metabolism of sweat and sebum on the skin.³ While many odors are physiologic and not cause for concern, others can signal underlying dermatologic pathologies.⁴ Odor-producing conditions can be categorized broadly into infectious diseases, disorders of keratinization and acantholysis, metabolic disorders, and organ dysfunction (Table). Infectious causes include bacterial infections and chronic wounds, which commonly emit characteristic offensive odors. For example, coryneform infections produce methanethiol, causing a cheesy odor of putrid fruit, and pseudomonal pyoderma infections emit a grape juice–like or mousy odor.

Bacterial and Fungal Infections

Bacterial and fungal infections often have distinct smells. Coryneform infections emit an odor of sweaty feet, pseudomonal infections emit a grape juice–like or mousy odor, and trichomycosis infections (caused by Corynebacterium tenuis) present with malodor.⁵ Pseudomonas can infect pyoderma gangrenosum lesions, producing a characteristic malodor.⁵ These smells can be clues for infectious etiology and guide further workup.

Pitted keratolysis, a malodorous pitted rash characterized by infection of the stratum corneum by Kytococcus sedentarius, Dermatophilus congolensis, or Corynebacterium species, is associated with a rotten smell. Its pungent odor, clinical location, and characteristic appearance often are enough to make a diagnosis. The amount of bacteria maintained in the stratum corneum is correlated with the extent of the lesion. Controlling excessive moisture in footwear, aluminum chloride, and topical microbial agents work together to eliminate the skin eruption.⁶ 

Hidradenitis suppurativa, a chronic inflammatory disease of apocrine gland–containing skin, can manifest with abscesses, draining sinuses, and nodules that produce a foul-smelling, purulent discharge. The disease can be debilitating, largely impacting patients’ quality of life, making early diagnosis and treatment critical.^7,8 Therapy is dependent on disease severity and includes topical antibiotics, systemic therapies, and biologics.⁸ 

Patients with atopic dermatitis often experience bacterial superinfection with Staphylococcus aureus. A case report described a patient who developed a fishy odor in this setting that resolved with antibiotic treatment, implicating S aureus in the etiology of the smell.⁹ 

A seminal fluid odor has been reported in cases of Pasteurella wound infection. In such cases, Pasteurella multocida subspecies septica was identified in the wounds caused by a dog scratch and a cat bite. The seminal fluid–like odor was apparent hours after the inciting incident and resolved after treatment with antibiotics.¹⁰ 

Fungal infections frequently emit musty or moldy odors. Tinea pedis (athlete’s foot) is the most prevalent cutaneous fungal infection. The presence of tinea pedis is associated with an intense foul-smelling odor, itching, fissuring, scaling, or maceration of the interdigital regions. The rash and odor resolve with use of topical antifungal agents.^11,12 Seborrheic dermatitis, a prevalent and chronic dermatosis, is characterized by yellow greasy scaling on an erythematous base. In severe cases, a greasy crust with an offensive odor can cover the entire scalp.¹³ The specific cause of this odor is unclear, but it is thought that sebum production and the immunological response to specific Malassezia yeast species may play a role.¹⁴

Genetic and Metabolic Disorders

An array of disorders of keratinization and acantholysis can manifest with distinctive smells that dermatologists frequently encounter. For example, Darier disease, characterized by keratotic papules progressing to crusted plaques, has a signature foul-smelling odor associated with cutaneous bacterial colonization.¹⁵ Similarly, Hailey-Hailey disease, an autosomal-dominant disorder with crusted erosions in skinfold areas, produces a distinct foul smell.¹⁶ Disorders such as pemphigus vulgaris and pemphigus foliaceus emit a peculiar fishy odor that can be helpful in making a diagnosis.¹⁷ Additionally, bullous ichthyosiform erythroderma, keratitis-ichthyosis-deafness syndrome, mal de Meleda, and Papillon-Lefèvre syndrome are all associated with malodor.⁵

Certain metabolic disorders can manifest and present initially with identifiable odors. Trimethylaminuria is a psychologically disabling disease known for its rotting fishy smell due to high amounts of trimethylamine appearing in affected individuals’ sweat, urine, and breath. Previously considered to be very rare, Messenger et al¹⁸ reported the disorder is likely underdiagnosed in those with idiopathic malodor production. Detection and treatment can greatly improve patient quality of life.

Phenylketonuria is an autosomal-recessive inborn error of phenylalanine metabolism that produces a musty body and urine odor as well as other neurologic and dermatologic symptoms.^19,20 Patients can present with eczematous rashes, fair skin, and blue eyes. Phenylacetic acid produces the characteristic odor in the bodily fluids, and the disease is treated with a phenylalanine-free diet.²¹ 

Maple syrup urine disease is a disorder of the oxidative decarboxylation of valine, leucine, and isoleucine (branched-chain amino acids) characterized by urine that smells sweet, resembling maple syrup, in afflicted individuals. The odor also can be present in other bodily secretions, such as sweat. Patients present early in infancy with poor feeding and vomiting as well as neurologic symptoms, eventually leading to intellectual disability. These individuals must avoid the branched-chain amino acids in their diets.²¹ 

Other metabolic storage disorders linked with specific odors are methionine adenosyltransferase deficiency (boiled cabbage), hypermethioninemia (fishy, boiled cabbage), isovaleric acidemia (sweaty feet), methionine malabsorption syndrome (pungent malodor), and dimethylglycine dehydrogenase deficiency (fishy).^5,21,22

In diabetic ketoacidosis, a life-threatening complication of diabetes, the excess of ketone bodies produced causes patients to have a distinct fruity breath and urine odor, as well as fatigue, polyuria, polydipsia, nausea, and vomiting.²² Although patients with type 1 diabetes typically comprise the cohort of patients presenting with diabetic ketoacidosis, patients with type 2 diabetes can exhibit cutaneous manifestations such as infection, xerosis, and inflammatory skin diseases.^23,24 

Organ Dysfunction

A peculiar body odor can be a sign of organ dysfunction. Renal dysfunction may present with both an odor and dermatologic manifestations. Patients with end-stage renal disease can have an ammonialike uremic breath odor as the result of excessive nitrogenous waste products and increased concentrations of urea in their saliva.^4,22 These patients also can exhibit pruritus, xerosis, pigmentation changes, nail changes, other dermatoses, and rarely uremic frost with white urate crystals present on the skin.^25,26 

Liver failure has been associated with an ammonialike musty breath odor termed fetor hepaticus. Shimamoto et al²⁷ reported notably higher levels of breath ammonia levels in patients with hepatic encephalopathy, indicating that excess ammonia is responsible for the odor. Fetor hepaticus has unique characteristics that can permit a diagnosis of liver disease, though it has been reported in cases in which a liver injury could not be identified.²⁸ 

Aging patients typically have a distinctive smell. Haze et al²⁹ analyzed the body odor of patients aged 26 to 75 years and discovered the compound 2-nonenal—an unsaturated aldehyde with a smell described as greasy and grassy—was found only in patients older than 40 years. The researchers’ analysis of skin-surface lipids also revealed that the presence of ω7 unsaturated fatty acids and lipid peroxides increased with age. They concluded that 2-nonenal is generated from the oxidative degradation of ω7 unsaturated fatty acids by lipid peroxides, suggesting that 2-nonenal may be a cause of the odor of old age.²⁹

Cutaneous Malignancies 

Research shows that the profiles of the body’s continuously released VOCs change in the presence of malignancy. Some studies suggest that melanoma may have a unique odor. Willis et al³⁰ reported that after a 13-month training period, a dog was able to correctly identify melanoma and distinguish it from basal cell carcinoma, benign nevi, and healthy skin based on olfaction alone. Additional cases have been reported in which dogs have been able to identify melanoma based on smell, suggesting that canine olfactory detection of melanoma could possibly aid in the diagnosis of skin cancer, which warrants further investigation.^31,32 There is limited evidence on the specific odors of other cutaneous malignancies, such as basal cell carcinoma and squamous cell carcinoma. 

Bacterial superinfection of cutaneous malignancy can secrete pungent odors. An offensive rotting odor has been associated with necrotic malignant ulcers of the vagina. This malodor likely is a result of the formation of putrescine, cadaverine, short-chain fatty acids (isovaleric and butyric acids) and sulfur-containing compounds by bacteria.³³ Recognition of similar smells may aid in management of these infections.

Diagnostic Techniques

Evaluating human skin odor is challenging, as the components of VOCs are complicated and typically found at trace levels. Studies indicate that gas chromatography–mass spectrometry is the most effective way to analyze human odor. This method separates, quantifies, and analyzes VOCs from samples containing odors.³⁴ Gas chromatography–mass spectrometry, however, has limitations, as the time for analysis is lengthy, the equipment is large, and the process is expensive.³ Research supports the usefulness and validity of quantitative gas chromatography–olfactometry to detect odorants and evaluate odor activity of VOCs in various samples.³⁵ With this technique, human assessors act in place of more conventional detectors, such as mass spectrometers. This method has been used to evaluate odorants in human urine with the goal of increasing understanding of metabolization and excretion processes.³⁶ However, gas chromatography–olfactometry typically is used in the analysis of food and drink, and future research should be aimed at applying this method to medicine. 

Zheng et al³ proposed a wearable electronic nose as a tool to identify human odor to emulate the odor recognition of a canine’s nose. They developed a sensor array based on the composites of carbon nanotubes and polymers able to examine and identify odors in the air. Study participants wore the electronic nose on the arm with the sensory array facing the armpits while they walked on a treadmill. Although many issues regarding odor measurement were not addressed in this study, the research suggests further studies are warranted to improve analysis of odor.³

Clinical Cases

Patient 1—Arseculeratne et al³⁷ described a 41-year-old man who presented with a fishy odor that others had noticed since the age of 13 years but that the patient could not smell himself. Based on his presentation, he was worked up for trimethylaminuria and found to have elevated levels of urinary trimethylamine (TMA) with a raised TMA/TMA-oxidase ratio. These findings were consistent with a diagnosis of primary trimethylaminuria, and the patient was referred to a dietician for counseling on foods that contain low amounts of choline and lecithin. Initially his urinary TMA level fell but then rose again, indicating possible relaxation of his diet. He then took a 10-day course of metronidazole, which helped reduce some of the malodor. The authors reported that the most impactful therapy for the patient was being able to discuss the disorder with his friends and family members.³⁷ This case highlighted the importance of confirming the diagnosis and early initiation of dietary and pharmacologic interventions in patients with trimethylaminuria. In patients reporting a persistent fishy body odor, trimethylaminuria should be on the differential.

Patient 2—In 1999, Schissel et al⁶ described a 20-year-old active-duty soldier who presented to the dermatology department with smelly trench foot and tinea pedis. The soldier reported having this malodorous pitted rash for more than 10 years. He also reported occasional interdigital burning and itching and noted no improvement despite using various topical antifungals. Physical examination revealed an “overpowering pungent odor” when the patient removed his shoes. He had many tender, white, and wet plaques with scalloped borders coalescing into shallow pits on the plantar surface of the feet and great toes. Potassium hydroxide preparation of the great toe plaques and interdigital web spaces were positive for fungal elements, and bacterial cultures isolated moderate coagulase-negative staphylococcal and Corynebacterium species. Additionally, fungal cultures identified Acremonium species. The patient was started on clotrimazole cream twice daily, clindamycin solution twice daily, and topical ammonium chloride nightly. Two weeks later, the patient reported resolution of symptoms, including the malodor.⁶ In pitted keratolysis, warm and wet environments within boots or shoes allow for the growth of bacteria and fungi. The extent of the lesions is related to the amount of bacteria within the stratum corneum. The diagnosis often is made based on odor, location, and appearance of the rash alone. The most common organisms implicated as causal agents in the condition are Kytococcus sedentarius, Dermatophilus congolensis, and species of Corynebacterium and Actinomyces. It is thought that these organisms release proteolytic enzymes that degrade the horny layer, releasing a mixture of thiols, thioesters, and sulfides, which cause the pungent odor. Familiarity with the characteristic odor aids in prompt diagnosis and treatment, which will ultimately heal the skin eruption. 

Patient 3—Srivastava et al³² described a 43-year-old woman who presented with a nevus on the back since childhood. She noticed that it had changed and grown over the past few years and reported that her dog would often sniff the lesion and try to scratch and bite the lesion. This reaction from her dog led the patient to seek out evaluation from a dermatologist. The patient had no personal history of skin cancer, bad sunburns, tanning bed use, or use of immunosuppressants. She reported that her father had a history of basal cell carcinoma. Physical examination revealed a 1.2×1.5-cm brown patch with an ulcerated nodule located on the lower aspect of the lesion. The patient underwent a wide local excision and sentinel lymph node biopsy with pathology showing a 4-mm-thick melanoma with positive lymph nodes. She then underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. Following the surgery, the patient’s dog would sniff the back and calmly rest his head in her lap. She has not had a recurrence and credits her dog for saving her life.³² Canine olfaction may play a role in detecting skin cancers, as evidenced by this case. Patients and dermatologists should pay attention to the behavior of dogs toward skin lesions. Harnessing this sense into a method to noninvasively screen for melanoma in humans should be further investigated.

