Cutis

Sunscreen formulations typically protect from UV radiation (290–400 nm), as this is a well-established cause of photodamage, photoaging, and skin cancer.¹ However, sunlight also consists of visible (400–700 nm) and infrared (>700 nm) radiation.² In fact, UV radiation only comprises 5% to 7% of the solar radiation that reaches the surface of the earth, while visible and infrared lights comprise 44% and 53%, respectively.³ Visible light (VL) is the only portion of the solar spectrum visible to the human eye; it penetrates the skin to a depth range of 90 to 750 µm compared to 1.5 to 90 µm for UV radiation.⁴ Visible light also may come from artificial sources such as light bulbs and digital screens. The rapidly increasing use of smartphones, tablets, laptops, and other digital screens that emit high levels of short-wavelength VL has increased concerns about the safety of these devices. Although blue light exposure from screens is small compared with the amount of exposure from the sun, there is concern about the long-term effects of excessive screen time. Recent studies have demonstrated that exposure to light emitted from electronic devices, even for as little as 1 hour, may cause reactive oxygen species generation, apoptosis, collagen degradation, and necrosis of skin cells.⁵ Visible light increases tyrosinase activity and induces immediate erythema in light-skinned individuals and long-lasting pigmentation in dark-skinned individuals.^4,6

Sunscreens consist of chemical and mineral active ingredients that contain UV filters designed to absorb, scatter, and reflect UV photons with wavelengths up to 380 nm. Historically, traditional options do not protect against the effects induced by VL, as these sunscreens use nanosized particles that help to reduce the white appearance and result in transparency of the product.⁷ To block VL, the topical agent must be visible. Tinted sunscreens (TSs) are products that combine UV and VL filters. They give a colored base coverage that is achieved by incorporating a blend of black, red, and yellow iron oxides (IOs) and/or pigmentary titanium dioxide (PTD)(ie, titanium dioxide [TD] that is not nanosized). Because TSs offer an instant glow and protect the skin from both sun and artificial light, they have become increasingly popular and have been incorporated into makeup and skin care products to facilitate daily convenient use.

The purpose of this analysis was to study current available options and product factors that may influence consumer preference when choosing a TS based on the reviewer characteristics.

Methods

The keyword sunscreen was searched in the broader category of skin care products on an online supplier of sunscreens (www.sephora.com). This supplier was chosen because, unlike other sources, specific reviewer characteristics regarding underlying skin tone also were available. The search produced 161 results. For the purpose of this analysis, only facial TSs containing IO and/or PTD were included. Each sunscreen was checked by the authors, and 58 sunscreens that met the inclusion criteria were identified and further reviewed. Descriptive data, including formulation, sun protection factor (SPF), ingredient type (chemical or physical), pigments used, shades available, additional benefits, price range, rating, and user reviews, were gathered. The authors extracted these data from the product information on the website, manufacturer claims, ratings, and reviewer comments on each of the listed sunscreens.

For each product, the content of the top 10 most helpful positive and negative reviews as voted by consumers (1160 total reviews, consisting of 1 or more comments) was analyzed. Two authors (H.D.L.G. and P.V.) coded consumer-reported comments for positive and negative descriptors into the categories of cosmetic elegance, performance, skin compatibility and tolerance, tone compatibility, and affordability. Cosmetic elegance was defined as any feature associated with skin sensation (eg, greasy), color (eg, white cast), scent, ability to blend, and overall appearance of the product on the skin. Product performance included SPF, effectiveness in preventing sunburn, coverage, and finish claims (ie, matte, glow, invisible). Skin compatibility and tolerance were represented in the reviewers’ comments and reflected how the product performed in association with underlying dermatologic conditions, skin type, and if there were any side effects such as irritation or allergic reactions. Tone compatibility referred to TS color similarity with users’ skin and shades available for individual products. Affordability reflected consumers’ perceptions of the product price. Comments may be included in multiple categories (eg, a product was noted to blend well on the skin but did not provide enough coverage). Of entries, 10% (116/1160 reviews) were coded by first author (H.D.L.G.) to ensure internal validity. Reviewer characteristics were consistently available and were used to determine the top 5 recommended products for light-, medium-, and dark-skinned individuals based on the number of 5-star ratings in each group. Porcelain, fair, and light were considered light skin tones. Medium, tan, and olive were considered medium skin tones. Deep, dark, and ebony were considered dark skin tones.

Results

Sunscreen Characteristics—Among the 161 screened products, 58 met the inclusion criteria. Four types of formulations were included: lotion, cream, liquid, and powder. Twenty-nine (50%) were creams, followed by lotions (19%), liquids (28%), and powders (3%). More than 79% (46/58) of products had a reported SPF of 30 or higher. Sunscreens with an active physical ingredient—the minerals TD and/or zinc oxide (ZO)—were most common (33/58 [57%]), followed by the chemical sunscreens avobenzone, octinoxate, oxybenzone, homosalate, octisalate, and/or octocrylene active ingredients (14/58 [24%]), and a combination of chemical and physical sunscreens (11/58 [19%]). Nearly all products (55/58 [95%]) contained pigmentary IO (red, CI 77491; yellow, CI 77492; black, CI 77499). Notably, only 38% (22/58) of products had more than 1 shade. All products had additional claims associated with being hydrating, having antiaging effects, smoothing texture, minimizing the appearance of pores, softening lines, and/or promoting even skin tone. Traditional physical sunscreens (those containing TD and/or ZO) were more expensive than chemical sunscreens, with a median price of $30. The median review rating was 4.5 of 5 stars, with a median of 2300 customer reviews per product. Findings are summarized in Table 1.

Positive Features of Sunscreens—Based on an analysis of total reviews (N=1160), cosmetic elegance was the most cited positive feature associated with TS products (31%), followed by product performance (10%). Skin compatibility and tolerance (7%), tone compatibility (7%), and affordability (7%) were cited less commonly as positive features. When negative features were cited, consumers mostly noted tone incompatibility (16%) and cosmetic elegance concerns (14%). Product performance (13%) was comparatively cited as a negative feature (Table 1). Exemplary positive comments categorized in cosmetic elegance included the subthemes of rubs in well and natural glow. Exemplary negative comments in cosmetic elegance and tone compatibility categories included the subthemes patchy/dry finish and color mismatch. Table 1 illustrates these findings.

Product Recommendations—The top 5 recommendations of the best TS for each skin tone are listed in Table 2. The mean price of the recommended products was $42 for 1 to 1.9 oz. Laura Mercier Tinted Moisturizer Oil Free Natural Skin Perfector broad spectrum SPF 20 (Laura Mercier) was the top product for all 3 groups. Similarly, of 58 products available, the same 5 products—Laura Mercier Tinted Moisturizer Oil Free Natural Skin Perfector broad spectrum SPF 20, IT Cosmetics CC+ Cream with SPF 50 (IT Cosmetics, LLC), Tarte Amazonian Clay BB Tinted Moisturizer Broad Spectrum SPF 20 (Tarte Cosmetics), NARS Pure Radiant Tinted Moisturizer Broad Spectrum SPF 30 (NARS Cosmetics), and Laura Mercier Tinted Moisturizer Natural Skin Perfector broad spectrum SPF 30—were considered the best among consumers of all skin tones, with the addition of 2 different products (bareMinerals Original Liquid Mineral Foundation Broad Spectrum SPF 20 [bareMinerals] and ILIA Super Serum Skin Tint SPF 40 Foundation [ILIA Beauty]) in the dark skin group. Notably, these products were the only ones on Sephora’s website that offered up to 30 (22 on average) different shades.

Comment

Tone Compatibility—Tinted sunscreens were created to extend the range of photoprotection into the VL spectrum. The goal of TSs is to incorporate pigments that blend in with the natural skin tone, produce a glow, and have an aesthetically pleasing appearance. To accommodate a variety of skin colors, different shades can be obtained by mixing different amounts of yellow, red, and black IO with or without PTD. The pigments and reflective compounds provide color, opacity, and a natural coverage. Our qualitative analysis provides information on the lack of diversity among shades available for TS, especially for darker skin tones. Of the 58 products evaluated, 62% (32/58) only had 1 shade. In our cohort, tone compatibility was the most commonly cited negative feature. Of note, 89% of these comments were from consumers with dark skin tones, and there was a disproportional number of reviews by darker-skinned individuals compared to users with light and medium skin tones. This is of particular importance, as TSs have been shown to protect against dermatoses that disproportionally affect individuals with skin of color. When comparing sunscreen formulations containing IO with regular mineral sunscreens, Dumbuya et al³ found that IO-containing formulations significantly protected against VL-induced pigmentation compared with untreated skin or mineral sunscreen with SPF 50 or higher in individuals with Fitzpatrick skin type IV (P<.001). Similarly, Bernstein et al⁸ found that exposing patients with Fitzpatrick skin types III and IV to blue-violet light resulted in marked hyperpigmentation that lasted up to 3 months. Visible light elicits immediate and persistent pigment darkening in individuals with Fitzpatrick skin phototype III and above via the photo-oxidation of pre-existing melanin and de novo melanogenesis.⁹ Tinted sunscreens formulated with IO have been shown to aid in the treatment of melasma and prevent hyperpigmentation in individuals with Fitzpatrick skin types IV to VI.¹⁰ Patients with darker skin tones with dermatoses aggravated or induced by VL, such as melasma and postinflammatory hyperpigmentation, may seek photoprotection provided by TS but find the lack of matching shades unappealing. The dearth of shade diversity that matches all skin tones can lead to inequities and disproportionally affect those with darker skin.

Performance—Tinted sunscreen formulations containing IO have been proven effective in protecting against high-energy VL, especially when combined synergistically with ZO.¹¹ Kaye et al¹² found that TSs containing IO and the inorganic filters TD or ZO reduced transmittance of VL more effectively than nontinted sunscreens containing TD or ZO alone or products containing organic filters. The decreased VL transmittance in the former is due to synergistic effects of the VL-scattering properties of the TD and the VL absorption properties of the IO. Similarly, Sayre et al¹³ demonstrated that IO was superior to TD and ZO in attenuating the transmission of VL. Bernstein et al¹⁴ found that darker shades containing higher percentages of IO increased the attenuation of VL to 98% compared with lighter shades attenuating 93%. This correlates with the results of prior studies highlighting the potential of TSs in protecting individuals with skin of color.³ In our cohort, comments regarding product performance and protection were mostly positive, claiming that consistent use reduced hyperpigmentation on the skin surface, giving the appearance of a more even skin tone.

Tolerability—Iron oxides are minerals known to be safe, gentle, and nontoxic on the surface of the skin.¹⁵ Two case reports of contact dermatitis due to IO have been reported.^16,17 Within our cohort, only a few of the comments (6%) described negative product tolerance or compatibility with their skin type. However, it is more likely that these incompatibilities were due to other ingredients in the product or the individuals’ underlying dermatologic conditions.

Cosmetic Elegance—Most of the sunscreens available on the market today contain micronized forms of TD and ZO particles because they have better cosmetic acceptability.¹⁸ However, their reduced size compromises the protection provided against VL whereby the addition of IO is of vital importance. According to the RealSelf Sun Safety Report, only 11% of Americans wear sunscreen daily, and 46% never wear sunscreen.¹⁹ The most common reasons consumers reported for not wearing sunscreen included not liking how it looks on the skin, forgetting to apply it, and/or believing that application is inconvenient and time-consuming. Currently, TSs have been incorporated into daily-life products such as makeup, moisturizers, and serums, making application for users easy and convenient, decreasing the necessity of using multiple products, and offering the opportunity to choose from different presentations to make decisions for convenience and/or diverse occasions. Products containing IO blend in with the natural skin tone and have an aesthetically pleasing cosmetic appearance. In our cohort, comments regarding cosmetic elegance were highly valued and were present in multiple reviews (45%), with 69% being positive.