Patient 4—Matthews et al³⁸ described a 32-year-old woman who presented to an emergency eye clinic with a white “lump” on the left upper eyelid of 6 months’ duration. Physical examination revealed 3 nodular and cystic lesions oozing a thick yellow-white discharge. Cultures were taken, and the patient was started on chloramphenicol ointment once daily to the skin. At follow-up, the lesions had not changed, and the cultures were negative. The patient reported an intermittent malodorous discharge and noted multiple similar lesions on her body. Excisional biopsy demonstrated histologic findings including dyskeratosis, papillomatosis, and suprabasal acantholysis associated with focal underlying chronic inflammatory infiltrate. She was referred to a dermatologist and was diagnosed with Darier disease. She was started on clobetasone butyrate when necessary and adapalene nocte. Understanding the smell associated with Darier disease in conjunction with the cutaneous findings may aid in earlier diagnosis, improving outcomes for affected patients.³⁸ 

Conclusion

The sense of smell may be an overlooked diagnostic tool that dermatologists innately possess. Odors detected when examining patients should be considered, as these odors may help guide a diagnosis. Early diagnosis and treatment are important in many dermatologic diseases, so it is imperative to consider all diagnostic clues. Although physician olfaction may aid in diagnosis, its utility remains challenging, as there is a lack of consensus and terminology regarding odor in disease. A limitation of training to identify disease-specific odors is the requirement of engaging in often unpleasant odors. Methods to objectively measure odor are expensive and still in the early stages of development. Further research and exploration of olfactory-based diagnostic techniques is warranted to potentially improve dermatologic diagnosis. 

Humans possess the ability to recognize and distinguish a large range of odors that can be utilized in a wide range of applications. For example, sommeliers can classify more than 88 smells specific to the roughly 800 volatile organic compounds (VOCs) in wine. Thorough physical examination is essential in dermatology, and although sight and touch play the most important diagnostic roles, the sense of smell often is overlooked. Dermatologists are rigorously trained on the many visual aspects of skin disease and have a plethora of terms to describe these features while there is minimal characterization of odors. Research on odors and the role of olfaction in dermatologic practice is limited.^1,2 We conducted a literature review of PubMed and Google Scholar for peer-reviewed articles discussing the role of odors in dermatologic diseases. Keywords included odor + dermatology, smell + dermatology, cutaneous odor, odor + diagnosis, and disease odor. Relevant studies were identified by screening their abstracts, followed by a full-text review. A total of 38 articles written in English that presented information on the odor associated with dermatologic diseases were included. Articles that were unrelated to the topic or written in a language other than English were excluded.

Common Skin Odors

The human body emits odorants—small VOCs—in various forms (skin/sweat, breath, urine, reproductive fluids). Human odor originates from the oxidation and bacterial metabolism of sweat and sebum on the skin.³ While many odors are physiologic and not cause for concern, others can signal underlying dermatologic pathologies.⁴ Odor-producing conditions can be categorized broadly into infectious diseases, disorders of keratinization and acantholysis, metabolic disorders, and organ dysfunction (Table). Infectious causes include bacterial infections and chronic wounds, which commonly emit characteristic offensive odors. For example, coryneform infections produce methanethiol, causing a cheesy odor of putrid fruit, and pseudomonal pyoderma infections emit a grape juice–like or mousy odor.

Bacterial and Fungal Infections

Bacterial and fungal infections often have distinct smells. Coryneform infections emit an odor of sweaty feet, pseudomonal infections emit a grape juice–like or mousy odor, and trichomycosis infections (caused by Corynebacterium tenuis) present with malodor.⁵ Pseudomonas can infect pyoderma gangrenosum lesions, producing a characteristic malodor.⁵ These smells can be clues for infectious etiology and guide further workup.

Pitted keratolysis, a malodorous pitted rash characterized by infection of the stratum corneum by Kytococcus sedentarius, Dermatophilus congolensis, or Corynebacterium species, is associated with a rotten smell. Its pungent odor, clinical location, and characteristic appearance often are enough to make a diagnosis. The amount of bacteria maintained in the stratum corneum is correlated with the extent of the lesion. Controlling excessive moisture in footwear, aluminum chloride, and topical microbial agents work together to eliminate the skin eruption.⁶ 

Hidradenitis suppurativa, a chronic inflammatory disease of apocrine gland–containing skin, can manifest with abscesses, draining sinuses, and nodules that produce a foul-smelling, purulent discharge. The disease can be debilitating, largely impacting patients’ quality of life, making early diagnosis and treatment critical.^7,8 Therapy is dependent on disease severity and includes topical antibiotics, systemic therapies, and biologics.⁸ 

Patients with atopic dermatitis often experience bacterial superinfection with Staphylococcus aureus. A case report described a patient who developed a fishy odor in this setting that resolved with antibiotic treatment, implicating S aureus in the etiology of the smell.⁹ 

A seminal fluid odor has been reported in cases of Pasteurella wound infection. In such cases, Pasteurella multocida subspecies septica was identified in the wounds caused by a dog scratch and a cat bite. The seminal fluid–like odor was apparent hours after the inciting incident and resolved after treatment with antibiotics.¹⁰ 

Fungal infections frequently emit musty or moldy odors. Tinea pedis (athlete’s foot) is the most prevalent cutaneous fungal infection. The presence of tinea pedis is associated with an intense foul-smelling odor, itching, fissuring, scaling, or maceration of the interdigital regions. The rash and odor resolve with use of topical antifungal agents.^11,12 Seborrheic dermatitis, a prevalent and chronic dermatosis, is characterized by yellow greasy scaling on an erythematous base. In severe cases, a greasy crust with an offensive odor can cover the entire scalp.¹³ The specific cause of this odor is unclear, but it is thought that sebum production and the immunological response to specific Malassezia yeast species may play a role.¹⁴

Genetic and Metabolic Disorders

An array of disorders of keratinization and acantholysis can manifest with distinctive smells that dermatologists frequently encounter. For example, Darier disease, characterized by keratotic papules progressing to crusted plaques, has a signature foul-smelling odor associated with cutaneous bacterial colonization.¹⁵ Similarly, Hailey-Hailey disease, an autosomal-dominant disorder with crusted erosions in skinfold areas, produces a distinct foul smell.¹⁶ Disorders such as pemphigus vulgaris and pemphigus foliaceus emit a peculiar fishy odor that can be helpful in making a diagnosis.¹⁷ Additionally, bullous ichthyosiform erythroderma, keratitis-ichthyosis-deafness syndrome, mal de Meleda, and Papillon-Lefèvre syndrome are all associated with malodor.⁵

Certain metabolic disorders can manifest and present initially with identifiable odors. Trimethylaminuria is a psychologically disabling disease known for its rotting fishy smell due to high amounts of trimethylamine appearing in affected individuals’ sweat, urine, and breath. Previously considered to be very rare, Messenger et al¹⁸ reported the disorder is likely underdiagnosed in those with idiopathic malodor production. Detection and treatment can greatly improve patient quality of life.

Phenylketonuria is an autosomal-recessive inborn error of phenylalanine metabolism that produces a musty body and urine odor as well as other neurologic and dermatologic symptoms.^19,20 Patients can present with eczematous rashes, fair skin, and blue eyes. Phenylacetic acid produces the characteristic odor in the bodily fluids, and the disease is treated with a phenylalanine-free diet.²¹ 

Maple syrup urine disease is a disorder of the oxidative decarboxylation of valine, leucine, and isoleucine (branched-chain amino acids) characterized by urine that smells sweet, resembling maple syrup, in afflicted individuals. The odor also can be present in other bodily secretions, such as sweat. Patients present early in infancy with poor feeding and vomiting as well as neurologic symptoms, eventually leading to intellectual disability. These individuals must avoid the branched-chain amino acids in their diets.²¹ 

Other metabolic storage disorders linked with specific odors are methionine adenosyltransferase deficiency (boiled cabbage), hypermethioninemia (fishy, boiled cabbage), isovaleric acidemia (sweaty feet), methionine malabsorption syndrome (pungent malodor), and dimethylglycine dehydrogenase deficiency (fishy).^5,21,22

In diabetic ketoacidosis, a life-threatening complication of diabetes, the excess of ketone bodies produced causes patients to have a distinct fruity breath and urine odor, as well as fatigue, polyuria, polydipsia, nausea, and vomiting.²² Although patients with type 1 diabetes typically comprise the cohort of patients presenting with diabetic ketoacidosis, patients with type 2 diabetes can exhibit cutaneous manifestations such as infection, xerosis, and inflammatory skin diseases.^23,24 

Organ Dysfunction

A peculiar body odor can be a sign of organ dysfunction. Renal dysfunction may present with both an odor and dermatologic manifestations. Patients with end-stage renal disease can have an ammonialike uremic breath odor as the result of excessive nitrogenous waste products and increased concentrations of urea in their saliva.^4,22 These patients also can exhibit pruritus, xerosis, pigmentation changes, nail changes, other dermatoses, and rarely uremic frost with white urate crystals present on the skin.^25,26 

Liver failure has been associated with an ammonialike musty breath odor termed fetor hepaticus. Shimamoto et al²⁷ reported notably higher levels of breath ammonia levels in patients with hepatic encephalopathy, indicating that excess ammonia is responsible for the odor. Fetor hepaticus has unique characteristics that can permit a diagnosis of liver disease, though it has been reported in cases in which a liver injury could not be identified.²⁸ 

Aging patients typically have a distinctive smell. Haze et al²⁹ analyzed the body odor of patients aged 26 to 75 years and discovered the compound 2-nonenal—an unsaturated aldehyde with a smell described as greasy and grassy—was found only in patients older than 40 years. The researchers’ analysis of skin-surface lipids also revealed that the presence of ω7 unsaturated fatty acids and lipid peroxides increased with age. They concluded that 2-nonenal is generated from the oxidative degradation of ω7 unsaturated fatty acids by lipid peroxides, suggesting that 2-nonenal may be a cause of the odor of old age.²⁹

Cutaneous Malignancies 

Research shows that the profiles of the body’s continuously released VOCs change in the presence of malignancy. Some studies suggest that melanoma may have a unique odor. Willis et al³⁰ reported that after a 13-month training period, a dog was able to correctly identify melanoma and distinguish it from basal cell carcinoma, benign nevi, and healthy skin based on olfaction alone. Additional cases have been reported in which dogs have been able to identify melanoma based on smell, suggesting that canine olfactory detection of melanoma could possibly aid in the diagnosis of skin cancer, which warrants further investigation.^31,32 There is limited evidence on the specific odors of other cutaneous malignancies, such as basal cell carcinoma and squamous cell carcinoma. 

Bacterial superinfection of cutaneous malignancy can secrete pungent odors. An offensive rotting odor has been associated with necrotic malignant ulcers of the vagina. This malodor likely is a result of the formation of putrescine, cadaverine, short-chain fatty acids (isovaleric and butyric acids) and sulfur-containing compounds by bacteria.³³ Recognition of similar smells may aid in management of these infections.

Diagnostic Techniques

Evaluating human skin odor is challenging, as the components of VOCs are complicated and typically found at trace levels. Studies indicate that gas chromatography–mass spectrometry is the most effective way to analyze human odor. This method separates, quantifies, and analyzes VOCs from samples containing odors.³⁴ Gas chromatography–mass spectrometry, however, has limitations, as the time for analysis is lengthy, the equipment is large, and the process is expensive.³ Research supports the usefulness and validity of quantitative gas chromatography–olfactometry to detect odorants and evaluate odor activity of VOCs in various samples.³⁵ With this technique, human assessors act in place of more conventional detectors, such as mass spectrometers. This method has been used to evaluate odorants in human urine with the goal of increasing understanding of metabolization and excretion processes.³⁶ However, gas chromatography–olfactometry typically is used in the analysis of food and drink, and future research should be aimed at applying this method to medicine. 

Zheng et al³ proposed a wearable electronic nose as a tool to identify human odor to emulate the odor recognition of a canine’s nose. They developed a sensor array based on the composites of carbon nanotubes and polymers able to examine and identify odors in the air. Study participants wore the electronic nose on the arm with the sensory array facing the armpits while they walked on a treadmill. Although many issues regarding odor measurement were not addressed in this study, the research suggests further studies are warranted to improve analysis of odor.³

Clinical Cases

Patient 1—Arseculeratne et al³⁷ described a 41-year-old man who presented with a fishy odor that others had noticed since the age of 13 years but that the patient could not smell himself. Based on his presentation, he was worked up for trimethylaminuria and found to have elevated levels of urinary trimethylamine (TMA) with a raised TMA/TMA-oxidase ratio. These findings were consistent with a diagnosis of primary trimethylaminuria, and the patient was referred to a dietician for counseling on foods that contain low amounts of choline and lecithin. Initially his urinary TMA level fell but then rose again, indicating possible relaxation of his diet. He then took a 10-day course of metronidazole, which helped reduce some of the malodor. The authors reported that the most impactful therapy for the patient was being able to discuss the disorder with his friends and family members.³⁷ This case highlighted the importance of confirming the diagnosis and early initiation of dietary and pharmacologic interventions in patients with trimethylaminuria. In patients reporting a persistent fishy body odor, trimethylaminuria should be on the differential.

Patient 2—In 1999, Schissel et al⁶ described a 20-year-old active-duty soldier who presented to the dermatology department with smelly trench foot and tinea pedis. The soldier reported having this malodorous pitted rash for more than 10 years. He also reported occasional interdigital burning and itching and noted no improvement despite using various topical antifungals. Physical examination revealed an “overpowering pungent odor” when the patient removed his shoes. He had many tender, white, and wet plaques with scalloped borders coalescing into shallow pits on the plantar surface of the feet and great toes. Potassium hydroxide preparation of the great toe plaques and interdigital web spaces were positive for fungal elements, and bacterial cultures isolated moderate coagulase-negative staphylococcal and Corynebacterium species. Additionally, fungal cultures identified Acremonium species. The patient was started on clotrimazole cream twice daily, clindamycin solution twice daily, and topical ammonium chloride nightly. Two weeks later, the patient reported resolution of symptoms, including the malodor.⁶ In pitted keratolysis, warm and wet environments within boots or shoes allow for the growth of bacteria and fungi. The extent of the lesions is related to the amount of bacteria within the stratum corneum. The diagnosis often is made based on odor, location, and appearance of the rash alone. The most common organisms implicated as causal agents in the condition are Kytococcus sedentarius, Dermatophilus congolensis, and species of Corynebacterium and Actinomyces. It is thought that these organisms release proteolytic enzymes that degrade the horny layer, releasing a mixture of thiols, thioesters, and sulfides, which cause the pungent odor. Familiarity with the characteristic odor aids in prompt diagnosis and treatment, which will ultimately heal the skin eruption. 