Affordability—In our cohort, product price was not predominantly mentioned in consumers’ reviews. However, negative comments regarding affordability were slightly higher than the positive (56% vs 44%). Notably, the mean price of our top recommendations was $42. Higher price was associated with products with a wider range of shades available. Prior studies have found similar results demonstrating that websites with recommendations on sunscreens for patients with skin of color compared with sunscreens for white or fair skin were more likely to recommend more expensive products (median, $14/oz vs $11.3/oz) despite the lower SPF level.²⁰ According to Schneider,²¹ daily use of the cheapest sunscreen on the head/neck region recommended for white/pale skin ($2/oz) would lead to an annual cost of $61 compared to $182 for darker skin ($6/oz). This showcases the considerable variation in sunscreen prices for both populations that could potentiate disparities and vulnerability in the latter group.

Conclusion

Tinted sunscreens provide both functional and cosmetic benefits and are a safe, effective, and convenient way to protect against high-energy VL. This study suggests that patients with skin of color encounter difficulties in finding matching shades in TS products. These difficulties may stem from the lack of knowledge regarding dark complexions and undertones and the lack of representation of black and brown skin that has persisted in dermatology research journals and textbooks for decades.²² Our study provides important insights to help dermatologists improve their familiarity with the brands and characteristics of TSs geared to patients with all skin tones, including skin of color. Limitations include single-retailer information and inclusion of both highly and poorly rated comments with subjective data, limiting generalizability. The limited selection of shades for darker skin poses a roadblock to proper treatment and prevention. These data represent an area for improvement within the beauty industry and the dermatologic field to deliver culturally sensitive care by being knowledgeable about darker skin tones and TS formulations tailored to people with skin of color.

Sunscreen formulations typically protect from UV radiation (290–400 nm), as this is a well-established cause of photodamage, photoaging, and skin cancer.¹ However, sunlight also consists of visible (400–700 nm) and infrared (>700 nm) radiation.² In fact, UV radiation only comprises 5% to 7% of the solar radiation that reaches the surface of the earth, while visible and infrared lights comprise 44% and 53%, respectively.³ Visible light (VL) is the only portion of the solar spectrum visible to the human eye; it penetrates the skin to a depth range of 90 to 750 µm compared to 1.5 to 90 µm for UV radiation.⁴ Visible light also may come from artificial sources such as light bulbs and digital screens. The rapidly increasing use of smartphones, tablets, laptops, and other digital screens that emit high levels of short-wavelength VL has increased concerns about the safety of these devices. Although blue light exposure from screens is small compared with the amount of exposure from the sun, there is concern about the long-term effects of excessive screen time. Recent studies have demonstrated that exposure to light emitted from electronic devices, even for as little as 1 hour, may cause reactive oxygen species generation, apoptosis, collagen degradation, and necrosis of skin cells.⁵ Visible light increases tyrosinase activity and induces immediate erythema in light-skinned individuals and long-lasting pigmentation in dark-skinned individuals.^4,6

Sunscreens consist of chemical and mineral active ingredients that contain UV filters designed to absorb, scatter, and reflect UV photons with wavelengths up to 380 nm. Historically, traditional options do not protect against the effects induced by VL, as these sunscreens use nanosized particles that help to reduce the white appearance and result in transparency of the product.⁷ To block VL, the topical agent must be visible. Tinted sunscreens (TSs) are products that combine UV and VL filters. They give a colored base coverage that is achieved by incorporating a blend of black, red, and yellow iron oxides (IOs) and/or pigmentary titanium dioxide (PTD)(ie, titanium dioxide [TD] that is not nanosized). Because TSs offer an instant glow and protect the skin from both sun and artificial light, they have become increasingly popular and have been incorporated into makeup and skin care products to facilitate daily convenient use.

The purpose of this analysis was to study current available options and product factors that may influence consumer preference when choosing a TS based on the reviewer characteristics.

Methods

The keyword sunscreen was searched in the broader category of skin care products on an online supplier of sunscreens (www.sephora.com). This supplier was chosen because, unlike other sources, specific reviewer characteristics regarding underlying skin tone also were available. The search produced 161 results. For the purpose of this analysis, only facial TSs containing IO and/or PTD were included. Each sunscreen was checked by the authors, and 58 sunscreens that met the inclusion criteria were identified and further reviewed. Descriptive data, including formulation, sun protection factor (SPF), ingredient type (chemical or physical), pigments used, shades available, additional benefits, price range, rating, and user reviews, were gathered. The authors extracted these data from the product information on the website, manufacturer claims, ratings, and reviewer comments on each of the listed sunscreens.

For each product, the content of the top 10 most helpful positive and negative reviews as voted by consumers (1160 total reviews, consisting of 1 or more comments) was analyzed. Two authors (H.D.L.G. and P.V.) coded consumer-reported comments for positive and negative descriptors into the categories of cosmetic elegance, performance, skin compatibility and tolerance, tone compatibility, and affordability. Cosmetic elegance was defined as any feature associated with skin sensation (eg, greasy), color (eg, white cast), scent, ability to blend, and overall appearance of the product on the skin. Product performance included SPF, effectiveness in preventing sunburn, coverage, and finish claims (ie, matte, glow, invisible). Skin compatibility and tolerance were represented in the reviewers’ comments and reflected how the product performed in association with underlying dermatologic conditions, skin type, and if there were any side effects such as irritation or allergic reactions. Tone compatibility referred to TS color similarity with users’ skin and shades available for individual products. Affordability reflected consumers’ perceptions of the product price. Comments may be included in multiple categories (eg, a product was noted to blend well on the skin but did not provide enough coverage). Of entries, 10% (116/1160 reviews) were coded by first author (H.D.L.G.) to ensure internal validity. Reviewer characteristics were consistently available and were used to determine the top 5 recommended products for light-, medium-, and dark-skinned individuals based on the number of 5-star ratings in each group. Porcelain, fair, and light were considered light skin tones. Medium, tan, and olive were considered medium skin tones. Deep, dark, and ebony were considered dark skin tones.

Results

Sunscreen Characteristics—Among the 161 screened products, 58 met the inclusion criteria. Four types of formulations were included: lotion, cream, liquid, and powder. Twenty-nine (50%) were creams, followed by lotions (19%), liquids (28%), and powders (3%). More than 79% (46/58) of products had a reported SPF of 30 or higher. Sunscreens with an active physical ingredient—the minerals TD and/or zinc oxide (ZO)—were most common (33/58 [57%]), followed by the chemical sunscreens avobenzone, octinoxate, oxybenzone, homosalate, octisalate, and/or octocrylene active ingredients (14/58 [24%]), and a combination of chemical and physical sunscreens (11/58 [19%]). Nearly all products (55/58 [95%]) contained pigmentary IO (red, CI 77491; yellow, CI 77492; black, CI 77499). Notably, only 38% (22/58) of products had more than 1 shade. All products had additional claims associated with being hydrating, having antiaging effects, smoothing texture, minimizing the appearance of pores, softening lines, and/or promoting even skin tone. Traditional physical sunscreens (those containing TD and/or ZO) were more expensive than chemical sunscreens, with a median price of $30. The median review rating was 4.5 of 5 stars, with a median of 2300 customer reviews per product. Findings are summarized in Table 1.

Positive Features of Sunscreens—Based on an analysis of total reviews (N=1160), cosmetic elegance was the most cited positive feature associated with TS products (31%), followed by product performance (10%). Skin compatibility and tolerance (7%), tone compatibility (7%), and affordability (7%) were cited less commonly as positive features. When negative features were cited, consumers mostly noted tone incompatibility (16%) and cosmetic elegance concerns (14%). Product performance (13%) was comparatively cited as a negative feature (Table 1). Exemplary positive comments categorized in cosmetic elegance included the subthemes of rubs in well and natural glow. Exemplary negative comments in cosmetic elegance and tone compatibility categories included the subthemes patchy/dry finish and color mismatch. Table 1 illustrates these findings.

Product Recommendations—The top 5 recommendations of the best TS for each skin tone are listed in Table 2. The mean price of the recommended products was $42 for 1 to 1.9 oz. Laura Mercier Tinted Moisturizer Oil Free Natural Skin Perfector broad spectrum SPF 20 (Laura Mercier) was the top product for all 3 groups. Similarly, of 58 products available, the same 5 products—Laura Mercier Tinted Moisturizer Oil Free Natural Skin Perfector broad spectrum SPF 20, IT Cosmetics CC+ Cream with SPF 50 (IT Cosmetics, LLC), Tarte Amazonian Clay BB Tinted Moisturizer Broad Spectrum SPF 20 (Tarte Cosmetics), NARS Pure Radiant Tinted Moisturizer Broad Spectrum SPF 30 (NARS Cosmetics), and Laura Mercier Tinted Moisturizer Natural Skin Perfector broad spectrum SPF 30—were considered the best among consumers of all skin tones, with the addition of 2 different products (bareMinerals Original Liquid Mineral Foundation Broad Spectrum SPF 20 [bareMinerals] and ILIA Super Serum Skin Tint SPF 40 Foundation [ILIA Beauty]) in the dark skin group. Notably, these products were the only ones on Sephora’s website that offered up to 30 (22 on average) different shades.

Comment

Tone Compatibility—Tinted sunscreens were created to extend the range of photoprotection into the VL spectrum. The goal of TSs is to incorporate pigments that blend in with the natural skin tone, produce a glow, and have an aesthetically pleasing appearance. To accommodate a variety of skin colors, different shades can be obtained by mixing different amounts of yellow, red, and black IO with or without PTD. The pigments and reflective compounds provide color, opacity, and a natural coverage. Our qualitative analysis provides information on the lack of diversity among shades available for TS, especially for darker skin tones. Of the 58 products evaluated, 62% (32/58) only had 1 shade. In our cohort, tone compatibility was the most commonly cited negative feature. Of note, 89% of these comments were from consumers with dark skin tones, and there was a disproportional number of reviews by darker-skinned individuals compared to users with light and medium skin tones. This is of particular importance, as TSs have been shown to protect against dermatoses that disproportionally affect individuals with skin of color. When comparing sunscreen formulations containing IO with regular mineral sunscreens, Dumbuya et al³ found that IO-containing formulations significantly protected against VL-induced pigmentation compared with untreated skin or mineral sunscreen with SPF 50 or higher in individuals with Fitzpatrick skin type IV (P<.001). Similarly, Bernstein et al⁸ found that exposing patients with Fitzpatrick skin types III and IV to blue-violet light resulted in marked hyperpigmentation that lasted up to 3 months. Visible light elicits immediate and persistent pigment darkening in individuals with Fitzpatrick skin phototype III and above via the photo-oxidation of pre-existing melanin and de novo melanogenesis.⁹ Tinted sunscreens formulated with IO have been shown to aid in the treatment of melasma and prevent hyperpigmentation in individuals with Fitzpatrick skin types IV to VI.¹⁰ Patients with darker skin tones with dermatoses aggravated or induced by VL, such as melasma and postinflammatory hyperpigmentation, may seek photoprotection provided by TS but find the lack of matching shades unappealing. The dearth of shade diversity that matches all skin tones can lead to inequities and disproportionally affect those with darker skin.