Patient 3—Srivastava et al³² described a 43-year-old woman who presented with a nevus on the back since childhood. She noticed that it had changed and grown over the past few years and reported that her dog would often sniff the lesion and try to scratch and bite the lesion. This reaction from her dog led the patient to seek out evaluation from a dermatologist. The patient had no personal history of skin cancer, bad sunburns, tanning bed use, or use of immunosuppressants. She reported that her father had a history of basal cell carcinoma. Physical examination revealed a 1.2×1.5-cm brown patch with an ulcerated nodule located on the lower aspect of the lesion. The patient underwent a wide local excision and sentinel lymph node biopsy with pathology showing a 4-mm-thick melanoma with positive lymph nodes. She then underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. Following the surgery, the patient’s dog would sniff the back and calmly rest his head in her lap. She has not had a recurrence and credits her dog for saving her life.³² Canine olfaction may play a role in detecting skin cancers, as evidenced by this case. Patients and dermatologists should pay attention to the behavior of dogs toward skin lesions. Harnessing this sense into a method to noninvasively screen for melanoma in humans should be further investigated.

Patient 4—Matthews et al³⁸ described a 32-year-old woman who presented to an emergency eye clinic with a white “lump” on the left upper eyelid of 6 months’ duration. Physical examination revealed 3 nodular and cystic lesions oozing a thick yellow-white discharge. Cultures were taken, and the patient was started on chloramphenicol ointment once daily to the skin. At follow-up, the lesions had not changed, and the cultures were negative. The patient reported an intermittent malodorous discharge and noted multiple similar lesions on her body. Excisional biopsy demonstrated histologic findings including dyskeratosis, papillomatosis, and suprabasal acantholysis associated with focal underlying chronic inflammatory infiltrate. She was referred to a dermatologist and was diagnosed with Darier disease. She was started on clobetasone butyrate when necessary and adapalene nocte. Understanding the smell associated with Darier disease in conjunction with the cutaneous findings may aid in earlier diagnosis, improving outcomes for affected patients.³⁸ 

Conclusion

The sense of smell may be an overlooked diagnostic tool that dermatologists innately possess. Odors detected when examining patients should be considered, as these odors may help guide a diagnosis. Early diagnosis and treatment are important in many dermatologic diseases, so it is imperative to consider all diagnostic clues. Although physician olfaction may aid in diagnosis, its utility remains challenging, as there is a lack of consensus and terminology regarding odor in disease. A limitation of training to identify disease-specific odors is the requirement of engaging in often unpleasant odors. Methods to objectively measure odor are expensive and still in the early stages of development. Further research and exploration of olfactory-based diagnostic techniques is warranted to potentially improve dermatologic diagnosis. 

THE DIAGNOSIS: Impetigo Herpetiformis

Histopathology revealed epidermal acanthosis and spongiosis with overlying parakeratosis associated with subcorneal and intracorneal neutrophils, papillary dermal edema, and dermal mixed inflammation with neutrophils and eosinophils. Both direct immunofluorescence and periodic acid–Schiff studies were negative. Blood and pustule cultures were sterile and the skin flora were normal. Based on these findings, a diagnosis of impetigo herpetiformis (IH) was made. The condition improved with systemic and topical steroids, supportive care, and an intravenous infusion of infliximab 5 mg/kg. At 3 weeks’ follow-up, the patient demonstrated near-complete resolution and later delivered successfully at 40 weeks’ gestation without complications.

Impetigo herpetiformis, also known as pustular psoriasis of pregnancy, is an exceedingly rare gestational dermatosis that typically manifests in the third trimester and can be life-threatening for both the mother and fetus. The term was first used in 1872 to describe 5 pregnant women with extensive acute pustular eruptions, all in unstable condition; 4 (80%)of the cases resulted in maternal death, and all resulted in fetal death.¹ Impetigo herpetiformis is characterized by pruritic and painful erythematous patches studded at the periphery with subcorneal pustules. Eruptions usually occur in the flexural areas and spread centrifugally, with extension of the lesions peripherally as the center erodes and crusts. Sparing of the face, palms, and soles is expected, and mucosal involvement is rare. Generalized involvement and exfoliation may occur in extreme cases.² While IH typically manifests during the third trimester, it may occur any time throughout pregnancy or immediately postpartum.³ A few cases have been reported in the puerperium.² Common symptoms include fever, chills, malaise, anorexia, nausea, vomiting, diarrhea, and arthralgias. Less common complications include hypoalbuminemia and severe hypocalcemia leading to tetany, seizures, and delirium.^2,3 While maternal mortality is uncommon, fetal mortality often is a more pressing risk and is attributed to placental insufficiency.^3,4 For this reason, early delivery commonly is considered in severe cases.

Whether IH is a separate entity or a variant of pustular psoriasis remains heavily debated. Although the histopathology of IH is identical to pustular psoriasis, the lack of a personal and family history of psoriasis, symptom resolution with delivery, and possible recurrence during successive pregnancies help differentiate IH from generalized pustular psoriasis.^2,5 Earlier onset, diffuse involvement, faster progression, and recurrence in subsequent pregnancies all have been linked to a worse prognosis.⁴

The differential diagnosis for IH includes acute generalized exanthematous pustulosis, pemphigoid gestationis, dermatitis herpetiformis, and subcorneal pustular dermatosis. Acute generalized exanthematous pustulosis is an uncommon severe cutaneous drug reaction characterized by the sudden onset of numerous sterile pustules on erythematous skin within 48 hours of exposure. The most common offending medications include pristinamycin and beta-lactam antibiotics. A high fever, neutrophilic leukocytosis, and hypocalcemia often accompany acute generalized exanthematous pustulosis.⁶ Prompt diagnosis and withdrawal of the offending drug as well as supportive care and symptomatic treatment are crucial for disease management, as systemic symptoms and even organ involvement may occur.⁶

Pemphigoid gestationis, also known as gestational pemphigoid or herpes gestationis, is a rare autoimmune blistering disorder that primarily affects pregnant women. It typically manifests in the second or third trimester or shortly after delivery. Clinically, it manifests as an intensely pruritic polymorphic eruption of urticarial papules and plaques accompanied by vesicles and bullae and often is distributed on the abdomen and extends to other body regions. Although the exact etiology is unknown, pemphigoid gestationis is caused by autoantibodies targeting the BP180 and BP230 hemidesmosomal proteins.⁷ Treatment usually involves systemic corticosteroids and may require additional immunosuppressive therapy. In most cases, patients see resolution within 6 months of delivery.⁷

Dermatitis herpetiformis is a chronic autoimmune blistering skin disorder characterized by intensely pruritic, grouped vesicles and papules, often distributed symmetrically on extensor surfaces such as the elbows, knees, buttocks, and back. It is closely associated with celiac disease and is triggered by gluten ingestion in genetically predisposed individuals with human leukocyte antigen DQ2 and DQ8 haplotypes. Dermatitis herpetiformis is caused by deposition of IgA antibodies that target tissue transglutaminase 3 at the dermal papillae, leading to inflammation and blister formation. ⁸ Treatment typically involves a gluten-free diet and medications such as dapsone to alleviate symptoms and prevent recurrence.

Subcorneal pustular dermatosis, also known as Sneddon-Wilkinson disease, is a rare chronic relapsing pustular dermatosis characterized by sterile superficial pustules arranged in annular or circinate patterns on erythematous plaques. It predominantly affects middleaged women and often is associated with underlying conditions such as IgA gammopathy or monoclonal gammopathy of undetermined significance. The pathogenesis remains unclear, but immune dysregulation is thought to play a role. Some authors still question whether subcorneal pustular dermatosis is a distinct entity from pustular psoriasis.^4,5,12 Dapsone is the preferred first-line treatment, with adjunct therapies including topical or systemic corticosteroids, other immunosuppressive agents, tumor necrosis factor inhibitors, and UV light therapy.⁹

Definitive management of IH is achieved through early delivery; however, systemic corticosteroids often are used in varying doses to control the disease and to extend the pregnancy period closer to term or until delivery is considered viable. Additional therapies that can be considered include infliximab, cyclosporine, and topical corticosteroids, in conjunction with fluid and electrolyte maintenance.^2,4,10 If symptoms persist despite supportive care and pharmacologic intervention, induction of labor or termination of pregnancy may be indicated. In nonbreastfeeding postpartum mothers with persistent disease, therapies commonly used in generalized pustular psoriasis may be given.¹¹

THE DIAGNOSIS: Impetigo Herpetiformis

Histopathology revealed epidermal acanthosis and spongiosis with overlying parakeratosis associated with subcorneal and intracorneal neutrophils, papillary dermal edema, and dermal mixed inflammation with neutrophils and eosinophils. Both direct immunofluorescence and periodic acid–Schiff studies were negative. Blood and pustule cultures were sterile and the skin flora were normal. Based on these findings, a diagnosis of impetigo herpetiformis (IH) was made. The condition improved with systemic and topical steroids, supportive care, and an intravenous infusion of infliximab 5 mg/kg. At 3 weeks’ follow-up, the patient demonstrated near-complete resolution and later delivered successfully at 40 weeks’ gestation without complications.

Impetigo herpetiformis, also known as pustular psoriasis of pregnancy, is an exceedingly rare gestational dermatosis that typically manifests in the third trimester and can be life-threatening for both the mother and fetus. The term was first used in 1872 to describe 5 pregnant women with extensive acute pustular eruptions, all in unstable condition; 4 (80%)of the cases resulted in maternal death, and all resulted in fetal death.¹ Impetigo herpetiformis is characterized by pruritic and painful erythematous patches studded at the periphery with subcorneal pustules. Eruptions usually occur in the flexural areas and spread centrifugally, with extension of the lesions peripherally as the center erodes and crusts. Sparing of the face, palms, and soles is expected, and mucosal involvement is rare. Generalized involvement and exfoliation may occur in extreme cases.² While IH typically manifests during the third trimester, it may occur any time throughout pregnancy or immediately postpartum.³ A few cases have been reported in the puerperium.² Common symptoms include fever, chills, malaise, anorexia, nausea, vomiting, diarrhea, and arthralgias. Less common complications include hypoalbuminemia and severe hypocalcemia leading to tetany, seizures, and delirium.^2,3 While maternal mortality is uncommon, fetal mortality often is a more pressing risk and is attributed to placental insufficiency.^3,4 For this reason, early delivery commonly is considered in severe cases.

Whether IH is a separate entity or a variant of pustular psoriasis remains heavily debated. Although the histopathology of IH is identical to pustular psoriasis, the lack of a personal and family history of psoriasis, symptom resolution with delivery, and possible recurrence during successive pregnancies help differentiate IH from generalized pustular psoriasis.^2,5 Earlier onset, diffuse involvement, faster progression, and recurrence in subsequent pregnancies all have been linked to a worse prognosis.⁴

The differential diagnosis for IH includes acute generalized exanthematous pustulosis, pemphigoid gestationis, dermatitis herpetiformis, and subcorneal pustular dermatosis. Acute generalized exanthematous pustulosis is an uncommon severe cutaneous drug reaction characterized by the sudden onset of numerous sterile pustules on erythematous skin within 48 hours of exposure. The most common offending medications include pristinamycin and beta-lactam antibiotics. A high fever, neutrophilic leukocytosis, and hypocalcemia often accompany acute generalized exanthematous pustulosis.⁶ Prompt diagnosis and withdrawal of the offending drug as well as supportive care and symptomatic treatment are crucial for disease management, as systemic symptoms and even organ involvement may occur.⁶

Pemphigoid gestationis, also known as gestational pemphigoid or herpes gestationis, is a rare autoimmune blistering disorder that primarily affects pregnant women. It typically manifests in the second or third trimester or shortly after delivery. Clinically, it manifests as an intensely pruritic polymorphic eruption of urticarial papules and plaques accompanied by vesicles and bullae and often is distributed on the abdomen and extends to other body regions. Although the exact etiology is unknown, pemphigoid gestationis is caused by autoantibodies targeting the BP180 and BP230 hemidesmosomal proteins.⁷ Treatment usually involves systemic corticosteroids and may require additional immunosuppressive therapy. In most cases, patients see resolution within 6 months of delivery.⁷

Dermatitis herpetiformis is a chronic autoimmune blistering skin disorder characterized by intensely pruritic, grouped vesicles and papules, often distributed symmetrically on extensor surfaces such as the elbows, knees, buttocks, and back. It is closely associated with celiac disease and is triggered by gluten ingestion in genetically predisposed individuals with human leukocyte antigen DQ2 and DQ8 haplotypes. Dermatitis herpetiformis is caused by deposition of IgA antibodies that target tissue transglutaminase 3 at the dermal papillae, leading to inflammation and blister formation. ⁸ Treatment typically involves a gluten-free diet and medications such as dapsone to alleviate symptoms and prevent recurrence.