Performance—Tinted sunscreen formulations containing IO have been proven effective in protecting against high-energy VL, especially when combined synergistically with ZO.¹¹ Kaye et al¹² found that TSs containing IO and the inorganic filters TD or ZO reduced transmittance of VL more effectively than nontinted sunscreens containing TD or ZO alone or products containing organic filters. The decreased VL transmittance in the former is due to synergistic effects of the VL-scattering properties of the TD and the VL absorption properties of the IO. Similarly, Sayre et al¹³ demonstrated that IO was superior to TD and ZO in attenuating the transmission of VL. Bernstein et al¹⁴ found that darker shades containing higher percentages of IO increased the attenuation of VL to 98% compared with lighter shades attenuating 93%. This correlates with the results of prior studies highlighting the potential of TSs in protecting individuals with skin of color.³ In our cohort, comments regarding product performance and protection were mostly positive, claiming that consistent use reduced hyperpigmentation on the skin surface, giving the appearance of a more even skin tone.

Tolerability—Iron oxides are minerals known to be safe, gentle, and nontoxic on the surface of the skin.¹⁵ Two case reports of contact dermatitis due to IO have been reported.^16,17 Within our cohort, only a few of the comments (6%) described negative product tolerance or compatibility with their skin type. However, it is more likely that these incompatibilities were due to other ingredients in the product or the individuals’ underlying dermatologic conditions.

Cosmetic Elegance—Most of the sunscreens available on the market today contain micronized forms of TD and ZO particles because they have better cosmetic acceptability.¹⁸ However, their reduced size compromises the protection provided against VL whereby the addition of IO is of vital importance. According to the RealSelf Sun Safety Report, only 11% of Americans wear sunscreen daily, and 46% never wear sunscreen.¹⁹ The most common reasons consumers reported for not wearing sunscreen included not liking how it looks on the skin, forgetting to apply it, and/or believing that application is inconvenient and time-consuming. Currently, TSs have been incorporated into daily-life products such as makeup, moisturizers, and serums, making application for users easy and convenient, decreasing the necessity of using multiple products, and offering the opportunity to choose from different presentations to make decisions for convenience and/or diverse occasions. Products containing IO blend in with the natural skin tone and have an aesthetically pleasing cosmetic appearance. In our cohort, comments regarding cosmetic elegance were highly valued and were present in multiple reviews (45%), with 69% being positive.

Affordability—In our cohort, product price was not predominantly mentioned in consumers’ reviews. However, negative comments regarding affordability were slightly higher than the positive (56% vs 44%). Notably, the mean price of our top recommendations was $42. Higher price was associated with products with a wider range of shades available. Prior studies have found similar results demonstrating that websites with recommendations on sunscreens for patients with skin of color compared with sunscreens for white or fair skin were more likely to recommend more expensive products (median, $14/oz vs $11.3/oz) despite the lower SPF level.²⁰ According to Schneider,²¹ daily use of the cheapest sunscreen on the head/neck region recommended for white/pale skin ($2/oz) would lead to an annual cost of $61 compared to $182 for darker skin ($6/oz). This showcases the considerable variation in sunscreen prices for both populations that could potentiate disparities and vulnerability in the latter group.

Conclusion

Tinted sunscreens provide both functional and cosmetic benefits and are a safe, effective, and convenient way to protect against high-energy VL. This study suggests that patients with skin of color encounter difficulties in finding matching shades in TS products. These difficulties may stem from the lack of knowledge regarding dark complexions and undertones and the lack of representation of black and brown skin that has persisted in dermatology research journals and textbooks for decades.²² Our study provides important insights to help dermatologists improve their familiarity with the brands and characteristics of TSs geared to patients with all skin tones, including skin of color. Limitations include single-retailer information and inclusion of both highly and poorly rated comments with subjective data, limiting generalizability. The limited selection of shades for darker skin poses a roadblock to proper treatment and prevention. These data represent an area for improvement within the beauty industry and the dermatologic field to deliver culturally sensitive care by being knowledgeable about darker skin tones and TS formulations tailored to people with skin of color.

Sunscreen formulations typically protect from UV radiation (290–400 nm), as this is a well-established cause of photodamage, photoaging, and skin cancer.¹ However, sunlight also consists of visible (400–700 nm) and infrared (>700 nm) radiation.² In fact, UV radiation only comprises 5% to 7% of the solar radiation that reaches the surface of the earth, while visible and infrared lights comprise 44% and 53%, respectively.³ Visible light (VL) is the only portion of the solar spectrum visible to the human eye; it penetrates the skin to a depth range of 90 to 750 µm compared to 1.5 to 90 µm for UV radiation.⁴ Visible light also may come from artificial sources such as light bulbs and digital screens. The rapidly increasing use of smartphones, tablets, laptops, and other digital screens that emit high levels of short-wavelength VL has increased concerns about the safety of these devices. Although blue light exposure from screens is small compared with the amount of exposure from the sun, there is concern about the long-term effects of excessive screen time. Recent studies have demonstrated that exposure to light emitted from electronic devices, even for as little as 1 hour, may cause reactive oxygen species generation, apoptosis, collagen degradation, and necrosis of skin cells.⁵ Visible light increases tyrosinase activity and induces immediate erythema in light-skinned individuals and long-lasting pigmentation in dark-skinned individuals.^4,6

Sunscreens consist of chemical and mineral active ingredients that contain UV filters designed to absorb, scatter, and reflect UV photons with wavelengths up to 380 nm. Historically, traditional options do not protect against the effects induced by VL, as these sunscreens use nanosized particles that help to reduce the white appearance and result in transparency of the product.⁷ To block VL, the topical agent must be visible. Tinted sunscreens (TSs) are products that combine UV and VL filters. They give a colored base coverage that is achieved by incorporating a blend of black, red, and yellow iron oxides (IOs) and/or pigmentary titanium dioxide (PTD)(ie, titanium dioxide [TD] that is not nanosized). Because TSs offer an instant glow and protect the skin from both sun and artificial light, they have become increasingly popular and have been incorporated into makeup and skin care products to facilitate daily convenient use.

The purpose of this analysis was to study current available options and product factors that may influence consumer preference when choosing a TS based on the reviewer characteristics.

Methods

The keyword sunscreen was searched in the broader category of skin care products on an online supplier of sunscreens (www.sephora.com). This supplier was chosen because, unlike other sources, specific reviewer characteristics regarding underlying skin tone also were available. The search produced 161 results. For the purpose of this analysis, only facial TSs containing IO and/or PTD were included. Each sunscreen was checked by the authors, and 58 sunscreens that met the inclusion criteria were identified and further reviewed. Descriptive data, including formulation, sun protection factor (SPF), ingredient type (chemical or physical), pigments used, shades available, additional benefits, price range, rating, and user reviews, were gathered. The authors extracted these data from the product information on the website, manufacturer claims, ratings, and reviewer comments on each of the listed sunscreens.

For each product, the content of the top 10 most helpful positive and negative reviews as voted by consumers (1160 total reviews, consisting of 1 or more comments) was analyzed. Two authors (H.D.L.G. and P.V.) coded consumer-reported comments for positive and negative descriptors into the categories of cosmetic elegance, performance, skin compatibility and tolerance, tone compatibility, and affordability. Cosmetic elegance was defined as any feature associated with skin sensation (eg, greasy), color (eg, white cast), scent, ability to blend, and overall appearance of the product on the skin. Product performance included SPF, effectiveness in preventing sunburn, coverage, and finish claims (ie, matte, glow, invisible). Skin compatibility and tolerance were represented in the reviewers’ comments and reflected how the product performed in association with underlying dermatologic conditions, skin type, and if there were any side effects such as irritation or allergic reactions. Tone compatibility referred to TS color similarity with users’ skin and shades available for individual products. Affordability reflected consumers’ perceptions of the product price. Comments may be included in multiple categories (eg, a product was noted to blend well on the skin but did not provide enough coverage). Of entries, 10% (116/1160 reviews) were coded by first author (H.D.L.G.) to ensure internal validity. Reviewer characteristics were consistently available and were used to determine the top 5 recommended products for light-, medium-, and dark-skinned individuals based on the number of 5-star ratings in each group. Porcelain, fair, and light were considered light skin tones. Medium, tan, and olive were considered medium skin tones. Deep, dark, and ebony were considered dark skin tones.

Results

Sunscreen Characteristics—Among the 161 screened products, 58 met the inclusion criteria. Four types of formulations were included: lotion, cream, liquid, and powder. Twenty-nine (50%) were creams, followed by lotions (19%), liquids (28%), and powders (3%). More than 79% (46/58) of products had a reported SPF of 30 or higher. Sunscreens with an active physical ingredient—the minerals TD and/or zinc oxide (ZO)—were most common (33/58 [57%]), followed by the chemical sunscreens avobenzone, octinoxate, oxybenzone, homosalate, octisalate, and/or octocrylene active ingredients (14/58 [24%]), and a combination of chemical and physical sunscreens (11/58 [19%]). Nearly all products (55/58 [95%]) contained pigmentary IO (red, CI 77491; yellow, CI 77492; black, CI 77499). Notably, only 38% (22/58) of products had more than 1 shade. All products had additional claims associated with being hydrating, having antiaging effects, smoothing texture, minimizing the appearance of pores, softening lines, and/or promoting even skin tone. Traditional physical sunscreens (those containing TD and/or ZO) were more expensive than chemical sunscreens, with a median price of $30. The median review rating was 4.5 of 5 stars, with a median of 2300 customer reviews per product. Findings are summarized in Table 1.

Positive Features of Sunscreens—Based on an analysis of total reviews (N=1160), cosmetic elegance was the most cited positive feature associated with TS products (31%), followed by product performance (10%). Skin compatibility and tolerance (7%), tone compatibility (7%), and affordability (7%) were cited less commonly as positive features. When negative features were cited, consumers mostly noted tone incompatibility (16%) and cosmetic elegance concerns (14%). Product performance (13%) was comparatively cited as a negative feature (Table 1). Exemplary positive comments categorized in cosmetic elegance included the subthemes of rubs in well and natural glow. Exemplary negative comments in cosmetic elegance and tone compatibility categories included the subthemes patchy/dry finish and color mismatch. Table 1 illustrates these findings.

Product Recommendations—The top 5 recommendations of the best TS for each skin tone are listed in Table 2. The mean price of the recommended products was $42 for 1 to 1.9 oz. Laura Mercier Tinted Moisturizer Oil Free Natural Skin Perfector broad spectrum SPF 20 (Laura Mercier) was the top product for all 3 groups. Similarly, of 58 products available, the same 5 products—Laura Mercier Tinted Moisturizer Oil Free Natural Skin Perfector broad spectrum SPF 20, IT Cosmetics CC+ Cream with SPF 50 (IT Cosmetics, LLC), Tarte Amazonian Clay BB Tinted Moisturizer Broad Spectrum SPF 20 (Tarte Cosmetics), NARS Pure Radiant Tinted Moisturizer Broad Spectrum SPF 30 (NARS Cosmetics), and Laura Mercier Tinted Moisturizer Natural Skin Perfector broad spectrum SPF 30—were considered the best among consumers of all skin tones, with the addition of 2 different products (bareMinerals Original Liquid Mineral Foundation Broad Spectrum SPF 20 [bareMinerals] and ILIA Super Serum Skin Tint SPF 40 Foundation [ILIA Beauty]) in the dark skin group. Notably, these products were the only ones on Sephora’s website that offered up to 30 (22 on average) different shades.

Comment

Tone Compatibility—Tinted sunscreens were created to extend the range of photoprotection into the VL spectrum. The goal of TSs is to incorporate pigments that blend in with the natural skin tone, produce a glow, and have an aesthetically pleasing appearance. To accommodate a variety of skin colors, different shades can be obtained by mixing different amounts of yellow, red, and black IO with or without PTD. The pigments and reflective compounds provide color, opacity, and a natural coverage. Our qualitative analysis provides information on the lack of diversity among shades available for TS, especially for darker skin tones. Of the 58 products evaluated, 62% (32/58) only had 1 shade. In our cohort, tone compatibility was the most commonly cited negative feature. Of note, 89% of these comments were from consumers with dark skin tones, and there was a disproportional number of reviews by darker-skinned individuals compared to users with light and medium skin tones. This is of particular importance, as TSs have been shown to protect against dermatoses that disproportionally affect individuals with skin of color. When comparing sunscreen formulations containing IO with regular mineral sunscreens, Dumbuya et al³ found that IO-containing formulations significantly protected against VL-induced pigmentation compared with untreated skin or mineral sunscreen with SPF 50 or higher in individuals with Fitzpatrick skin type IV (P<.001). Similarly, Bernstein et al⁸ found that exposing patients with Fitzpatrick skin types III and IV to blue-violet light resulted in marked hyperpigmentation that lasted up to 3 months. Visible light elicits immediate and persistent pigment darkening in individuals with Fitzpatrick skin phototype III and above via the photo-oxidation of pre-existing melanin and de novo melanogenesis.⁹ Tinted sunscreens formulated with IO have been shown to aid in the treatment of melasma and prevent hyperpigmentation in individuals with Fitzpatrick skin types IV to VI.¹⁰ Patients with darker skin tones with dermatoses aggravated or induced by VL, such as melasma and postinflammatory hyperpigmentation, may seek photoprotection provided by TS but find the lack of matching shades unappealing. The dearth of shade diversity that matches all skin tones can lead to inequities and disproportionally affect those with darker skin.

Performance—Tinted sunscreen formulations containing IO have been proven effective in protecting against high-energy VL, especially when combined synergistically with ZO.¹¹ Kaye et al¹² found that TSs containing IO and the inorganic filters TD or ZO reduced transmittance of VL more effectively than nontinted sunscreens containing TD or ZO alone or products containing organic filters. The decreased VL transmittance in the former is due to synergistic effects of the VL-scattering properties of the TD and the VL absorption properties of the IO. Similarly, Sayre et al¹³ demonstrated that IO was superior to TD and ZO in attenuating the transmission of VL. Bernstein et al¹⁴ found that darker shades containing higher percentages of IO increased the attenuation of VL to 98% compared with lighter shades attenuating 93%. This correlates with the results of prior studies highlighting the potential of TSs in protecting individuals with skin of color.³ In our cohort, comments regarding product performance and protection were mostly positive, claiming that consistent use reduced hyperpigmentation on the skin surface, giving the appearance of a more even skin tone.

Tolerability—Iron oxides are minerals known to be safe, gentle, and nontoxic on the surface of the skin.¹⁵ Two case reports of contact dermatitis due to IO have been reported.^16,17 Within our cohort, only a few of the comments (6%) described negative product tolerance or compatibility with their skin type. However, it is more likely that these incompatibilities were due to other ingredients in the product or the individuals’ underlying dermatologic conditions.

Cosmetic Elegance—Most of the sunscreens available on the market today contain micronized forms of TD and ZO particles because they have better cosmetic acceptability.¹⁸ However, their reduced size compromises the protection provided against VL whereby the addition of IO is of vital importance. According to the RealSelf Sun Safety Report, only 11% of Americans wear sunscreen daily, and 46% never wear sunscreen.¹⁹ The most common reasons consumers reported for not wearing sunscreen included not liking how it looks on the skin, forgetting to apply it, and/or believing that application is inconvenient and time-consuming. Currently, TSs have been incorporated into daily-life products such as makeup, moisturizers, and serums, making application for users easy and convenient, decreasing the necessity of using multiple products, and offering the opportunity to choose from different presentations to make decisions for convenience and/or diverse occasions. Products containing IO blend in with the natural skin tone and have an aesthetically pleasing cosmetic appearance. In our cohort, comments regarding cosmetic elegance were highly valued and were present in multiple reviews (45%), with 69% being positive.

Affordability—In our cohort, product price was not predominantly mentioned in consumers’ reviews. However, negative comments regarding affordability were slightly higher than the positive (56% vs 44%). Notably, the mean price of our top recommendations was $42. Higher price was associated with products with a wider range of shades available. Prior studies have found similar results demonstrating that websites with recommendations on sunscreens for patients with skin of color compared with sunscreens for white or fair skin were more likely to recommend more expensive products (median, $14/oz vs $11.3/oz) despite the lower SPF level.²⁰ According to Schneider,²¹ daily use of the cheapest sunscreen on the head/neck region recommended for white/pale skin ($2/oz) would lead to an annual cost of $61 compared to $182 for darker skin ($6/oz). This showcases the considerable variation in sunscreen prices for both populations that could potentiate disparities and vulnerability in the latter group.

Conclusion

Tinted sunscreens provide both functional and cosmetic benefits and are a safe, effective, and convenient way to protect against high-energy VL. This study suggests that patients with skin of color encounter difficulties in finding matching shades in TS products. These difficulties may stem from the lack of knowledge regarding dark complexions and undertones and the lack of representation of black and brown skin that has persisted in dermatology research journals and textbooks for decades.²² Our study provides important insights to help dermatologists improve their familiarity with the brands and characteristics of TSs geared to patients with all skin tones, including skin of color. Limitations include single-retailer information and inclusion of both highly and poorly rated comments with subjective data, limiting generalizability. The limited selection of shades for darker skin poses a roadblock to proper treatment and prevention. These data represent an area for improvement within the beauty industry and the dermatologic field to deliver culturally sensitive care by being knowledgeable about darker skin tones and TS formulations tailored to people with skin of color.

Edema blisters are a common but often underreported entity most commonly seen on the lower extremities in the setting of acute edema. ¹ Reported risk factors and associations include chronic venous insufficiency, congestive heart failure, hereditary angioedema, and medications (eg, amlodipine). ^1,2 We report a newly described variant that we have termed anasarca-induced desquamation in which a patient sloughed the entire cutaneous surface of the body after gaining almost 40 pounds over 5 days.

Case Report

A 50-year-old man without a home was found minimally responsive in a yard. His core body temperature was 25.5 °C. He was profoundly acidotic (pH, <6.733 [reference range, 7.35–7.45]; lactic acid, 20.5 mmol/L [reference range, 0.5–2.2 mmol/L]) at admission. His medical history was notable for diabetes mellitus, hypertension, alcohol abuse, and pulmonary embolism. The patient was resuscitated with rewarming and intravenous fluids in the setting of acute renal insufficiency. By day 5 of the hospital stay, he had a net positive intake of 21.8 L and an 18-kg (39.7-lb) weight gain.

Dermatology was consulted for skin sloughing. Physical examination revealed nonpainful desquamation of the vermilion lip, periorbital skin, right shoulder, and hips without notable mucosal changes. Two 4-mm punch biopsies of the shoulder revealed an intracorneal split with desquamation of the stratum corneum and a mild dermal lymphocytic infiltrate, consistent with exfoliation secondary to edema or staphylococcal scalded skin syndrome (Figure 1). No staphylococcal growth was noted on blood, urine, nasal, wound, and ocular cultures throughout the hospital stay.

As the patient’s anasarca improved with diuretics and continuous renal replacement therapy, the entire cutaneous surface—head to toe—underwent desquamation, including the palms and soles. He was managed with supportive skin care. The anasarca healed completely with residual hypopigmentation (Figures 2 and 3).

Comment

Anasarca-induced desquamation represents a more diffuse form of a known entity: edema blisters. Occurring most commonly in the setting of acute exacerbation of chronic venous insufficiency, edema blisters can mimic other vesiculobullous conditions, such as bullous pemphigoid and herpes zoster.³

Pathogenesis of Edema Blisters—Edema develops in the skin when the capillary filtration rate, determined by the hydrostatic and oncotic pressures of the capillaries and interstitium, exceeds venous and lymphatic drainage. The appearance of edema blisters in the acute setting likely is related to the speed at which edema develops in skin.¹ Although edema blisters often are described as tense, there is a paucity of histologic data at the anatomical level of split in the skin.In our patient, desquamation was within the stratum corneum and likely multifactorial. His weight gain of nearly 40 lb, the result of intravenous instillation of fluids and low urine output, was undeniably a contributing factor. The anasarca was aggravated by hypoalbuminemia (2.1 g/dL) in the setting of known liver disease. Other possible contributing factors were hypotension, which required vasopressor therapy that led to hypoperfusion of the skin, and treatment of hypothermia, with resulting reactive vasodilation and capillary leak.

Management—Treatment of acute edema blisters is focused on the underlying cause of the edema. In a study of 13 patients with edema blisters, all had blisters on the legs that resolved with treatment, such as diuretics or compression therapy.¹

Anasarca-induced desquamation is an inherently benign condition that mimics potentially fatal disorders, such as Stevens-Johnson syndrome, staphylococcal scalded skin syndrome, and toxic shock syndrome. Therefore, patients presenting with diffuse superficial desquamation should be assessed for the mucosal changes of Stevens-Johnson syndrome and a history of acute edema in the affected areas to avoid potentially harmful empiric treatments, such as corticosteroids and intravenous antibiotics.

Conclusion

Anasarca-induced desquamation represents a more diffuse form of edema blisters. This desquamation can mimic a potentially fatal rash, such as Stevens-Johnson syndrome and staphylococcal scalded skin syndrome.

Edema blisters are a common but often underreported entity most commonly seen on the lower extremities in the setting of acute edema. ¹ Reported risk factors and associations include chronic venous insufficiency, congestive heart failure, hereditary angioedema, and medications (eg, amlodipine). ^1,2 We report a newly described variant that we have termed anasarca-induced desquamation in which a patient sloughed the entire cutaneous surface of the body after gaining almost 40 pounds over 5 days.

Case Report

A 50-year-old man without a home was found minimally responsive in a yard. His core body temperature was 25.5 °C. He was profoundly acidotic (pH, <6.733 [reference range, 7.35–7.45]; lactic acid, 20.5 mmol/L [reference range, 0.5–2.2 mmol/L]) at admission. His medical history was notable for diabetes mellitus, hypertension, alcohol abuse, and pulmonary embolism. The patient was resuscitated with rewarming and intravenous fluids in the setting of acute renal insufficiency. By day 5 of the hospital stay, he had a net positive intake of 21.8 L and an 18-kg (39.7-lb) weight gain.