Subcorneal pustular dermatosis, also known as Sneddon-Wilkinson disease, is a rare chronic relapsing pustular dermatosis characterized by sterile superficial pustules arranged in annular or circinate patterns on erythematous plaques. It predominantly affects middleaged women and often is associated with underlying conditions such as IgA gammopathy or monoclonal gammopathy of undetermined significance. The pathogenesis remains unclear, but immune dysregulation is thought to play a role. Some authors still question whether subcorneal pustular dermatosis is a distinct entity from pustular psoriasis.^4,5,12 Dapsone is the preferred first-line treatment, with adjunct therapies including topical or systemic corticosteroids, other immunosuppressive agents, tumor necrosis factor inhibitors, and UV light therapy.⁹

Definitive management of IH is achieved through early delivery; however, systemic corticosteroids often are used in varying doses to control the disease and to extend the pregnancy period closer to term or until delivery is considered viable. Additional therapies that can be considered include infliximab, cyclosporine, and topical corticosteroids, in conjunction with fluid and electrolyte maintenance.^2,4,10 If symptoms persist despite supportive care and pharmacologic intervention, induction of labor or termination of pregnancy may be indicated. In nonbreastfeeding postpartum mothers with persistent disease, therapies commonly used in generalized pustular psoriasis may be given.¹¹

THE DIAGNOSIS: Impetigo Herpetiformis

Histopathology revealed epidermal acanthosis and spongiosis with overlying parakeratosis associated with subcorneal and intracorneal neutrophils, papillary dermal edema, and dermal mixed inflammation with neutrophils and eosinophils. Both direct immunofluorescence and periodic acid–Schiff studies were negative. Blood and pustule cultures were sterile and the skin flora were normal. Based on these findings, a diagnosis of impetigo herpetiformis (IH) was made. The condition improved with systemic and topical steroids, supportive care, and an intravenous infusion of infliximab 5 mg/kg. At 3 weeks’ follow-up, the patient demonstrated near-complete resolution and later delivered successfully at 40 weeks’ gestation without complications.

Impetigo herpetiformis, also known as pustular psoriasis of pregnancy, is an exceedingly rare gestational dermatosis that typically manifests in the third trimester and can be life-threatening for both the mother and fetus. The term was first used in 1872 to describe 5 pregnant women with extensive acute pustular eruptions, all in unstable condition; 4 (80%)of the cases resulted in maternal death, and all resulted in fetal death.¹ Impetigo herpetiformis is characterized by pruritic and painful erythematous patches studded at the periphery with subcorneal pustules. Eruptions usually occur in the flexural areas and spread centrifugally, with extension of the lesions peripherally as the center erodes and crusts. Sparing of the face, palms, and soles is expected, and mucosal involvement is rare. Generalized involvement and exfoliation may occur in extreme cases.² While IH typically manifests during the third trimester, it may occur any time throughout pregnancy or immediately postpartum.³ A few cases have been reported in the puerperium.² Common symptoms include fever, chills, malaise, anorexia, nausea, vomiting, diarrhea, and arthralgias. Less common complications include hypoalbuminemia and severe hypocalcemia leading to tetany, seizures, and delirium.^2,3 While maternal mortality is uncommon, fetal mortality often is a more pressing risk and is attributed to placental insufficiency.^3,4 For this reason, early delivery commonly is considered in severe cases.

Whether IH is a separate entity or a variant of pustular psoriasis remains heavily debated. Although the histopathology of IH is identical to pustular psoriasis, the lack of a personal and family history of psoriasis, symptom resolution with delivery, and possible recurrence during successive pregnancies help differentiate IH from generalized pustular psoriasis.^2,5 Earlier onset, diffuse involvement, faster progression, and recurrence in subsequent pregnancies all have been linked to a worse prognosis.⁴

The differential diagnosis for IH includes acute generalized exanthematous pustulosis, pemphigoid gestationis, dermatitis herpetiformis, and subcorneal pustular dermatosis. Acute generalized exanthematous pustulosis is an uncommon severe cutaneous drug reaction characterized by the sudden onset of numerous sterile pustules on erythematous skin within 48 hours of exposure. The most common offending medications include pristinamycin and beta-lactam antibiotics. A high fever, neutrophilic leukocytosis, and hypocalcemia often accompany acute generalized exanthematous pustulosis.⁶ Prompt diagnosis and withdrawal of the offending drug as well as supportive care and symptomatic treatment are crucial for disease management, as systemic symptoms and even organ involvement may occur.⁶

Pemphigoid gestationis, also known as gestational pemphigoid or herpes gestationis, is a rare autoimmune blistering disorder that primarily affects pregnant women. It typically manifests in the second or third trimester or shortly after delivery. Clinically, it manifests as an intensely pruritic polymorphic eruption of urticarial papules and plaques accompanied by vesicles and bullae and often is distributed on the abdomen and extends to other body regions. Although the exact etiology is unknown, pemphigoid gestationis is caused by autoantibodies targeting the BP180 and BP230 hemidesmosomal proteins.⁷ Treatment usually involves systemic corticosteroids and may require additional immunosuppressive therapy. In most cases, patients see resolution within 6 months of delivery.⁷

Dermatitis herpetiformis is a chronic autoimmune blistering skin disorder characterized by intensely pruritic, grouped vesicles and papules, often distributed symmetrically on extensor surfaces such as the elbows, knees, buttocks, and back. It is closely associated with celiac disease and is triggered by gluten ingestion in genetically predisposed individuals with human leukocyte antigen DQ2 and DQ8 haplotypes. Dermatitis herpetiformis is caused by deposition of IgA antibodies that target tissue transglutaminase 3 at the dermal papillae, leading to inflammation and blister formation. ⁸ Treatment typically involves a gluten-free diet and medications such as dapsone to alleviate symptoms and prevent recurrence.

Subcorneal pustular dermatosis, also known as Sneddon-Wilkinson disease, is a rare chronic relapsing pustular dermatosis characterized by sterile superficial pustules arranged in annular or circinate patterns on erythematous plaques. It predominantly affects middleaged women and often is associated with underlying conditions such as IgA gammopathy or monoclonal gammopathy of undetermined significance. The pathogenesis remains unclear, but immune dysregulation is thought to play a role. Some authors still question whether subcorneal pustular dermatosis is a distinct entity from pustular psoriasis.^4,5,12 Dapsone is the preferred first-line treatment, with adjunct therapies including topical or systemic corticosteroids, other immunosuppressive agents, tumor necrosis factor inhibitors, and UV light therapy.⁹

Definitive management of IH is achieved through early delivery; however, systemic corticosteroids often are used in varying doses to control the disease and to extend the pregnancy period closer to term or until delivery is considered viable. Additional therapies that can be considered include infliximab, cyclosporine, and topical corticosteroids, in conjunction with fluid and electrolyte maintenance.^2,4,10 If symptoms persist despite supportive care and pharmacologic intervention, induction of labor or termination of pregnancy may be indicated. In nonbreastfeeding postpartum mothers with persistent disease, therapies commonly used in generalized pustular psoriasis may be given.¹¹

Fluoroscopy is an imaging technique that allows for real-time visualization of internal structures in the body using continuous radiography beams. More than 1 million fluoroscopy-guided procedures are performed annually in the United States.¹ Utilization of these procedures continues to increase, and so does the probability of related complications, as prolonged exposure to ionizing radiation can cause skin injuries.² Fortunately, the incidence of radiation-induced skin injuries compared with the total number of fluoroscopic procedures performed remains small,² although one study suggested the incidence may be as high as 8.9% in at-risk populations.³

Radiation dermatitis is well recognized in dermatology as a complication of oncologic management; however, radiation dermatitis as a complication of fluoroscopic procedures is underrecognized.⁴ Fluoroscopy-induced radiation dermatitis can be categorized as acute, subacute, or chronic.⁵ Common fluoroscopic procedures that have been associated with fluoroscopy-induced radiation dermatitis include interventional cardiac procedures, neurovascular procedures, transjugular intrahepatic portosystemic shunt procedures, and endovascular abdominal aortic aneurysm repairs.^6,7

Patients with fluoroscopy-induced radiation dermatitis, particularly fluoroscopy-induced chronic radiation dermatitis (FICRD), can present to dermatology up to several years after the initial fluoroscopy procedure with no awareness of the association between the procedure and their skin findings. This presents a diagnostic challenge, and FICRD often is overlooked.^5,8-10

We conducted a literature search of PubMed articles indexed for MEDLINE using the search terms ­fluoroscopy and dermatitis. In this reappraisal, we will provide a comprehensive overview of fluoroscopy-induced ­radiation dermatitis with an emphasis on FICRD, covering its clinical manifestations, pathophysiology, risk factors, ­differential diagnosis, histology, and management. The aim of this review is to highlight the salient features and mimickers of FICRD and inform readers how to approach suspected cases, leading to accurate diagnosis and ­effective management.

Pathophysiology 

Fluoroscopy-induced radiation dermatitis is the result of dose-dependent radiation-induced tissue damage. As the peak skin dosage (PSD) of radiation increases over the course of a procedure or multiple procedures, the severity of skin injury predictably increases. During fluoroscopic procedures, the standard irradiation dosage ranges from 0.02 Gy/min to 0.05 Gy/min.¹¹ Transient skin changes may start to be seen around 2 Gy of cumulative exposure. Fluoroscopic procedures typically range in duration from 60 to 120 minutes; however, complex cases may exceed that. Additionally, multiple procedures performed within shorter intervals can result in greater PSD accumulation. Shorter intervals between procedures do not allow enough time for damage repair from the previous ­procedure and can result in further severe damage when the skin is re-exposed to radiation.² The American College of Radiology recommends medical follow-up after 10 Gy of cumulative exposure, while cumulative exposure above 15 Gy within a 6- to 12-month period is defined as a sentinel event, according to The Joint Commission.^12-14

Depending on the patient’s total radiation dosage during one or more procedures, the result of the tissue damage manifests differently at varying times: early skin changes are categorized as fluoroscopy-induced acute radiation dermatitis, and late skin changes are categorized as FICRD (Table 1).

Clinical Manifestations

Acute radiation dermatitis from fluoroscopic procedures manifests within hours to days up to 90 days following radiation exposure and can be characterized by erythema with blistering, desquamation, epilation, pigmentation changes, and even necrosis if the accumulated dosage exceeds 15 Gy.¹⁵ Chronic radiation dermatitis (which as related to fluoroscopic procedures is termed FICRD) has a longer onset of weeks to years and is clinically characterized by telangiectasias, permanent erythema, dermal atrophy, or ulcerations. Clinically, subacute radiation dermatitis shares features of both acute and chronic radiation dermatitis; therefore, it is differentiated based on its histologic features.^5,16

Although fluoroscopy-induced acute radiation dermatitis (Table 1) may precede FICRD, acute manifestations of fluoroscopy-related dermatitis can be subtle and often manifest in areas not easily visualized. Because referrals to dermatologists for full-skin examinations after fluoroscopy procedures are not standard, patients may not be aware of the association between these procedures and the development of skin lesions. Nonetheless, some patients may report a history of skin changes such as redness days or weeks after a fluoroscopic procedure with accompanying pain and pruritus limited to the fluoroscopy-exposed region, which tend to self-resolve.¹⁷ The risk for FICRD is thought to increase if a history of fluoroscopy-induced acute radiation dermatitis is present.¹⁸

The location of the skin findings correlates to the area exposed to prolonged radiation during the procedure(s). The most common areas include the scapular and subscapular regions, the right lateral trunk inferior to the axilla, the mid back, and the right anterolateral chest.^16,19,20 These regions are associated with more complex (eg, cardiac) procedures that have been reported to lead to prolonged radiation exposure. The skin findings in FICRD are described as geometric, corresponding to the squarish or rectangular radiography beam that is directed at the patient. Additionally, radiography beams spread outward as they travel in space; therefore, skin injuries are common at the region more distal to the path of origination of the beam.^21-23 Subsequently, a geometric, dyspigmented, indurated or atrophic plaque with telangiectasias and erosions or ulcerations with progressive worsening is a common manifestation of FICRD.^5,16,23 Patients also commonly present with pruritus or severe pain associated with the lesion.^24,25  

Dermatologic Manifestations of FICRD

Skin responses seen weeks to years after a fluoroscopic procedure and typically after cumulative radiation exposure of 10 Gy or greater are categorized as FICRD (Table 2). These changes also can be clinically graded based on the Radiation Therapy Oncology Group classification of radiation dermatitis (Tables 3 and 4).²⁶ Chronic changes in the skin largely result from remodeling of the vasculature and the subcutaneous tissue over time. Unlike acute changes, chronic changes typically persist and continue to worsen.²⁷

Telangiectasias—Anywhere from months to 1 year after exposure to 10 Gy of radiation, proliferation of atypical superficial vessels in the dermis can be seen, typically manifesting as telangiectasias on physical examination. Telangiectasias can increase with time and can even exhibit a dose-dependent relationship to the radiation exposure.²⁸

Atrophy—Atrophic-appearing skin after radiation exposure is the result of direct injury to both the epidermis and fibroblasts in the dermis. The destruction of keratinocytes leads to a thin epidermis, and destruction of dermal fibroblasts causes insufficient collagen production.²⁹ Clinically, this process manifests as an atrophic plaque that can be seen 12 weeks to 1 year after the procedure. 