Dermatology was consulted for skin sloughing. Physical examination revealed nonpainful desquamation of the vermilion lip, periorbital skin, right shoulder, and hips without notable mucosal changes. Two 4-mm punch biopsies of the shoulder revealed an intracorneal split with desquamation of the stratum corneum and a mild dermal lymphocytic infiltrate, consistent with exfoliation secondary to edema or staphylococcal scalded skin syndrome (Figure 1). No staphylococcal growth was noted on blood, urine, nasal, wound, and ocular cultures throughout the hospital stay.

As the patient’s anasarca improved with diuretics and continuous renal replacement therapy, the entire cutaneous surface—head to toe—underwent desquamation, including the palms and soles. He was managed with supportive skin care. The anasarca healed completely with residual hypopigmentation (Figures 2 and 3).

Comment

Anasarca-induced desquamation represents a more diffuse form of a known entity: edema blisters. Occurring most commonly in the setting of acute exacerbation of chronic venous insufficiency, edema blisters can mimic other vesiculobullous conditions, such as bullous pemphigoid and herpes zoster.³

Pathogenesis of Edema Blisters—Edema develops in the skin when the capillary filtration rate, determined by the hydrostatic and oncotic pressures of the capillaries and interstitium, exceeds venous and lymphatic drainage. The appearance of edema blisters in the acute setting likely is related to the speed at which edema develops in skin.¹ Although edema blisters often are described as tense, there is a paucity of histologic data at the anatomical level of split in the skin.In our patient, desquamation was within the stratum corneum and likely multifactorial. His weight gain of nearly 40 lb, the result of intravenous instillation of fluids and low urine output, was undeniably a contributing factor. The anasarca was aggravated by hypoalbuminemia (2.1 g/dL) in the setting of known liver disease. Other possible contributing factors were hypotension, which required vasopressor therapy that led to hypoperfusion of the skin, and treatment of hypothermia, with resulting reactive vasodilation and capillary leak.

Management—Treatment of acute edema blisters is focused on the underlying cause of the edema. In a study of 13 patients with edema blisters, all had blisters on the legs that resolved with treatment, such as diuretics or compression therapy.¹

Anasarca-induced desquamation is an inherently benign condition that mimics potentially fatal disorders, such as Stevens-Johnson syndrome, staphylococcal scalded skin syndrome, and toxic shock syndrome. Therefore, patients presenting with diffuse superficial desquamation should be assessed for the mucosal changes of Stevens-Johnson syndrome and a history of acute edema in the affected areas to avoid potentially harmful empiric treatments, such as corticosteroids and intravenous antibiotics.

Conclusion

Anasarca-induced desquamation represents a more diffuse form of edema blisters. This desquamation can mimic a potentially fatal rash, such as Stevens-Johnson syndrome and staphylococcal scalded skin syndrome.

Edema blisters are a common but often underreported entity most commonly seen on the lower extremities in the setting of acute edema. ¹ Reported risk factors and associations include chronic venous insufficiency, congestive heart failure, hereditary angioedema, and medications (eg, amlodipine). ^1,2 We report a newly described variant that we have termed anasarca-induced desquamation in which a patient sloughed the entire cutaneous surface of the body after gaining almost 40 pounds over 5 days.

Case Report

A 50-year-old man without a home was found minimally responsive in a yard. His core body temperature was 25.5 °C. He was profoundly acidotic (pH, <6.733 [reference range, 7.35–7.45]; lactic acid, 20.5 mmol/L [reference range, 0.5–2.2 mmol/L]) at admission. His medical history was notable for diabetes mellitus, hypertension, alcohol abuse, and pulmonary embolism. The patient was resuscitated with rewarming and intravenous fluids in the setting of acute renal insufficiency. By day 5 of the hospital stay, he had a net positive intake of 21.8 L and an 18-kg (39.7-lb) weight gain.

Dermatology was consulted for skin sloughing. Physical examination revealed nonpainful desquamation of the vermilion lip, periorbital skin, right shoulder, and hips without notable mucosal changes. Two 4-mm punch biopsies of the shoulder revealed an intracorneal split with desquamation of the stratum corneum and a mild dermal lymphocytic infiltrate, consistent with exfoliation secondary to edema or staphylococcal scalded skin syndrome (Figure 1). No staphylococcal growth was noted on blood, urine, nasal, wound, and ocular cultures throughout the hospital stay.

As the patient’s anasarca improved with diuretics and continuous renal replacement therapy, the entire cutaneous surface—head to toe—underwent desquamation, including the palms and soles. He was managed with supportive skin care. The anasarca healed completely with residual hypopigmentation (Figures 2 and 3).

Comment

Anasarca-induced desquamation represents a more diffuse form of a known entity: edema blisters. Occurring most commonly in the setting of acute exacerbation of chronic venous insufficiency, edema blisters can mimic other vesiculobullous conditions, such as bullous pemphigoid and herpes zoster.³

Pathogenesis of Edema Blisters—Edema develops in the skin when the capillary filtration rate, determined by the hydrostatic and oncotic pressures of the capillaries and interstitium, exceeds venous and lymphatic drainage. The appearance of edema blisters in the acute setting likely is related to the speed at which edema develops in skin.¹ Although edema blisters often are described as tense, there is a paucity of histologic data at the anatomical level of split in the skin.In our patient, desquamation was within the stratum corneum and likely multifactorial. His weight gain of nearly 40 lb, the result of intravenous instillation of fluids and low urine output, was undeniably a contributing factor. The anasarca was aggravated by hypoalbuminemia (2.1 g/dL) in the setting of known liver disease. Other possible contributing factors were hypotension, which required vasopressor therapy that led to hypoperfusion of the skin, and treatment of hypothermia, with resulting reactive vasodilation and capillary leak.

Management—Treatment of acute edema blisters is focused on the underlying cause of the edema. In a study of 13 patients with edema blisters, all had blisters on the legs that resolved with treatment, such as diuretics or compression therapy.¹

Anasarca-induced desquamation is an inherently benign condition that mimics potentially fatal disorders, such as Stevens-Johnson syndrome, staphylococcal scalded skin syndrome, and toxic shock syndrome. Therefore, patients presenting with diffuse superficial desquamation should be assessed for the mucosal changes of Stevens-Johnson syndrome and a history of acute edema in the affected areas to avoid potentially harmful empiric treatments, such as corticosteroids and intravenous antibiotics.

Conclusion

Anasarca-induced desquamation represents a more diffuse form of edema blisters. This desquamation can mimic a potentially fatal rash, such as Stevens-Johnson syndrome and staphylococcal scalded skin syndrome.

In recent years, direct-to-consumer (DTC) teledermatology platforms have gained popularity as telehealth business models, allowing patients to directly initiate visits with physicians and purchase medications from single platforms. A shortage of dermatologists, improved technology, drug patent expirations, and rising health care costs accelerated the growth of DTC dermatology.¹ During the COVID-19 pandemic, teledermatology adoption surged due to the need to provide care while social distancing and minimizing viral exposure. These needs prompted additional federal funding and loosened regulatory provisions.² As the userbase of these companies has grown, so have their valuations.³ Although the DTC model has attracted the attention of patients and investors, its rise provokes many questions about patients acting as consumers in health care. Indeed, DTC telemedicine offers greater autonomy and convenience for patients, but it may impact the quality of care and the nature of physician-patient relationships, perhaps making them more transactional.

Evolution of DTC in Health Care

The DTC model emphasizes individual choice and accessible health care. Although the definition has evolved, the core idea is not new.⁴ Over decades, pharmaceutical companies have spent billions of dollars on DTC advertising, circumventing physicians by directly reaching patients with campaigns on prescription drugs and laboratory tests and shaping public definitions of diseases.⁵

The DTC model of care is fundamentally different from traditional care models in that it changes the roles of the patient and physician. Whereas early telehealth models required a health care provider to initiate teleconsultations with specialists, DTC telemedicine bypasses this step (eg, the patient can consult a dermatologist without needing a primary care provider’s input first). This care can then be provided by dermatologists with whom patients may or may not have pre-established relationships.^4,6

Dermatology was an early adopter of DTC telemedicine. The shortage of dermatologists in the United States created demand for increasing accessibility to dermatologic care. Additionally, the visual nature of diagnosing dermatologic disease was ideal for platforms supporting image sharing.⁷ Early DTC providers were primarily individual companies offering teledermatology. However, many dermatologists can now offer DTC capabilities via companies such as Amwell and Teladoc Health.⁸

Over the last 2 decades, start-ups such as Warby Parker (eyeglasses) and Casper (mattresses) defined the DTC industry using borrowed supply chains, cohesive branding, heavy social media marketing, and web-only retail. Scalability, lack of competition, and abundant venture capital created competition across numerous markets.⁹ Health care capitalized on this DTC model, creating a $700 billion market for products ranging from hearing aids to over-the-counter medications.¹⁰

Borrowing from this DTC playbook, platforms were created to offer delivery of generic prescription drugs to patients’ doorsteps. However, unlike with other products bought online, a consumer cannot simply add prescription drugs to their shopping cart and check out. In all models of American medical practice, physicians still serve as gatekeepers, providing a safeguard for patients to ensure appropriate prescription and avoid negative consequences of unnecessary drug use. This new model effectively streamlines diagnosis, prescription, and drug delivery without the patient ever having to leave home. Combining the prescribing and selling of medications (2 tasks that traditionally have been separated) potentially creates financial conflicts of interest (COIs). Additionally, high utilization of health care, including more prescriptions and visits, does not necessarily equal high quality of care. The companies stand to benefit from extra care regardless of need, and thus these models must be scrutinized for any incentives driving unnecessary care and prescriptions.

Ultimately, DTC has evolved to encompass multiple definitions in health care (Table 1). Although all models provide health care, each offers a different modality of delivery. The primary service may be the sale of prescription drugs or simply telemedicine visits. This review primarily discusses DTC pharmaceutical telemedicine platforms that sell private-label drugs and also offer telemedicine services to streamline care. However, the history, risks, and benefits discussed may apply to all models.

The DTC Landscape

Most DTC companies employ variations on a model with the same 3 main components: a triage questionnaire, telehealth services, and prescription/drug delivery (Figure). The triage questionnaire elicits a history of the patient’s presentation and medical history. Some companies may use artificial intelligence (AI) algorithms to tailor questions to patient needs. There are 2 modalities for patient-provider communication: synchronous and asynchronous. Synchronous communication entails real-time patient-physician conversations via audio only or video call. Asynchronous (or store-and-forward) communication refers to consultations provided via messaging or text-based modality, where a provider may respond to a patient within 24 hours.⁶ Direct-to-consumer platforms primarily use asynchronous visits (Table 2). However, some also use synchronous modalities if the provider deems it necessary or if state laws require it.

Once a provider has consulted with the patient, they can prescribe medication as needed. In certain cases, with adequate history, a prescription may be issued without a full physician visit. Furthermore, DTC companies require purchase of their custom-branded generic drugs. Prescriptions are fulfilled by the company’s pharmacy network and directly shipped to patients; few will allow patients to transfer a prescription to a pharmacy of their choice. Some platforms also sell supplements and over-the-counter medications.

Payment models vary among these companies, and most do not accept insurance (Table 2). Select models may provide free consultations and only require payment for pharmaceuticals. Others charge for consultations but reallocate payment to the cost of medication if prescribed. Another model involves flat rates for consultations and additional charges for drugs but unlimited messaging with providers for the duration of the prescription. Moreover, patients can subscribe to monthly deliveries of their medications.

Foundation of DTC

Technological advances have enabled patients to receive remote treatment from a single platform offering video calls, AI, electronic medical record interoperability, and integration of drug supply chains. Even in its simplest form, AI is increasingly used, as it allows for programs and chatbots to screen and triage patients.¹¹ Technology also has improved at targeted mass marketing through social media platforms and search engines (eg, companies can use age, interests, location, and other parameters to target individuals likely needing acne treatment).

Drug patent expirations are a key catalyst for the rise of DTC companies, creating an attractive business model with generic drugs as the core product. Since 2008, patents for medications treating chronic conditions, such as erectile dysfunction, have expired. These patent expirations are responsible for $198 billion in projected prescription sales between 2019 and 2024.¹ Thus, it follows that DTC companies have seized this opportunity to act as middlemen, taking advantage of these generic medications’ lower costs to create platforms focused on personalization and accessibility.

Rising deductibles have led patients to consider cheaper out-of-pocket alternatives that are not covered by insurance.¹ For example, insurers typically do not cover finasteride treatment for conditions deemed cosmetic, such as androgenetic alopecia.¹² The low cost of generic drugs creates an attractive business model for patients and investors. According to GoodRx, the average retail price for a 30-day supply of brand-name finasteride (Propecia [Merck]) is $135.92, whereas generic finasteride is $75.24.¹³ Direct-to-consumer pharmaceutical companies offer a 30-day supply of generic finasteride ranging from $8.33 to $30.¹⁴ The average wholesale cost for retailers is an estimated $2.31 for 30 days.¹⁵ Although profit margins on generic medications may be lower, more affordable drugs increase the size of the total market. These prescriptions are available as subscription plans, resulting in recurring revenue.

Lax US pharmaceutical marketing regulations allow direct advertising to the general public.¹⁶ In 1997, the US Food and Drug Administration allowed DTC advertisements to replace summaries of serious and common adverse effects with short statements covering important risks or referrals to other sources for complete information. In 2015, the US Food and Drug Administration guidelines preventing encouragement of self-diagnosis and self-treatment were withdrawn.⁵ These changes enable DTC companies to launch large advertising campaigns and to accelerate customer acquisition, as the industry often describes it, with ease.

Rapid Growth and Implications

Increasing generic drug availability and improving telemedicine capabilities have the potential to reduce costs and barriers but also have the potential for financial gain. Venture capital funds have recognized this opportunity, reflected by millions of dollars of investments, and accelerated the growth of DTC health care start-ups. For example, Ro has raised $376 million from venture capital, valuing the company at $1.5 billion.³

Direct-to-consumer companies require a heavy focus on marketing campaigns for customer acquisition. Their aesthetically pleasing websites and aggressive campaigns target specific audiences based on demographics, digital use habits, and purchasing behavior.⁴ Some campaigns celebrate the ease of obtaining prescriptions.¹⁷ Companies have been effective in recruiting so-called millennial and Generation Z patients, known to search the internet for remedies prior to seeking physician consultations.¹⁸ Recognizing these needs, some platforms offer guides on diseases they treat, creating effective customer-acquisition funnels. Recruitment of these technology-friendly patients has proven effective, especially given the largely positive media coverage of DTC platforms––potentially serving as a surrogate for medical credibility for patients.¹⁸

Some DTC companies also market physically; skin care ads may be strategically placed in social media feeds, or even found near mirrors in public bathrooms.¹⁹ Marketing campaigns also involve disease awareness; such efforts serve to increase diagnoses and prescribed treatments while destigmatizing diseases. Although DTC companies argue this strategy empowers patients, these marketing habits have the potential to take advantage of uninformed patients. Campaigns could potentially medicalize normal experiences and expand disease definitions resulting in overdiagnosis, overtreatment, and wasted resources.⁵ For example, off-label propranolol use has been advertised to attract patients who might have “nerves that come creeping before an important presentation.”¹⁷ Disease awareness campaigns also may lead people to falsely believe unproven drug benefits.⁵ According to studies, DTC pharmaceutical advertisements are low in informational quality and result in increased patient visits and prescriptions despite cost-effective alternatives.^5,20-22

Fragmentation of the health care system is another possible complication of DTC teledermatology. These companies operate as for-profit organizations separated from the rest of the health care system, raising concerns about care coordination.⁸ Vital health data may not be conveyed as patients move among different providers and pharmacies. One study found DTC teledermatology rarely offered to provide medical records or facilitate a referral to a local physician.²³ Such a lack of communication is concerning, as medication errors are the leading cause of avoidable harm in health care.²⁴

Direct-to-consumer care models also seemingly redefine the physician-patient relationship by turning patients into consumers. Patient interactions may seem transactional and streamlined toward sales. For these platforms, a visit often is set up as an evaluation of a patient’s suitability for a prescription, not necessarily for the best treatment modality for the problem. These companies primarily make money through the sale of prescription drugs, creating a potential COI that may undermine the patient-physician relationship. Although some companies have made it clear that medical care and pharmaceutical sales are provided by legally separate business entities and that they do not pay physicians on commission, a conflict may still exist given the financial importance of physicians prescribing medication to the success of the business.¹⁶

Even as DTC models advertise upon expanded access and choice, the companies largely prohibit patients from choosing their own pharmacy. Instead, they encourage patients to fill prescriptions with the company’s pharmacy network by claiming lower costs compared with competitors. One DTC company, Hims, is launching a prescription-fulfillment center to further consolidate their business.^17,19,25 The inherent COI of issuing and fulfilling prescriptions raises concerns of patient harm.²⁶ For example, when Dermatology.com launched as a DTC prescription skin medication shop backed by Bausch Health Companies Inc, its model included telemedicine consultation. Although consultations were provided by RxDefine, a third party, only Dermatology.com drugs were prescribed. Given the poor quality of care and obvious financial COI, an uproar in the dermatology community and advocacy by the American Academy of Dermatology led to the shutdown of Dermatology.com’s online prescription services.²⁶

The quality of care among DTC telemedicine platforms has been equivocal. Some studies have reported equivalent care in person and online, while others have reported poor adherence to guidelines, overuse of antibiotics, and misdiagnosis.^8,23 A vital portion of the DTC experience is the history questionnaire, which is geared to diagnosis and risk assessment.²⁵ Resneck et al²³ found diagnostic quality to be adequate for simple dermatologic clinical scenarios but poor for scenarios requiring more than basic histories. Although Ro has reported leveraging data from millions of interactions to ask the right questions and streamline visits, it is still unclear whether history questionnaires are adequate.^17,27 Additionally, consultations may lack sufficient counseling on adverse effects, risks, or pregnancy warnings, as well as discussions on alternative treatments and preventative care.^17,23 Finally, patients often are limited in their choice of dermatologist; the lack of a fully developed relationship increases concerns of follow-up and monitoring practices. Although some DTC platforms offer unlimited interactions with physicians for the duration of a prescription, it is unknown how often these services are utilized or how adequate the quality of these interactions is. This potential for lax follow-up is especially concerning for prescriptions that autorenew on a monthly basis and could result in unnecessary overtreatment.

Postpandemic and Future Outlook

The COVID-19 pandemic dramatically impacted the use of telemedicine. To minimize COVID-19 transmission, the Centers for Medicare & Medicaid Services and private payers expanded telehealth coverage and eliminated reimbursement and licensing barriers.²⁸ A decade’s worth of regulatory changes and consumer adoption was accelerated to weeks, resulting in telemedicine companies reaching record-high visit numbers.²⁹ McKinsey & Company estimated that telehealth visit numbers surged 50- to 175-fold compared with pre–COVID-19 numbers. Additionally, 76% of patients were interested in future telehealth use, and 64% of providers were more comfortable using telehealth than before the pandemic.³⁰ For their part, US dermatologists reported an increase in telemedicine use from 14.1% to 96.9% since COVID-19.³¹

Exactly how much DTC pharmaceutical telemedicine companies are growing is unclear, but private investments may be an indication. A record $14.7 billion was invested in the digital health sector in the first half of 2021; the majority went to telehealth companies.³⁰ Ro, which reported $230 million in revenue in 2020 and has served 6 million visits, raised $200 milllion in July 2020 and $500 million in March 2021.³² Although post–COVID-19 health care will certainly involve increased telemedicine, the extent remains unclear, as telehealth vendors saw decreased usage upon reopening of state economies. Ultimately, the postpandemic regulatory landscape is hard to predict.³⁰

Although COVID-19 appears to have caused rapid growth for DTC platforms, it also may have spurred competition. Telemedicine providers have given independent dermatologists and health care systems the infrastructure to implement custom DTC services.³³ Although systems do not directly sell prescription drugs, the target market is essentially the same: patients looking for instant virtual dermatologic care. Therefore, sustained telemedicine services offered by traditional practices and systems may prove detrimental to DTC companies. However, unlike most telemedicine services, DTC models are less affected by certain changes in regulation since they do not rely on insurance. If regulations are tightened and reimbursements for telehealth are not attractive for dermatologists, teledermatology services may see an overall decrease. If so, patients who appreciate teledermatology may shift to using DTC platforms, even if their insurance does not cover them. Still, a nationwide survey found 56% of respondents felt an established relationship with a physician prior to a telemedicine visit is important, which may create a barrier for DTC adoption.³⁴

Conclusion

Direct-to-consumer teledermatology represents a growing for-profit model of health care that provides patients with seemingly affordable and convenient care. However, there is potential for overtreatment, misdiagnosis, and fragmentation of health care. It will be important to monitor and evaluate the quality of care that DTC teledermatology offers and advocate for appropriate regulations and oversight. Eventually, more patients will have medications prescribed and dermatologic care administered through DTC companies. Dermatologists will benefit from this knowledge of DTC models to properly counsel patients on the risks and benefits of their use.

In recent years, direct-to-consumer (DTC) teledermatology platforms have gained popularity as telehealth business models, allowing patients to directly initiate visits with physicians and purchase medications from single platforms. A shortage of dermatologists, improved technology, drug patent expirations, and rising health care costs accelerated the growth of DTC dermatology.¹ During the COVID-19 pandemic, teledermatology adoption surged due to the need to provide care while social distancing and minimizing viral exposure. These needs prompted additional federal funding and loosened regulatory provisions.² As the userbase of these companies has grown, so have their valuations.³ Although the DTC model has attracted the attention of patients and investors, its rise provokes many questions about patients acting as consumers in health care. Indeed, DTC telemedicine offers greater autonomy and convenience for patients, but it may impact the quality of care and the nature of physician-patient relationships, perhaps making them more transactional.