Fibrosis—Approximately 1 year after the exposure, the initial damage can lead to disruption of molecular pathways, causing fibrosis. Transforming growth factor (TGF) β1 is the main factor involved.²⁹ Damage to the endothelial cells results in increased TGF-β1 levels, which causes increased stimulation of remaining atypical fibroblasts and thus increased irregular collagen deposition.³⁰ Further adding to this knowledge, Wei et al³¹ recently proposed that damage to the epidermal keratinocytes leads to disruption of yes-associated protein 1, which is a protective factor released from keratinocytes that regulates the dermal fibroblasts. However, extensive damage to the keratinocytes can lead to lower yes-associated protein 1 levels and its downstream activity, leading to increased levels of TGF-β1 and fibroblast activity.³¹ Clinically, this fibrotic stage is seen as indurated plaques in patients. 

Necrosis—There are 2 forms of necrosis that can be seen. Ischemic dermal necrosis typically occurs in the acute phase after 10 weeks and approximately 18 Gy of cumulative exposure. It results from substantial skin damage, including microvascular damage and reduction in dermal capillaries, leading to ischemia of the tissue.² Late dermal necrosis is the process seen in the chronic stage of FICRD and radiation dermatitis not related to ­fluoroscopy. It results from the inability of the fibrotic dermis to vascularly support the epidermis above it.² It can be seen anywhere from 1 to 4 years after the procedure. This stage clinically manifests as worsening ulcerations with major pain and increased risk for secondary infections.¹⁶ 

Dyspigmentation—Dyspigmentation at the site of the radiation exposure can be seen acutely and chronically. Dosage above 15 to 18 Gy can lead to destruction of melanocytes, which can cause hypopigmentation in exposed areas. However, melanocytes are relatively resistant to radiation; therefore, dosages below the threshold of destruction of 15 to 18 Gy can cause melanocytic hyperactivity leading to hyperpigmentation.³² Hence, pigmentary changes can vary greatly. Classically, a central area of hypopigmentation with surrounding hyperpigmentation is seen.

Histology 

Histologic appearance of radiation dermatitis varies depending on its stage. Acute radiation dermatitis primarily demonstrates superficial dermal edema, damage to the basal cell layer, small vessel dilation with thrombi, and hemorrhage along with a sparse inflammatory cell infiltrate.³³ Histology typically is the only way to characterize subacute radiation dermatitis.⁵ Lichenoid tissue reaction is its characteristic feature. Mononuclear cells are found adjected to necrotic keratinocytes along with prominent vacuolization of the basal cell layer.³³

The key histologic features of chronic radiation dermatitis include epidermal atrophy, hyperkeratosis, telangiectasias, loss of adnexal structures, and dermal fibrosis along with sparse atypical stellate fibroblasts.³⁴ However, clinical context of fluoroscopic exposure is required for the dermatopathologist to differentiate chronic radiation dermatitis from its histologic differential of morphea and lichen sclerosus. In a cross-sectional study, only 1 of 6 cases (16.7%) was correctly diagnosed as chronic radiation dermatitis in the absence of correlating clinical history.³⁵ 

Risk Factors for FICRD 

Since the diagnosis of FICRD can be a clinical challenge, understanding the risk factors can be helpful. The general likelihood of developing FICRD is related to the duration, frequency, interval, intensity, and area of radiation exposure. Procedures exceeding the normal duration of 60 to 120 minutes have been well documented as a substantial risk factor for radiation dermatitis and FICRD.^36-38 The risk tends to be higher in longer procedures because they result in more radiation exposure and higher accumulated PSD. Obesity (ie, body mass index >26) is the major risk factor that has been associated with longer procedure times, as higher radiation dosages are necessary to penetrate the body of a larger patient and a larger skin surface area is exposed.^37-39

Other risk factors associated with FICRD relate to how prone a patient is to radiation-induced DNA damage. Older patients are at higher risk due to lower intrinsic ability of the tissue to repair itself.¹¹ Patients with a history of connective tissue diseases—particularly lupus, scleroderma, and mixed connective tissue disease—are at an increased risk.⁴⁰ Furthermore, patients with genetic disorders that impair DNA repair are more susceptible to radiation-induced DNA damage; therefore, patients with ataxia-telangiectasia, xeroderma pigmentosum, Fanconi anemia, and hereditary nevoid basal cell carcinoma are at higher risk for FICRD.³⁹ Similarly, medications that can affect DNA repair also have been shown to be risk factors. These medications include chemotherapeutic agents such as actinomycin D, cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil.^2,39 Diabetes, hyperthyroidism, and tobacco use also have been shown to increase a patient’s risk for FICRD.³⁹ It also is reasonable to believe that patients with defects in fibroblasts or with elastin or collagen disorders (eg, Ehlers-Danlos syndrome) would be at higher risk, but there are no known studies highlighting the association in the literature.

Differential Diagnosis of FICRD 

Acute allergic or irritant contact dermatitis manifests with a localized area of erythematous skin accompanied by pruritus.⁴¹ Patients with FICRD can present with a localized area of erythema and hyperpigmentation with minimal atrophy. The lesion may accompany substantial pruritus, which can favor the more common diagnosis of contact dermatitis.^35,42,43

Fixed-drug eruption manifests as a well-defined, hyperpigmented plaque in a fixed location that occurs upon ingestion of a drug.⁴⁴ Fluoroscopy-induced chronic radiation dermatitis lesions are well demarcated and geometrically shaped and therefore can mimic lesions seen in fixed-drug eruptions.⁴⁵ Additionally, the patient population undergoing fluoroscopic procedures tends to have major comorbidities requiring multiple medications.⁴

Decubitus ulcers are a result of vascular compromise to an area of skin due to constant pressure and are most commonly seen in the sacral region of patients with ­obesity.⁴⁶ Ulcerated FICRD lesions can manifest on the lower midback. These lesions can be seen after endovascular repair of abdominal aortic aneurysm or prostatic artery embolization.^20,21 The location of these lesions can mimic decubitus ulcers if fluoroscopic history is unknown. As mentioned, obesity also increases the risk for FICRD. 

Morphea can manifest as a localized area of induration and hyperpigmentation of the skin.⁴⁷ When FICRD has progressed to dermal fibrosis, patients can present with indurated plaques without ulcerations, which can be hard to differentiate from morphea.^16,48 However, the presence of ulcerations or hyperkeratosis can differentiate morphea from FICRD.¹⁶

Ultimately, it is the location of FICRD lesions that remains the biggest diagnostic clue. Any suspicious lesion present on the scapular or subscapular areas, anterolateral chest, and/or mid back should prompt an investigation into recent or remote history of fluoroscopic procedures. 

Management of FICRD

Diagnosis of FICRD should be made clinically based on the history and physical examination whenever possible, since a biopsy is not recommended.³⁵ Wound healing in FICRD is delayed, and biopsies can lead to ulcerations or secondary infections.¹⁷ Therefore, it is important to remain suspicious for FICRD. Management of FICRD should correspond to the clinical findings outlined by a recent Delphi consensus survey.⁴⁹ Regardless, the core of FICRD management framework should always include good hygiene, maintenance of skin hydration to improve epithelialization, and sufficient photoprotection.^49,50

Among the first signs of FICRD are telangiectasias. Although asymptomatic, their appearance can be distressing for patients. Pulsed dye laser therapy is a first-line option that has been studied and has shown clinical efficacy for treatment of telangiectasias and vascular changes in patients with FICRD.^49,51

If patients develop fibrotic changes, treatment options are limited. Fibrosis is hard to reverse, and the management approach is limited to symptomatic relief. Mechanical and deep-friction massages have been shown to be effective at reducing skin induration in patients.⁵² Fractional ablative lasers also may be utilized for skin contractures, especially if range of motion is affected.^53,54 Although it comes with its own challenges, autologous fat grafting has shown promise in reducing postradiation fibrosis and inducing angiogenesis in tissue.⁵⁵ Oral pentoxifylline also has shown mild efficacy, as it may be able to suppress TGF-β1 levels.⁵³ However, prevention of fibrotic changes may be the most important. Wei et al³¹ suggested that low-dose oral prednisolone at 5 mg twice daily for 3 weeks might be an option to prevent the progression of skin changes and even reverse fibrosis to an extent; however, further evidence regarding its efficacy still is necessary. Additionally, no evidence was identified to support the use of topical corticosteroids for fibrotic changes seen in FICRD.⁵⁶

Patients with FICRD or even acute radiation dermatitis after fluoroscopy tend to develop superficial ulcerations from minor traumas. Good wound hygiene, antiseptic care, and absorbent dressings, such as hydrogel and hydrocolloid, may be sufficient for treating these wounds, as seen in the Figure.^42,48 However, once patients develop refractory ulcerations or necrosis, treatment options are then limited to surgical removal with a flap or graft.^5,33,42,45
 

Risk for basal cell carcinomas and squamous cell carcinomas is higher in patients with radiation exposure; however, the exact risk from fluoroscopic procedures is unknown. One study demonstrated an increased risk of 6.9% in development of skin cancer after a median radiation exposure of 15.5 Gy and a mean latency period of 38.3 years,⁵⁷ and in another retrospective study, the risk was higher in Fitzpatrick skin types I and II.⁵⁸ Unlike the development of radiodermatitis itself, which shows a dose-dependent response, development of skin cancers follows a stochastic pattern (not dose dependent).⁵⁹ Therefore, it is important to identify these high-risk patients and establish follow-up.

Conclusion

Fluoroscopy-induced chronic radiation dermatitis can be a diagnostic challenge, as skin changes may not be readily associated with the procedure by patients. Therefore, any lesion with a geometric shape and accompanying chronic radiation dermatitis features located on the scapular or subscapular areas, anterolateral chest, and midback should prompt an investigation into history of fluoroscopic procedures. Treatment of chronic skin changes in FICRD depends on the clinical manifestations. Good hygiene, skin hydration, and sufficient photoprotection are crucial. Finally, long-term monitoring with skin examinations is important to assess for the development of skin cancers in the treated area.

Fluoroscopy is an imaging technique that allows for real-time visualization of internal structures in the body using continuous radiography beams. More than 1 million fluoroscopy-guided procedures are performed annually in the United States.¹ Utilization of these procedures continues to increase, and so does the probability of related complications, as prolonged exposure to ionizing radiation can cause skin injuries.² Fortunately, the incidence of radiation-induced skin injuries compared with the total number of fluoroscopic procedures performed remains small,² although one study suggested the incidence may be as high as 8.9% in at-risk populations.³

Radiation dermatitis is well recognized in dermatology as a complication of oncologic management; however, radiation dermatitis as a complication of fluoroscopic procedures is underrecognized.⁴ Fluoroscopy-induced radiation dermatitis can be categorized as acute, subacute, or chronic.⁵ Common fluoroscopic procedures that have been associated with fluoroscopy-induced radiation dermatitis include interventional cardiac procedures, neurovascular procedures, transjugular intrahepatic portosystemic shunt procedures, and endovascular abdominal aortic aneurysm repairs.^6,7

Patients with fluoroscopy-induced radiation dermatitis, particularly fluoroscopy-induced chronic radiation dermatitis (FICRD), can present to dermatology up to several years after the initial fluoroscopy procedure with no awareness of the association between the procedure and their skin findings. This presents a diagnostic challenge, and FICRD often is overlooked.^5,8-10

We conducted a literature search of PubMed articles indexed for MEDLINE using the search terms ­fluoroscopy and dermatitis. In this reappraisal, we will provide a comprehensive overview of fluoroscopy-induced ­radiation dermatitis with an emphasis on FICRD, covering its clinical manifestations, pathophysiology, risk factors, ­differential diagnosis, histology, and management. The aim of this review is to highlight the salient features and mimickers of FICRD and inform readers how to approach suspected cases, leading to accurate diagnosis and ­effective management.

Pathophysiology 

Fluoroscopy-induced radiation dermatitis is the result of dose-dependent radiation-induced tissue damage. As the peak skin dosage (PSD) of radiation increases over the course of a procedure or multiple procedures, the severity of skin injury predictably increases. During fluoroscopic procedures, the standard irradiation dosage ranges from 0.02 Gy/min to 0.05 Gy/min.¹¹ Transient skin changes may start to be seen around 2 Gy of cumulative exposure. Fluoroscopic procedures typically range in duration from 60 to 120 minutes; however, complex cases may exceed that. Additionally, multiple procedures performed within shorter intervals can result in greater PSD accumulation. Shorter intervals between procedures do not allow enough time for damage repair from the previous ­procedure and can result in further severe damage when the skin is re-exposed to radiation.² The American College of Radiology recommends medical follow-up after 10 Gy of cumulative exposure, while cumulative exposure above 15 Gy within a 6- to 12-month period is defined as a sentinel event, according to The Joint Commission.^12-14

Depending on the patient’s total radiation dosage during one or more procedures, the result of the tissue damage manifests differently at varying times: early skin changes are categorized as fluoroscopy-induced acute radiation dermatitis, and late skin changes are categorized as FICRD (Table 1).

Clinical Manifestations

Acute radiation dermatitis from fluoroscopic procedures manifests within hours to days up to 90 days following radiation exposure and can be characterized by erythema with blistering, desquamation, epilation, pigmentation changes, and even necrosis if the accumulated dosage exceeds 15 Gy.¹⁵ Chronic radiation dermatitis (which as related to fluoroscopic procedures is termed FICRD) has a longer onset of weeks to years and is clinically characterized by telangiectasias, permanent erythema, dermal atrophy, or ulcerations. Clinically, subacute radiation dermatitis shares features of both acute and chronic radiation dermatitis; therefore, it is differentiated based on its histologic features.^5,16

Although fluoroscopy-induced acute radiation dermatitis (Table 1) may precede FICRD, acute manifestations of fluoroscopy-related dermatitis can be subtle and often manifest in areas not easily visualized. Because referrals to dermatologists for full-skin examinations after fluoroscopy procedures are not standard, patients may not be aware of the association between these procedures and the development of skin lesions. Nonetheless, some patients may report a history of skin changes such as redness days or weeks after a fluoroscopic procedure with accompanying pain and pruritus limited to the fluoroscopy-exposed region, which tend to self-resolve.¹⁷ The risk for FICRD is thought to increase if a history of fluoroscopy-induced acute radiation dermatitis is present.¹⁸

The location of the skin findings correlates to the area exposed to prolonged radiation during the procedure(s). The most common areas include the scapular and subscapular regions, the right lateral trunk inferior to the axilla, the mid back, and the right anterolateral chest.^16,19,20 These regions are associated with more complex (eg, cardiac) procedures that have been reported to lead to prolonged radiation exposure. The skin findings in FICRD are described as geometric, corresponding to the squarish or rectangular radiography beam that is directed at the patient. Additionally, radiography beams spread outward as they travel in space; therefore, skin injuries are common at the region more distal to the path of origination of the beam.^21-23 Subsequently, a geometric, dyspigmented, indurated or atrophic plaque with telangiectasias and erosions or ulcerations with progressive worsening is a common manifestation of FICRD.^5,16,23 Patients also commonly present with pruritus or severe pain associated with the lesion.^24,25  

Dermatologic Manifestations of FICRD

Skin responses seen weeks to years after a fluoroscopic procedure and typically after cumulative radiation exposure of 10 Gy or greater are categorized as FICRD (Table 2). These changes also can be clinically graded based on the Radiation Therapy Oncology Group classification of radiation dermatitis (Tables 3 and 4).²⁶ Chronic changes in the skin largely result from remodeling of the vasculature and the subcutaneous tissue over time. Unlike acute changes, chronic changes typically persist and continue to worsen.²⁷

Telangiectasias—Anywhere from months to 1 year after exposure to 10 Gy of radiation, proliferation of atypical superficial vessels in the dermis can be seen, typically manifesting as telangiectasias on physical examination. Telangiectasias can increase with time and can even exhibit a dose-dependent relationship to the radiation exposure.²⁸

Atrophy—Atrophic-appearing skin after radiation exposure is the result of direct injury to both the epidermis and fibroblasts in the dermis. The destruction of keratinocytes leads to a thin epidermis, and destruction of dermal fibroblasts causes insufficient collagen production.²⁹ Clinically, this process manifests as an atrophic plaque that can be seen 12 weeks to 1 year after the procedure. 

Fibrosis—Approximately 1 year after the exposure, the initial damage can lead to disruption of molecular pathways, causing fibrosis. Transforming growth factor (TGF) β1 is the main factor involved.²⁹ Damage to the endothelial cells results in increased TGF-β1 levels, which causes increased stimulation of remaining atypical fibroblasts and thus increased irregular collagen deposition.³⁰ Further adding to this knowledge, Wei et al³¹ recently proposed that damage to the epidermal keratinocytes leads to disruption of yes-associated protein 1, which is a protective factor released from keratinocytes that regulates the dermal fibroblasts. However, extensive damage to the keratinocytes can lead to lower yes-associated protein 1 levels and its downstream activity, leading to increased levels of TGF-β1 and fibroblast activity.³¹ Clinically, this fibrotic stage is seen as indurated plaques in patients. 

Necrosis—There are 2 forms of necrosis that can be seen. Ischemic dermal necrosis typically occurs in the acute phase after 10 weeks and approximately 18 Gy of cumulative exposure. It results from substantial skin damage, including microvascular damage and reduction in dermal capillaries, leading to ischemia of the tissue.² Late dermal necrosis is the process seen in the chronic stage of FICRD and radiation dermatitis not related to ­fluoroscopy. It results from the inability of the fibrotic dermis to vascularly support the epidermis above it.² It can be seen anywhere from 1 to 4 years after the procedure. This stage clinically manifests as worsening ulcerations with major pain and increased risk for secondary infections.¹⁶ 

Dyspigmentation—Dyspigmentation at the site of the radiation exposure can be seen acutely and chronically. Dosage above 15 to 18 Gy can lead to destruction of melanocytes, which can cause hypopigmentation in exposed areas. However, melanocytes are relatively resistant to radiation; therefore, dosages below the threshold of destruction of 15 to 18 Gy can cause melanocytic hyperactivity leading to hyperpigmentation.³² Hence, pigmentary changes can vary greatly. Classically, a central area of hypopigmentation with surrounding hyperpigmentation is seen.

Histology 

Histologic appearance of radiation dermatitis varies depending on its stage. Acute radiation dermatitis primarily demonstrates superficial dermal edema, damage to the basal cell layer, small vessel dilation with thrombi, and hemorrhage along with a sparse inflammatory cell infiltrate.³³ Histology typically is the only way to characterize subacute radiation dermatitis.⁵ Lichenoid tissue reaction is its characteristic feature. Mononuclear cells are found adjected to necrotic keratinocytes along with prominent vacuolization of the basal cell layer.³³

The key histologic features of chronic radiation dermatitis include epidermal atrophy, hyperkeratosis, telangiectasias, loss of adnexal structures, and dermal fibrosis along with sparse atypical stellate fibroblasts.³⁴ However, clinical context of fluoroscopic exposure is required for the dermatopathologist to differentiate chronic radiation dermatitis from its histologic differential of morphea and lichen sclerosus. In a cross-sectional study, only 1 of 6 cases (16.7%) was correctly diagnosed as chronic radiation dermatitis in the absence of correlating clinical history.³⁵ 

Risk Factors for FICRD 

Since the diagnosis of FICRD can be a clinical challenge, understanding the risk factors can be helpful. The general likelihood of developing FICRD is related to the duration, frequency, interval, intensity, and area of radiation exposure. Procedures exceeding the normal duration of 60 to 120 minutes have been well documented as a substantial risk factor for radiation dermatitis and FICRD.^36-38 The risk tends to be higher in longer procedures because they result in more radiation exposure and higher accumulated PSD. Obesity (ie, body mass index >26) is the major risk factor that has been associated with longer procedure times, as higher radiation dosages are necessary to penetrate the body of a larger patient and a larger skin surface area is exposed.^37-39

Other risk factors associated with FICRD relate to how prone a patient is to radiation-induced DNA damage. Older patients are at higher risk due to lower intrinsic ability of the tissue to repair itself.¹¹ Patients with a history of connective tissue diseases—particularly lupus, scleroderma, and mixed connective tissue disease—are at an increased risk.⁴⁰ Furthermore, patients with genetic disorders that impair DNA repair are more susceptible to radiation-induced DNA damage; therefore, patients with ataxia-telangiectasia, xeroderma pigmentosum, Fanconi anemia, and hereditary nevoid basal cell carcinoma are at higher risk for FICRD.³⁹ Similarly, medications that can affect DNA repair also have been shown to be risk factors. These medications include chemotherapeutic agents such as actinomycin D, cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil.^2,39 Diabetes, hyperthyroidism, and tobacco use also have been shown to increase a patient’s risk for FICRD.³⁹ It also is reasonable to believe that patients with defects in fibroblasts or with elastin or collagen disorders (eg, Ehlers-Danlos syndrome) would be at higher risk, but there are no known studies highlighting the association in the literature.

Differential Diagnosis of FICRD 

Acute allergic or irritant contact dermatitis manifests with a localized area of erythematous skin accompanied by pruritus.⁴¹ Patients with FICRD can present with a localized area of erythema and hyperpigmentation with minimal atrophy. The lesion may accompany substantial pruritus, which can favor the more common diagnosis of contact dermatitis.^35,42,43

Fixed-drug eruption manifests as a well-defined, hyperpigmented plaque in a fixed location that occurs upon ingestion of a drug.⁴⁴ Fluoroscopy-induced chronic radiation dermatitis lesions are well demarcated and geometrically shaped and therefore can mimic lesions seen in fixed-drug eruptions.⁴⁵ Additionally, the patient population undergoing fluoroscopic procedures tends to have major comorbidities requiring multiple medications.⁴

Decubitus ulcers are a result of vascular compromise to an area of skin due to constant pressure and are most commonly seen in the sacral region of patients with ­obesity.⁴⁶ Ulcerated FICRD lesions can manifest on the lower midback. These lesions can be seen after endovascular repair of abdominal aortic aneurysm or prostatic artery embolization.^20,21 The location of these lesions can mimic decubitus ulcers if fluoroscopic history is unknown. As mentioned, obesity also increases the risk for FICRD. 

Morphea can manifest as a localized area of induration and hyperpigmentation of the skin.⁴⁷ When FICRD has progressed to dermal fibrosis, patients can present with indurated plaques without ulcerations, which can be hard to differentiate from morphea.^16,48 However, the presence of ulcerations or hyperkeratosis can differentiate morphea from FICRD.¹⁶

Ultimately, it is the location of FICRD lesions that remains the biggest diagnostic clue. Any suspicious lesion present on the scapular or subscapular areas, anterolateral chest, and/or mid back should prompt an investigation into recent or remote history of fluoroscopic procedures. 

Management of FICRD

Diagnosis of FICRD should be made clinically based on the history and physical examination whenever possible, since a biopsy is not recommended.³⁵ Wound healing in FICRD is delayed, and biopsies can lead to ulcerations or secondary infections.¹⁷ Therefore, it is important to remain suspicious for FICRD. Management of FICRD should correspond to the clinical findings outlined by a recent Delphi consensus survey.⁴⁹ Regardless, the core of FICRD management framework should always include good hygiene, maintenance of skin hydration to improve epithelialization, and sufficient photoprotection.^49,50

Among the first signs of FICRD are telangiectasias. Although asymptomatic, their appearance can be distressing for patients. Pulsed dye laser therapy is a first-line option that has been studied and has shown clinical efficacy for treatment of telangiectasias and vascular changes in patients with FICRD.^49,51

If patients develop fibrotic changes, treatment options are limited. Fibrosis is hard to reverse, and the management approach is limited to symptomatic relief. Mechanical and deep-friction massages have been shown to be effective at reducing skin induration in patients.⁵² Fractional ablative lasers also may be utilized for skin contractures, especially if range of motion is affected.^53,54 Although it comes with its own challenges, autologous fat grafting has shown promise in reducing postradiation fibrosis and inducing angiogenesis in tissue.⁵⁵ Oral pentoxifylline also has shown mild efficacy, as it may be able to suppress TGF-β1 levels.⁵³ However, prevention of fibrotic changes may be the most important. Wei et al³¹ suggested that low-dose oral prednisolone at 5 mg twice daily for 3 weeks might be an option to prevent the progression of skin changes and even reverse fibrosis to an extent; however, further evidence regarding its efficacy still is necessary. Additionally, no evidence was identified to support the use of topical corticosteroids for fibrotic changes seen in FICRD.⁵⁶

Patients with FICRD or even acute radiation dermatitis after fluoroscopy tend to develop superficial ulcerations from minor traumas. Good wound hygiene, antiseptic care, and absorbent dressings, such as hydrogel and hydrocolloid, may be sufficient for treating these wounds, as seen in the Figure.^42,48 However, once patients develop refractory ulcerations or necrosis, treatment options are then limited to surgical removal with a flap or graft.^5,33,42,45
 

Risk for basal cell carcinomas and squamous cell carcinomas is higher in patients with radiation exposure; however, the exact risk from fluoroscopic procedures is unknown. One study demonstrated an increased risk of 6.9% in development of skin cancer after a median radiation exposure of 15.5 Gy and a mean latency period of 38.3 years,⁵⁷ and in another retrospective study, the risk was higher in Fitzpatrick skin types I and II.⁵⁸ Unlike the development of radiodermatitis itself, which shows a dose-dependent response, development of skin cancers follows a stochastic pattern (not dose dependent).⁵⁹ Therefore, it is important to identify these high-risk patients and establish follow-up.

Conclusion

Fluoroscopy-induced chronic radiation dermatitis can be a diagnostic challenge, as skin changes may not be readily associated with the procedure by patients. Therefore, any lesion with a geometric shape and accompanying chronic radiation dermatitis features located on the scapular or subscapular areas, anterolateral chest, and midback should prompt an investigation into history of fluoroscopic procedures. Treatment of chronic skin changes in FICRD depends on the clinical manifestations. Good hygiene, skin hydration, and sufficient photoprotection are crucial. Finally, long-term monitoring with skin examinations is important to assess for the development of skin cancers in the treated area.

Fluoroscopy is an imaging technique that allows for real-time visualization of internal structures in the body using continuous radiography beams. More than 1 million fluoroscopy-guided procedures are performed annually in the United States.¹ Utilization of these procedures continues to increase, and so does the probability of related complications, as prolonged exposure to ionizing radiation can cause skin injuries.² Fortunately, the incidence of radiation-induced skin injuries compared with the total number of fluoroscopic procedures performed remains small,² although one study suggested the incidence may be as high as 8.9% in at-risk populations.³

Radiation dermatitis is well recognized in dermatology as a complication of oncologic management; however, radiation dermatitis as a complication of fluoroscopic procedures is underrecognized.⁴ Fluoroscopy-induced radiation dermatitis can be categorized as acute, subacute, or chronic.⁵ Common fluoroscopic procedures that have been associated with fluoroscopy-induced radiation dermatitis include interventional cardiac procedures, neurovascular procedures, transjugular intrahepatic portosystemic shunt procedures, and endovascular abdominal aortic aneurysm repairs.^6,7

Patients with fluoroscopy-induced radiation dermatitis, particularly fluoroscopy-induced chronic radiation dermatitis (FICRD), can present to dermatology up to several years after the initial fluoroscopy procedure with no awareness of the association between the procedure and their skin findings. This presents a diagnostic challenge, and FICRD often is overlooked.^5,8-10

We conducted a literature search of PubMed articles indexed for MEDLINE using the search terms ­fluoroscopy and dermatitis. In this reappraisal, we will provide a comprehensive overview of fluoroscopy-induced ­radiation dermatitis with an emphasis on FICRD, covering its clinical manifestations, pathophysiology, risk factors, ­differential diagnosis, histology, and management. The aim of this review is to highlight the salient features and mimickers of FICRD and inform readers how to approach suspected cases, leading to accurate diagnosis and ­effective management.