Evolution of DTC in Health Care

The DTC model emphasizes individual choice and accessible health care. Although the definition has evolved, the core idea is not new.⁴ Over decades, pharmaceutical companies have spent billions of dollars on DTC advertising, circumventing physicians by directly reaching patients with campaigns on prescription drugs and laboratory tests and shaping public definitions of diseases.⁵

The DTC model of care is fundamentally different from traditional care models in that it changes the roles of the patient and physician. Whereas early telehealth models required a health care provider to initiate teleconsultations with specialists, DTC telemedicine bypasses this step (eg, the patient can consult a dermatologist without needing a primary care provider’s input first). This care can then be provided by dermatologists with whom patients may or may not have pre-established relationships.^4,6

Dermatology was an early adopter of DTC telemedicine. The shortage of dermatologists in the United States created demand for increasing accessibility to dermatologic care. Additionally, the visual nature of diagnosing dermatologic disease was ideal for platforms supporting image sharing.⁷ Early DTC providers were primarily individual companies offering teledermatology. However, many dermatologists can now offer DTC capabilities via companies such as Amwell and Teladoc Health.⁸

Over the last 2 decades, start-ups such as Warby Parker (eyeglasses) and Casper (mattresses) defined the DTC industry using borrowed supply chains, cohesive branding, heavy social media marketing, and web-only retail. Scalability, lack of competition, and abundant venture capital created competition across numerous markets.⁹ Health care capitalized on this DTC model, creating a $700 billion market for products ranging from hearing aids to over-the-counter medications.¹⁰

Borrowing from this DTC playbook, platforms were created to offer delivery of generic prescription drugs to patients’ doorsteps. However, unlike with other products bought online, a consumer cannot simply add prescription drugs to their shopping cart and check out. In all models of American medical practice, physicians still serve as gatekeepers, providing a safeguard for patients to ensure appropriate prescription and avoid negative consequences of unnecessary drug use. This new model effectively streamlines diagnosis, prescription, and drug delivery without the patient ever having to leave home. Combining the prescribing and selling of medications (2 tasks that traditionally have been separated) potentially creates financial conflicts of interest (COIs). Additionally, high utilization of health care, including more prescriptions and visits, does not necessarily equal high quality of care. The companies stand to benefit from extra care regardless of need, and thus these models must be scrutinized for any incentives driving unnecessary care and prescriptions.

Ultimately, DTC has evolved to encompass multiple definitions in health care (Table 1). Although all models provide health care, each offers a different modality of delivery. The primary service may be the sale of prescription drugs or simply telemedicine visits. This review primarily discusses DTC pharmaceutical telemedicine platforms that sell private-label drugs and also offer telemedicine services to streamline care. However, the history, risks, and benefits discussed may apply to all models.

The DTC Landscape

Most DTC companies employ variations on a model with the same 3 main components: a triage questionnaire, telehealth services, and prescription/drug delivery (Figure). The triage questionnaire elicits a history of the patient’s presentation and medical history. Some companies may use artificial intelligence (AI) algorithms to tailor questions to patient needs. There are 2 modalities for patient-provider communication: synchronous and asynchronous. Synchronous communication entails real-time patient-physician conversations via audio only or video call. Asynchronous (or store-and-forward) communication refers to consultations provided via messaging or text-based modality, where a provider may respond to a patient within 24 hours.⁶ Direct-to-consumer platforms primarily use asynchronous visits (Table 2). However, some also use synchronous modalities if the provider deems it necessary or if state laws require it.

Once a provider has consulted with the patient, they can prescribe medication as needed. In certain cases, with adequate history, a prescription may be issued without a full physician visit. Furthermore, DTC companies require purchase of their custom-branded generic drugs. Prescriptions are fulfilled by the company’s pharmacy network and directly shipped to patients; few will allow patients to transfer a prescription to a pharmacy of their choice. Some platforms also sell supplements and over-the-counter medications.

Payment models vary among these companies, and most do not accept insurance (Table 2). Select models may provide free consultations and only require payment for pharmaceuticals. Others charge for consultations but reallocate payment to the cost of medication if prescribed. Another model involves flat rates for consultations and additional charges for drugs but unlimited messaging with providers for the duration of the prescription. Moreover, patients can subscribe to monthly deliveries of their medications.

Foundation of DTC

Technological advances have enabled patients to receive remote treatment from a single platform offering video calls, AI, electronic medical record interoperability, and integration of drug supply chains. Even in its simplest form, AI is increasingly used, as it allows for programs and chatbots to screen and triage patients.¹¹ Technology also has improved at targeted mass marketing through social media platforms and search engines (eg, companies can use age, interests, location, and other parameters to target individuals likely needing acne treatment).

Drug patent expirations are a key catalyst for the rise of DTC companies, creating an attractive business model with generic drugs as the core product. Since 2008, patents for medications treating chronic conditions, such as erectile dysfunction, have expired. These patent expirations are responsible for $198 billion in projected prescription sales between 2019 and 2024.¹ Thus, it follows that DTC companies have seized this opportunity to act as middlemen, taking advantage of these generic medications’ lower costs to create platforms focused on personalization and accessibility.

Rising deductibles have led patients to consider cheaper out-of-pocket alternatives that are not covered by insurance.¹ For example, insurers typically do not cover finasteride treatment for conditions deemed cosmetic, such as androgenetic alopecia.¹² The low cost of generic drugs creates an attractive business model for patients and investors. According to GoodRx, the average retail price for a 30-day supply of brand-name finasteride (Propecia [Merck]) is $135.92, whereas generic finasteride is $75.24.¹³ Direct-to-consumer pharmaceutical companies offer a 30-day supply of generic finasteride ranging from $8.33 to $30.¹⁴ The average wholesale cost for retailers is an estimated $2.31 for 30 days.¹⁵ Although profit margins on generic medications may be lower, more affordable drugs increase the size of the total market. These prescriptions are available as subscription plans, resulting in recurring revenue.

Lax US pharmaceutical marketing regulations allow direct advertising to the general public.¹⁶ In 1997, the US Food and Drug Administration allowed DTC advertisements to replace summaries of serious and common adverse effects with short statements covering important risks or referrals to other sources for complete information. In 2015, the US Food and Drug Administration guidelines preventing encouragement of self-diagnosis and self-treatment were withdrawn.⁵ These changes enable DTC companies to launch large advertising campaigns and to accelerate customer acquisition, as the industry often describes it, with ease.

Rapid Growth and Implications

Increasing generic drug availability and improving telemedicine capabilities have the potential to reduce costs and barriers but also have the potential for financial gain. Venture capital funds have recognized this opportunity, reflected by millions of dollars of investments, and accelerated the growth of DTC health care start-ups. For example, Ro has raised $376 million from venture capital, valuing the company at $1.5 billion.³

Direct-to-consumer companies require a heavy focus on marketing campaigns for customer acquisition. Their aesthetically pleasing websites and aggressive campaigns target specific audiences based on demographics, digital use habits, and purchasing behavior.⁴ Some campaigns celebrate the ease of obtaining prescriptions.¹⁷ Companies have been effective in recruiting so-called millennial and Generation Z patients, known to search the internet for remedies prior to seeking physician consultations.¹⁸ Recognizing these needs, some platforms offer guides on diseases they treat, creating effective customer-acquisition funnels. Recruitment of these technology-friendly patients has proven effective, especially given the largely positive media coverage of DTC platforms––potentially serving as a surrogate for medical credibility for patients.¹⁸

Some DTC companies also market physically; skin care ads may be strategically placed in social media feeds, or even found near mirrors in public bathrooms.¹⁹ Marketing campaigns also involve disease awareness; such efforts serve to increase diagnoses and prescribed treatments while destigmatizing diseases. Although DTC companies argue this strategy empowers patients, these marketing habits have the potential to take advantage of uninformed patients. Campaigns could potentially medicalize normal experiences and expand disease definitions resulting in overdiagnosis, overtreatment, and wasted resources.⁵ For example, off-label propranolol use has been advertised to attract patients who might have “nerves that come creeping before an important presentation.”¹⁷ Disease awareness campaigns also may lead people to falsely believe unproven drug benefits.⁵ According to studies, DTC pharmaceutical advertisements are low in informational quality and result in increased patient visits and prescriptions despite cost-effective alternatives.^5,20-22

Fragmentation of the health care system is another possible complication of DTC teledermatology. These companies operate as for-profit organizations separated from the rest of the health care system, raising concerns about care coordination.⁸ Vital health data may not be conveyed as patients move among different providers and pharmacies. One study found DTC teledermatology rarely offered to provide medical records or facilitate a referral to a local physician.²³ Such a lack of communication is concerning, as medication errors are the leading cause of avoidable harm in health care.²⁴

Direct-to-consumer care models also seemingly redefine the physician-patient relationship by turning patients into consumers. Patient interactions may seem transactional and streamlined toward sales. For these platforms, a visit often is set up as an evaluation of a patient’s suitability for a prescription, not necessarily for the best treatment modality for the problem. These companies primarily make money through the sale of prescription drugs, creating a potential COI that may undermine the patient-physician relationship. Although some companies have made it clear that medical care and pharmaceutical sales are provided by legally separate business entities and that they do not pay physicians on commission, a conflict may still exist given the financial importance of physicians prescribing medication to the success of the business.¹⁶

Even as DTC models advertise upon expanded access and choice, the companies largely prohibit patients from choosing their own pharmacy. Instead, they encourage patients to fill prescriptions with the company’s pharmacy network by claiming lower costs compared with competitors. One DTC company, Hims, is launching a prescription-fulfillment center to further consolidate their business.^17,19,25 The inherent COI of issuing and fulfilling prescriptions raises concerns of patient harm.²⁶ For example, when Dermatology.com launched as a DTC prescription skin medication shop backed by Bausch Health Companies Inc, its model included telemedicine consultation. Although consultations were provided by RxDefine, a third party, only Dermatology.com drugs were prescribed. Given the poor quality of care and obvious financial COI, an uproar in the dermatology community and advocacy by the American Academy of Dermatology led to the shutdown of Dermatology.com’s online prescription services.²⁶

The quality of care among DTC telemedicine platforms has been equivocal. Some studies have reported equivalent care in person and online, while others have reported poor adherence to guidelines, overuse of antibiotics, and misdiagnosis.^8,23 A vital portion of the DTC experience is the history questionnaire, which is geared to diagnosis and risk assessment.²⁵ Resneck et al²³ found diagnostic quality to be adequate for simple dermatologic clinical scenarios but poor for scenarios requiring more than basic histories. Although Ro has reported leveraging data from millions of interactions to ask the right questions and streamline visits, it is still unclear whether history questionnaires are adequate.^17,27 Additionally, consultations may lack sufficient counseling on adverse effects, risks, or pregnancy warnings, as well as discussions on alternative treatments and preventative care.^17,23 Finally, patients often are limited in their choice of dermatologist; the lack of a fully developed relationship increases concerns of follow-up and monitoring practices. Although some DTC platforms offer unlimited interactions with physicians for the duration of a prescription, it is unknown how often these services are utilized or how adequate the quality of these interactions is. This potential for lax follow-up is especially concerning for prescriptions that autorenew on a monthly basis and could result in unnecessary overtreatment.