Pathophysiology 

Fluoroscopy-induced radiation dermatitis is the result of dose-dependent radiation-induced tissue damage. As the peak skin dosage (PSD) of radiation increases over the course of a procedure or multiple procedures, the severity of skin injury predictably increases. During fluoroscopic procedures, the standard irradiation dosage ranges from 0.02 Gy/min to 0.05 Gy/min.¹¹ Transient skin changes may start to be seen around 2 Gy of cumulative exposure. Fluoroscopic procedures typically range in duration from 60 to 120 minutes; however, complex cases may exceed that. Additionally, multiple procedures performed within shorter intervals can result in greater PSD accumulation. Shorter intervals between procedures do not allow enough time for damage repair from the previous ­procedure and can result in further severe damage when the skin is re-exposed to radiation.² The American College of Radiology recommends medical follow-up after 10 Gy of cumulative exposure, while cumulative exposure above 15 Gy within a 6- to 12-month period is defined as a sentinel event, according to The Joint Commission.^12-14

Depending on the patient’s total radiation dosage during one or more procedures, the result of the tissue damage manifests differently at varying times: early skin changes are categorized as fluoroscopy-induced acute radiation dermatitis, and late skin changes are categorized as FICRD (Table 1).

Clinical Manifestations

Acute radiation dermatitis from fluoroscopic procedures manifests within hours to days up to 90 days following radiation exposure and can be characterized by erythema with blistering, desquamation, epilation, pigmentation changes, and even necrosis if the accumulated dosage exceeds 15 Gy.¹⁵ Chronic radiation dermatitis (which as related to fluoroscopic procedures is termed FICRD) has a longer onset of weeks to years and is clinically characterized by telangiectasias, permanent erythema, dermal atrophy, or ulcerations. Clinically, subacute radiation dermatitis shares features of both acute and chronic radiation dermatitis; therefore, it is differentiated based on its histologic features.^5,16

Although fluoroscopy-induced acute radiation dermatitis (Table 1) may precede FICRD, acute manifestations of fluoroscopy-related dermatitis can be subtle and often manifest in areas not easily visualized. Because referrals to dermatologists for full-skin examinations after fluoroscopy procedures are not standard, patients may not be aware of the association between these procedures and the development of skin lesions. Nonetheless, some patients may report a history of skin changes such as redness days or weeks after a fluoroscopic procedure with accompanying pain and pruritus limited to the fluoroscopy-exposed region, which tend to self-resolve.¹⁷ The risk for FICRD is thought to increase if a history of fluoroscopy-induced acute radiation dermatitis is present.¹⁸

The location of the skin findings correlates to the area exposed to prolonged radiation during the procedure(s). The most common areas include the scapular and subscapular regions, the right lateral trunk inferior to the axilla, the mid back, and the right anterolateral chest.^16,19,20 These regions are associated with more complex (eg, cardiac) procedures that have been reported to lead to prolonged radiation exposure. The skin findings in FICRD are described as geometric, corresponding to the squarish or rectangular radiography beam that is directed at the patient. Additionally, radiography beams spread outward as they travel in space; therefore, skin injuries are common at the region more distal to the path of origination of the beam.^21-23 Subsequently, a geometric, dyspigmented, indurated or atrophic plaque with telangiectasias and erosions or ulcerations with progressive worsening is a common manifestation of FICRD.^5,16,23 Patients also commonly present with pruritus or severe pain associated with the lesion.^24,25  

Dermatologic Manifestations of FICRD

Skin responses seen weeks to years after a fluoroscopic procedure and typically after cumulative radiation exposure of 10 Gy or greater are categorized as FICRD (Table 2). These changes also can be clinically graded based on the Radiation Therapy Oncology Group classification of radiation dermatitis (Tables 3 and 4).²⁶ Chronic changes in the skin largely result from remodeling of the vasculature and the subcutaneous tissue over time. Unlike acute changes, chronic changes typically persist and continue to worsen.²⁷

Telangiectasias—Anywhere from months to 1 year after exposure to 10 Gy of radiation, proliferation of atypical superficial vessels in the dermis can be seen, typically manifesting as telangiectasias on physical examination. Telangiectasias can increase with time and can even exhibit a dose-dependent relationship to the radiation exposure.²⁸

Atrophy—Atrophic-appearing skin after radiation exposure is the result of direct injury to both the epidermis and fibroblasts in the dermis. The destruction of keratinocytes leads to a thin epidermis, and destruction of dermal fibroblasts causes insufficient collagen production.²⁹ Clinically, this process manifests as an atrophic plaque that can be seen 12 weeks to 1 year after the procedure. 

Fibrosis—Approximately 1 year after the exposure, the initial damage can lead to disruption of molecular pathways, causing fibrosis. Transforming growth factor (TGF) β1 is the main factor involved.²⁹ Damage to the endothelial cells results in increased TGF-β1 levels, which causes increased stimulation of remaining atypical fibroblasts and thus increased irregular collagen deposition.³⁰ Further adding to this knowledge, Wei et al³¹ recently proposed that damage to the epidermal keratinocytes leads to disruption of yes-associated protein 1, which is a protective factor released from keratinocytes that regulates the dermal fibroblasts. However, extensive damage to the keratinocytes can lead to lower yes-associated protein 1 levels and its downstream activity, leading to increased levels of TGF-β1 and fibroblast activity.³¹ Clinically, this fibrotic stage is seen as indurated plaques in patients. 

Necrosis—There are 2 forms of necrosis that can be seen. Ischemic dermal necrosis typically occurs in the acute phase after 10 weeks and approximately 18 Gy of cumulative exposure. It results from substantial skin damage, including microvascular damage and reduction in dermal capillaries, leading to ischemia of the tissue.² Late dermal necrosis is the process seen in the chronic stage of FICRD and radiation dermatitis not related to ­fluoroscopy. It results from the inability of the fibrotic dermis to vascularly support the epidermis above it.² It can be seen anywhere from 1 to 4 years after the procedure. This stage clinically manifests as worsening ulcerations with major pain and increased risk for secondary infections.¹⁶ 

Dyspigmentation—Dyspigmentation at the site of the radiation exposure can be seen acutely and chronically. Dosage above 15 to 18 Gy can lead to destruction of melanocytes, which can cause hypopigmentation in exposed areas. However, melanocytes are relatively resistant to radiation; therefore, dosages below the threshold of destruction of 15 to 18 Gy can cause melanocytic hyperactivity leading to hyperpigmentation.³² Hence, pigmentary changes can vary greatly. Classically, a central area of hypopigmentation with surrounding hyperpigmentation is seen.

Histology 

Histologic appearance of radiation dermatitis varies depending on its stage. Acute radiation dermatitis primarily demonstrates superficial dermal edema, damage to the basal cell layer, small vessel dilation with thrombi, and hemorrhage along with a sparse inflammatory cell infiltrate.³³ Histology typically is the only way to characterize subacute radiation dermatitis.⁵ Lichenoid tissue reaction is its characteristic feature. Mononuclear cells are found adjected to necrotic keratinocytes along with prominent vacuolization of the basal cell layer.³³

The key histologic features of chronic radiation dermatitis include epidermal atrophy, hyperkeratosis, telangiectasias, loss of adnexal structures, and dermal fibrosis along with sparse atypical stellate fibroblasts.³⁴ However, clinical context of fluoroscopic exposure is required for the dermatopathologist to differentiate chronic radiation dermatitis from its histologic differential of morphea and lichen sclerosus. In a cross-sectional study, only 1 of 6 cases (16.7%) was correctly diagnosed as chronic radiation dermatitis in the absence of correlating clinical history.³⁵ 

Risk Factors for FICRD 

Since the diagnosis of FICRD can be a clinical challenge, understanding the risk factors can be helpful. The general likelihood of developing FICRD is related to the duration, frequency, interval, intensity, and area of radiation exposure. Procedures exceeding the normal duration of 60 to 120 minutes have been well documented as a substantial risk factor for radiation dermatitis and FICRD.^36-38 The risk tends to be higher in longer procedures because they result in more radiation exposure and higher accumulated PSD. Obesity (ie, body mass index >26) is the major risk factor that has been associated with longer procedure times, as higher radiation dosages are necessary to penetrate the body of a larger patient and a larger skin surface area is exposed.^37-39

Other risk factors associated with FICRD relate to how prone a patient is to radiation-induced DNA damage. Older patients are at higher risk due to lower intrinsic ability of the tissue to repair itself.¹¹ Patients with a history of connective tissue diseases—particularly lupus, scleroderma, and mixed connective tissue disease—are at an increased risk.⁴⁰ Furthermore, patients with genetic disorders that impair DNA repair are more susceptible to radiation-induced DNA damage; therefore, patients with ataxia-telangiectasia, xeroderma pigmentosum, Fanconi anemia, and hereditary nevoid basal cell carcinoma are at higher risk for FICRD.³⁹ Similarly, medications that can affect DNA repair also have been shown to be risk factors. These medications include chemotherapeutic agents such as actinomycin D, cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil.^2,39 Diabetes, hyperthyroidism, and tobacco use also have been shown to increase a patient’s risk for FICRD.³⁹ It also is reasonable to believe that patients with defects in fibroblasts or with elastin or collagen disorders (eg, Ehlers-Danlos syndrome) would be at higher risk, but there are no known studies highlighting the association in the literature.

Differential Diagnosis of FICRD 

Acute allergic or irritant contact dermatitis manifests with a localized area of erythematous skin accompanied by pruritus.⁴¹ Patients with FICRD can present with a localized area of erythema and hyperpigmentation with minimal atrophy. The lesion may accompany substantial pruritus, which can favor the more common diagnosis of contact dermatitis.^35,42,43

Fixed-drug eruption manifests as a well-defined, hyperpigmented plaque in a fixed location that occurs upon ingestion of a drug.⁴⁴ Fluoroscopy-induced chronic radiation dermatitis lesions are well demarcated and geometrically shaped and therefore can mimic lesions seen in fixed-drug eruptions.⁴⁵ Additionally, the patient population undergoing fluoroscopic procedures tends to have major comorbidities requiring multiple medications.⁴

Decubitus ulcers are a result of vascular compromise to an area of skin due to constant pressure and are most commonly seen in the sacral region of patients with ­obesity.⁴⁶ Ulcerated FICRD lesions can manifest on the lower midback. These lesions can be seen after endovascular repair of abdominal aortic aneurysm or prostatic artery embolization.^20,21 The location of these lesions can mimic decubitus ulcers if fluoroscopic history is unknown. As mentioned, obesity also increases the risk for FICRD. 

Morphea can manifest as a localized area of induration and hyperpigmentation of the skin.⁴⁷ When FICRD has progressed to dermal fibrosis, patients can present with indurated plaques without ulcerations, which can be hard to differentiate from morphea.^16,48 However, the presence of ulcerations or hyperkeratosis can differentiate morphea from FICRD.¹⁶

Ultimately, it is the location of FICRD lesions that remains the biggest diagnostic clue. Any suspicious lesion present on the scapular or subscapular areas, anterolateral chest, and/or mid back should prompt an investigation into recent or remote history of fluoroscopic procedures. 

Management of FICRD

Diagnosis of FICRD should be made clinically based on the history and physical examination whenever possible, since a biopsy is not recommended.³⁵ Wound healing in FICRD is delayed, and biopsies can lead to ulcerations or secondary infections.¹⁷ Therefore, it is important to remain suspicious for FICRD. Management of FICRD should correspond to the clinical findings outlined by a recent Delphi consensus survey.⁴⁹ Regardless, the core of FICRD management framework should always include good hygiene, maintenance of skin hydration to improve epithelialization, and sufficient photoprotection.^49,50

Among the first signs of FICRD are telangiectasias. Although asymptomatic, their appearance can be distressing for patients. Pulsed dye laser therapy is a first-line option that has been studied and has shown clinical efficacy for treatment of telangiectasias and vascular changes in patients with FICRD.^49,51

If patients develop fibrotic changes, treatment options are limited. Fibrosis is hard to reverse, and the management approach is limited to symptomatic relief. Mechanical and deep-friction massages have been shown to be effective at reducing skin induration in patients.⁵² Fractional ablative lasers also may be utilized for skin contractures, especially if range of motion is affected.^53,54 Although it comes with its own challenges, autologous fat grafting has shown promise in reducing postradiation fibrosis and inducing angiogenesis in tissue.⁵⁵ Oral pentoxifylline also has shown mild efficacy, as it may be able to suppress TGF-β1 levels.⁵³ However, prevention of fibrotic changes may be the most important. Wei et al³¹ suggested that low-dose oral prednisolone at 5 mg twice daily for 3 weeks might be an option to prevent the progression of skin changes and even reverse fibrosis to an extent; however, further evidence regarding its efficacy still is necessary. Additionally, no evidence was identified to support the use of topical corticosteroids for fibrotic changes seen in FICRD.⁵⁶

Patients with FICRD or even acute radiation dermatitis after fluoroscopy tend to develop superficial ulcerations from minor traumas. Good wound hygiene, antiseptic care, and absorbent dressings, such as hydrogel and hydrocolloid, may be sufficient for treating these wounds, as seen in the Figure.^42,48 However, once patients develop refractory ulcerations or necrosis, treatment options are then limited to surgical removal with a flap or graft.^5,33,42,45
 

Risk for basal cell carcinomas and squamous cell carcinomas is higher in patients with radiation exposure; however, the exact risk from fluoroscopic procedures is unknown. One study demonstrated an increased risk of 6.9% in development of skin cancer after a median radiation exposure of 15.5 Gy and a mean latency period of 38.3 years,⁵⁷ and in another retrospective study, the risk was higher in Fitzpatrick skin types I and II.⁵⁸ Unlike the development of radiodermatitis itself, which shows a dose-dependent response, development of skin cancers follows a stochastic pattern (not dose dependent).⁵⁹ Therefore, it is important to identify these high-risk patients and establish follow-up.

Conclusion

Fluoroscopy-induced chronic radiation dermatitis can be a diagnostic challenge, as skin changes may not be readily associated with the procedure by patients. Therefore, any lesion with a geometric shape and accompanying chronic radiation dermatitis features located on the scapular or subscapular areas, anterolateral chest, and midback should prompt an investigation into history of fluoroscopic procedures. Treatment of chronic skin changes in FICRD depends on the clinical manifestations. Good hygiene, skin hydration, and sufficient photoprotection are crucial. Finally, long-term monitoring with skin examinations is important to assess for the development of skin cancers in the treated area.

THE DIAGNOSIS: Idiopathic Facial Aseptic Granuloma

Histopathology showed a ruptured follicle, perifollicular granulomatous inflammation, and admixed multinucleated giant cells in the superficial dermis. The deeper tissue exhibited edema, histiocytic/granulomatous inflammation forming ill-defined loose granulomas, and a single neutrophilic microabscess (Figure). Stains for periodic acid-Schiff with diastase and acid-fast bacillus were negative for microorganisms. The clinical examination and pathology findings supported a diagnosis of idiopathic facial aseptic granuloma (IFAG).

First reported in 1999, IFAG was described using the French term pyodermite froide du visage, which translates to “cold pyoderma of the face”; however, it was renamed to represent its granulomatous characteristics and noninfectious etiology.¹ The pathogenesis of IFAG is unknown, but the leading hypothesis is that it may be a type of childhood granulomatous rosacea, given its association with relapsing chalazions, papulopustular eruptions on the face, and facial flushing.² Other hypotheses are that IFAG is idiopathic or a granulomatous response to an insect bite, minor trauma, or embryologic remnant.³

A rare condition arising in early childhood, IFAG manifests as a single or multiple, painless, erythematous or violaceous nodule(s) on the face, most often on the cheeks or eyelids.⁴ A thorough history and clinical examination often suffice for diagnosis. Dermoscopy may reveal white perifollicular halos and follicular plugs on an erythematous base with linear vessels.⁴ If diagnostic tests are performed, there are notable characteristic findings: ultrasonography often shows a well-circumscribed, hypoechoic, ovoid dermal lesion without calcifications. Bacterial, fungal, and mycobacterial cultures commonly are negative.⁴ On biopsy, histopathology may reveal granulomatous inflammation in the superficial and deep dermis, multinucleated giant cells, and surrounding lymphocytic, neutrophilic, and eosinophilic infiltration with no calcium deposits.^3,5,6 Histopathology findings for IFAG and rosacea lesions are similar; both may demonstrate folliculitis, perifollicular granulomas, and admixed lymphohistiocytic inflammation.⁷

Differentiating IFAG from other dermatologic lesions can be challenging, as the differential includes benign neoplasms (eg, dermoid cyst, chalazion, pilomatricoma, xanthoma, xanthogranuloma²) and infectious etiologies such as bacterial pyoderma and mycobacterial, fungal, and parasitic infections (eg, cutaneous leishmaniasis). Pilomatricomas, although often seen on the face or extremities in young girls, more often are well circumscribed and located in the dermis. Ultrasonography of a pilomatricoma classically shows variable foci of calcification. Xanthoma and xanthogranuloma also were considered in our case since the lesion was subtly yellowish on examination. Similar to IFAG, these conditions may manifest as single or multiple lesions. Abnormalities in the patient’s blood lipid panel or family history may be needed to diagnose xanthoma. Biopsy of a juvenile xanthogranuloma would exhibit a dense dermal nodular proliferation of histiocytic cells with a smaller number of admixed lymphocytes, neutrophils, and eosinophils, in contrast to the multiple smaller loose epithelioid granulomas seen in IFAG. Additional diagnoses in the differential for IFAG include pyogenic granuloma, Spitz nevus, nodulocystic infantile acne, granulomatous rosacea, and hemangioma.^1,3,9 In particular, granulomatous rosacea is challenging to differentiate from IFAG given the overlapping clinical findings. Multiple lesions, the presence of papules and pustules, and associated rosacea symptoms such as flushing suggest a diagnosis of granulomatous rosacea over IFAG.²

The prognosis for IFAG is excellent; most lesions self-resolve without treatment or procedural intervention within 1 year without scarring or relapse.³ Topical and oral antibiotic treatments such as metronidazole 0.75% gel or cream, oral erythromycin, oral clarithromycin, and doxycycline (in patients older than 8 years) have been used to treat IFAG with variable clinic responses.^2,3,6,8 Persistent IFAG has been treated with surgical excision.³ Our patient was treated with a combination of gentamicin ointment 0.3% and tacrolimus ointment 0.3% and experienced approximately 50% improvement in the first month of treatment.

THE DIAGNOSIS: Idiopathic Facial Aseptic Granuloma

Histopathology showed a ruptured follicle, perifollicular granulomatous inflammation, and admixed multinucleated giant cells in the superficial dermis. The deeper tissue exhibited edema, histiocytic/granulomatous inflammation forming ill-defined loose granulomas, and a single neutrophilic microabscess (Figure). Stains for periodic acid-Schiff with diastase and acid-fast bacillus were negative for microorganisms. The clinical examination and pathology findings supported a diagnosis of idiopathic facial aseptic granuloma (IFAG).

First reported in 1999, IFAG was described using the French term pyodermite froide du visage, which translates to “cold pyoderma of the face”; however, it was renamed to represent its granulomatous characteristics and noninfectious etiology.¹ The pathogenesis of IFAG is unknown, but the leading hypothesis is that it may be a type of childhood granulomatous rosacea, given its association with relapsing chalazions, papulopustular eruptions on the face, and facial flushing.² Other hypotheses are that IFAG is idiopathic or a granulomatous response to an insect bite, minor trauma, or embryologic remnant.³

A rare condition arising in early childhood, IFAG manifests as a single or multiple, painless, erythematous or violaceous nodule(s) on the face, most often on the cheeks or eyelids.⁴ A thorough history and clinical examination often suffice for diagnosis. Dermoscopy may reveal white perifollicular halos and follicular plugs on an erythematous base with linear vessels.⁴ If diagnostic tests are performed, there are notable characteristic findings: ultrasonography often shows a well-circumscribed, hypoechoic, ovoid dermal lesion without calcifications. Bacterial, fungal, and mycobacterial cultures commonly are negative.⁴ On biopsy, histopathology may reveal granulomatous inflammation in the superficial and deep dermis, multinucleated giant cells, and surrounding lymphocytic, neutrophilic, and eosinophilic infiltration with no calcium deposits.^3,5,6 Histopathology findings for IFAG and rosacea lesions are similar; both may demonstrate folliculitis, perifollicular granulomas, and admixed lymphohistiocytic inflammation.⁷

Differentiating IFAG from other dermatologic lesions can be challenging, as the differential includes benign neoplasms (eg, dermoid cyst, chalazion, pilomatricoma, xanthoma, xanthogranuloma²) and infectious etiologies such as bacterial pyoderma and mycobacterial, fungal, and parasitic infections (eg, cutaneous leishmaniasis). Pilomatricomas, although often seen on the face or extremities in young girls, more often are well circumscribed and located in the dermis. Ultrasonography of a pilomatricoma classically shows variable foci of calcification. Xanthoma and xanthogranuloma also were considered in our case since the lesion was subtly yellowish on examination. Similar to IFAG, these conditions may manifest as single or multiple lesions. Abnormalities in the patient’s blood lipid panel or family history may be needed to diagnose xanthoma. Biopsy of a juvenile xanthogranuloma would exhibit a dense dermal nodular proliferation of histiocytic cells with a smaller number of admixed lymphocytes, neutrophils, and eosinophils, in contrast to the multiple smaller loose epithelioid granulomas seen in IFAG. Additional diagnoses in the differential for IFAG include pyogenic granuloma, Spitz nevus, nodulocystic infantile acne, granulomatous rosacea, and hemangioma.^1,3,9 In particular, granulomatous rosacea is challenging to differentiate from IFAG given the overlapping clinical findings. Multiple lesions, the presence of papules and pustules, and associated rosacea symptoms such as flushing suggest a diagnosis of granulomatous rosacea over IFAG.²

The prognosis for IFAG is excellent; most lesions self-resolve without treatment or procedural intervention within 1 year without scarring or relapse.³ Topical and oral antibiotic treatments such as metronidazole 0.75% gel or cream, oral erythromycin, oral clarithromycin, and doxycycline (in patients older than 8 years) have been used to treat IFAG with variable clinic responses.^2,3,6,8 Persistent IFAG has been treated with surgical excision.³ Our patient was treated with a combination of gentamicin ointment 0.3% and tacrolimus ointment 0.3% and experienced approximately 50% improvement in the first month of treatment.

THE DIAGNOSIS: Idiopathic Facial Aseptic Granuloma

Histopathology showed a ruptured follicle, perifollicular granulomatous inflammation, and admixed multinucleated giant cells in the superficial dermis. The deeper tissue exhibited edema, histiocytic/granulomatous inflammation forming ill-defined loose granulomas, and a single neutrophilic microabscess (Figure). Stains for periodic acid-Schiff with diastase and acid-fast bacillus were negative for microorganisms. The clinical examination and pathology findings supported a diagnosis of idiopathic facial aseptic granuloma (IFAG).

First reported in 1999, IFAG was described using the French term pyodermite froide du visage, which translates to “cold pyoderma of the face”; however, it was renamed to represent its granulomatous characteristics and noninfectious etiology.¹ The pathogenesis of IFAG is unknown, but the leading hypothesis is that it may be a type of childhood granulomatous rosacea, given its association with relapsing chalazions, papulopustular eruptions on the face, and facial flushing.² Other hypotheses are that IFAG is idiopathic or a granulomatous response to an insect bite, minor trauma, or embryologic remnant.³

A rare condition arising in early childhood, IFAG manifests as a single or multiple, painless, erythematous or violaceous nodule(s) on the face, most often on the cheeks or eyelids.⁴ A thorough history and clinical examination often suffice for diagnosis. Dermoscopy may reveal white perifollicular halos and follicular plugs on an erythematous base with linear vessels.⁴ If diagnostic tests are performed, there are notable characteristic findings: ultrasonography often shows a well-circumscribed, hypoechoic, ovoid dermal lesion without calcifications. Bacterial, fungal, and mycobacterial cultures commonly are negative.⁴ On biopsy, histopathology may reveal granulomatous inflammation in the superficial and deep dermis, multinucleated giant cells, and surrounding lymphocytic, neutrophilic, and eosinophilic infiltration with no calcium deposits.^3,5,6 Histopathology findings for IFAG and rosacea lesions are similar; both may demonstrate folliculitis, perifollicular granulomas, and admixed lymphohistiocytic inflammation.⁷

Differentiating IFAG from other dermatologic lesions can be challenging, as the differential includes benign neoplasms (eg, dermoid cyst, chalazion, pilomatricoma, xanthoma, xanthogranuloma²) and infectious etiologies such as bacterial pyoderma and mycobacterial, fungal, and parasitic infections (eg, cutaneous leishmaniasis). Pilomatricomas, although often seen on the face or extremities in young girls, more often are well circumscribed and located in the dermis. Ultrasonography of a pilomatricoma classically shows variable foci of calcification. Xanthoma and xanthogranuloma also were considered in our case since the lesion was subtly yellowish on examination. Similar to IFAG, these conditions may manifest as single or multiple lesions. Abnormalities in the patient’s blood lipid panel or family history may be needed to diagnose xanthoma. Biopsy of a juvenile xanthogranuloma would exhibit a dense dermal nodular proliferation of histiocytic cells with a smaller number of admixed lymphocytes, neutrophils, and eosinophils, in contrast to the multiple smaller loose epithelioid granulomas seen in IFAG. Additional diagnoses in the differential for IFAG include pyogenic granuloma, Spitz nevus, nodulocystic infantile acne, granulomatous rosacea, and hemangioma.^1,3,9 In particular, granulomatous rosacea is challenging to differentiate from IFAG given the overlapping clinical findings. Multiple lesions, the presence of papules and pustules, and associated rosacea symptoms such as flushing suggest a diagnosis of granulomatous rosacea over IFAG.²

The prognosis for IFAG is excellent; most lesions self-resolve without treatment or procedural intervention within 1 year without scarring or relapse.³ Topical and oral antibiotic treatments such as metronidazole 0.75% gel or cream, oral erythromycin, oral clarithromycin, and doxycycline (in patients older than 8 years) have been used to treat IFAG with variable clinic responses.^2,3,6,8 Persistent IFAG has been treated with surgical excision.³ Our patient was treated with a combination of gentamicin ointment 0.3% and tacrolimus ointment 0.3% and experienced approximately 50% improvement in the first month of treatment.

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