Postpandemic and Future Outlook

The COVID-19 pandemic dramatically impacted the use of telemedicine. To minimize COVID-19 transmission, the Centers for Medicare & Medicaid Services and private payers expanded telehealth coverage and eliminated reimbursement and licensing barriers.²⁸ A decade’s worth of regulatory changes and consumer adoption was accelerated to weeks, resulting in telemedicine companies reaching record-high visit numbers.²⁹ McKinsey & Company estimated that telehealth visit numbers surged 50- to 175-fold compared with pre–COVID-19 numbers. Additionally, 76% of patients were interested in future telehealth use, and 64% of providers were more comfortable using telehealth than before the pandemic.³⁰ For their part, US dermatologists reported an increase in telemedicine use from 14.1% to 96.9% since COVID-19.³¹

Exactly how much DTC pharmaceutical telemedicine companies are growing is unclear, but private investments may be an indication. A record $14.7 billion was invested in the digital health sector in the first half of 2021; the majority went to telehealth companies.³⁰ Ro, which reported $230 million in revenue in 2020 and has served 6 million visits, raised $200 milllion in July 2020 and $500 million in March 2021.³² Although post–COVID-19 health care will certainly involve increased telemedicine, the extent remains unclear, as telehealth vendors saw decreased usage upon reopening of state economies. Ultimately, the postpandemic regulatory landscape is hard to predict.³⁰

Although COVID-19 appears to have caused rapid growth for DTC platforms, it also may have spurred competition. Telemedicine providers have given independent dermatologists and health care systems the infrastructure to implement custom DTC services.³³ Although systems do not directly sell prescription drugs, the target market is essentially the same: patients looking for instant virtual dermatologic care. Therefore, sustained telemedicine services offered by traditional practices and systems may prove detrimental to DTC companies. However, unlike most telemedicine services, DTC models are less affected by certain changes in regulation since they do not rely on insurance. If regulations are tightened and reimbursements for telehealth are not attractive for dermatologists, teledermatology services may see an overall decrease. If so, patients who appreciate teledermatology may shift to using DTC platforms, even if their insurance does not cover them. Still, a nationwide survey found 56% of respondents felt an established relationship with a physician prior to a telemedicine visit is important, which may create a barrier for DTC adoption.³⁴

Conclusion

Direct-to-consumer teledermatology represents a growing for-profit model of health care that provides patients with seemingly affordable and convenient care. However, there is potential for overtreatment, misdiagnosis, and fragmentation of health care. It will be important to monitor and evaluate the quality of care that DTC teledermatology offers and advocate for appropriate regulations and oversight. Eventually, more patients will have medications prescribed and dermatologic care administered through DTC companies. Dermatologists will benefit from this knowledge of DTC models to properly counsel patients on the risks and benefits of their use.

In recent years, direct-to-consumer (DTC) teledermatology platforms have gained popularity as telehealth business models, allowing patients to directly initiate visits with physicians and purchase medications from single platforms. A shortage of dermatologists, improved technology, drug patent expirations, and rising health care costs accelerated the growth of DTC dermatology.¹ During the COVID-19 pandemic, teledermatology adoption surged due to the need to provide care while social distancing and minimizing viral exposure. These needs prompted additional federal funding and loosened regulatory provisions.² As the userbase of these companies has grown, so have their valuations.³ Although the DTC model has attracted the attention of patients and investors, its rise provokes many questions about patients acting as consumers in health care. Indeed, DTC telemedicine offers greater autonomy and convenience for patients, but it may impact the quality of care and the nature of physician-patient relationships, perhaps making them more transactional.

Evolution of DTC in Health Care

The DTC model emphasizes individual choice and accessible health care. Although the definition has evolved, the core idea is not new.⁴ Over decades, pharmaceutical companies have spent billions of dollars on DTC advertising, circumventing physicians by directly reaching patients with campaigns on prescription drugs and laboratory tests and shaping public definitions of diseases.⁵

The DTC model of care is fundamentally different from traditional care models in that it changes the roles of the patient and physician. Whereas early telehealth models required a health care provider to initiate teleconsultations with specialists, DTC telemedicine bypasses this step (eg, the patient can consult a dermatologist without needing a primary care provider’s input first). This care can then be provided by dermatologists with whom patients may or may not have pre-established relationships.^4,6

Dermatology was an early adopter of DTC telemedicine. The shortage of dermatologists in the United States created demand for increasing accessibility to dermatologic care. Additionally, the visual nature of diagnosing dermatologic disease was ideal for platforms supporting image sharing.⁷ Early DTC providers were primarily individual companies offering teledermatology. However, many dermatologists can now offer DTC capabilities via companies such as Amwell and Teladoc Health.⁸

Over the last 2 decades, start-ups such as Warby Parker (eyeglasses) and Casper (mattresses) defined the DTC industry using borrowed supply chains, cohesive branding, heavy social media marketing, and web-only retail. Scalability, lack of competition, and abundant venture capital created competition across numerous markets.⁹ Health care capitalized on this DTC model, creating a $700 billion market for products ranging from hearing aids to over-the-counter medications.¹⁰

Borrowing from this DTC playbook, platforms were created to offer delivery of generic prescription drugs to patients’ doorsteps. However, unlike with other products bought online, a consumer cannot simply add prescription drugs to their shopping cart and check out. In all models of American medical practice, physicians still serve as gatekeepers, providing a safeguard for patients to ensure appropriate prescription and avoid negative consequences of unnecessary drug use. This new model effectively streamlines diagnosis, prescription, and drug delivery without the patient ever having to leave home. Combining the prescribing and selling of medications (2 tasks that traditionally have been separated) potentially creates financial conflicts of interest (COIs). Additionally, high utilization of health care, including more prescriptions and visits, does not necessarily equal high quality of care. The companies stand to benefit from extra care regardless of need, and thus these models must be scrutinized for any incentives driving unnecessary care and prescriptions.

Ultimately, DTC has evolved to encompass multiple definitions in health care (Table 1). Although all models provide health care, each offers a different modality of delivery. The primary service may be the sale of prescription drugs or simply telemedicine visits. This review primarily discusses DTC pharmaceutical telemedicine platforms that sell private-label drugs and also offer telemedicine services to streamline care. However, the history, risks, and benefits discussed may apply to all models.

The DTC Landscape

Most DTC companies employ variations on a model with the same 3 main components: a triage questionnaire, telehealth services, and prescription/drug delivery (Figure). The triage questionnaire elicits a history of the patient’s presentation and medical history. Some companies may use artificial intelligence (AI) algorithms to tailor questions to patient needs. There are 2 modalities for patient-provider communication: synchronous and asynchronous. Synchronous communication entails real-time patient-physician conversations via audio only or video call. Asynchronous (or store-and-forward) communication refers to consultations provided via messaging or text-based modality, where a provider may respond to a patient within 24 hours.⁶ Direct-to-consumer platforms primarily use asynchronous visits (Table 2). However, some also use synchronous modalities if the provider deems it necessary or if state laws require it.

Once a provider has consulted with the patient, they can prescribe medication as needed. In certain cases, with adequate history, a prescription may be issued without a full physician visit. Furthermore, DTC companies require purchase of their custom-branded generic drugs. Prescriptions are fulfilled by the company’s pharmacy network and directly shipped to patients; few will allow patients to transfer a prescription to a pharmacy of their choice. Some platforms also sell supplements and over-the-counter medications.

Payment models vary among these companies, and most do not accept insurance (Table 2). Select models may provide free consultations and only require payment for pharmaceuticals. Others charge for consultations but reallocate payment to the cost of medication if prescribed. Another model involves flat rates for consultations and additional charges for drugs but unlimited messaging with providers for the duration of the prescription. Moreover, patients can subscribe to monthly deliveries of their medications.

Foundation of DTC

Technological advances have enabled patients to receive remote treatment from a single platform offering video calls, AI, electronic medical record interoperability, and integration of drug supply chains. Even in its simplest form, AI is increasingly used, as it allows for programs and chatbots to screen and triage patients.¹¹ Technology also has improved at targeted mass marketing through social media platforms and search engines (eg, companies can use age, interests, location, and other parameters to target individuals likely needing acne treatment).

Drug patent expirations are a key catalyst for the rise of DTC companies, creating an attractive business model with generic drugs as the core product. Since 2008, patents for medications treating chronic conditions, such as erectile dysfunction, have expired. These patent expirations are responsible for $198 billion in projected prescription sales between 2019 and 2024.¹ Thus, it follows that DTC companies have seized this opportunity to act as middlemen, taking advantage of these generic medications’ lower costs to create platforms focused on personalization and accessibility.

Rising deductibles have led patients to consider cheaper out-of-pocket alternatives that are not covered by insurance.¹ For example, insurers typically do not cover finasteride treatment for conditions deemed cosmetic, such as androgenetic alopecia.¹² The low cost of generic drugs creates an attractive business model for patients and investors. According to GoodRx, the average retail price for a 30-day supply of brand-name finasteride (Propecia [Merck]) is $135.92, whereas generic finasteride is $75.24.¹³ Direct-to-consumer pharmaceutical companies offer a 30-day supply of generic finasteride ranging from $8.33 to $30.¹⁴ The average wholesale cost for retailers is an estimated $2.31 for 30 days.¹⁵ Although profit margins on generic medications may be lower, more affordable drugs increase the size of the total market. These prescriptions are available as subscription plans, resulting in recurring revenue.

Lax US pharmaceutical marketing regulations allow direct advertising to the general public.¹⁶ In 1997, the US Food and Drug Administration allowed DTC advertisements to replace summaries of serious and common adverse effects with short statements covering important risks or referrals to other sources for complete information. In 2015, the US Food and Drug Administration guidelines preventing encouragement of self-diagnosis and self-treatment were withdrawn.⁵ These changes enable DTC companies to launch large advertising campaigns and to accelerate customer acquisition, as the industry often describes it, with ease.

Rapid Growth and Implications

Increasing generic drug availability and improving telemedicine capabilities have the potential to reduce costs and barriers but also have the potential for financial gain. Venture capital funds have recognized this opportunity, reflected by millions of dollars of investments, and accelerated the growth of DTC health care start-ups. For example, Ro has raised $376 million from venture capital, valuing the company at $1.5 billion.³

Direct-to-consumer companies require a heavy focus on marketing campaigns for customer acquisition. Their aesthetically pleasing websites and aggressive campaigns target specific audiences based on demographics, digital use habits, and purchasing behavior.⁴ Some campaigns celebrate the ease of obtaining prescriptions.¹⁷ Companies have been effective in recruiting so-called millennial and Generation Z patients, known to search the internet for remedies prior to seeking physician consultations.¹⁸ Recognizing these needs, some platforms offer guides on diseases they treat, creating effective customer-acquisition funnels. Recruitment of these technology-friendly patients has proven effective, especially given the largely positive media coverage of DTC platforms––potentially serving as a surrogate for medical credibility for patients.¹⁸

Some DTC companies also market physically; skin care ads may be strategically placed in social media feeds, or even found near mirrors in public bathrooms.¹⁹ Marketing campaigns also involve disease awareness; such efforts serve to increase diagnoses and prescribed treatments while destigmatizing diseases. Although DTC companies argue this strategy empowers patients, these marketing habits have the potential to take advantage of uninformed patients. Campaigns could potentially medicalize normal experiences and expand disease definitions resulting in overdiagnosis, overtreatment, and wasted resources.⁵ For example, off-label propranolol use has been advertised to attract patients who might have “nerves that come creeping before an important presentation.”¹⁷ Disease awareness campaigns also may lead people to falsely believe unproven drug benefits.⁵ According to studies, DTC pharmaceutical advertisements are low in informational quality and result in increased patient visits and prescriptions despite cost-effective alternatives.^5,20-22

Fragmentation of the health care system is another possible complication of DTC teledermatology. These companies operate as for-profit organizations separated from the rest of the health care system, raising concerns about care coordination.⁸ Vital health data may not be conveyed as patients move among different providers and pharmacies. One study found DTC teledermatology rarely offered to provide medical records or facilitate a referral to a local physician.²³ Such a lack of communication is concerning, as medication errors are the leading cause of avoidable harm in health care.²⁴

Direct-to-consumer care models also seemingly redefine the physician-patient relationship by turning patients into consumers. Patient interactions may seem transactional and streamlined toward sales. For these platforms, a visit often is set up as an evaluation of a patient’s suitability for a prescription, not necessarily for the best treatment modality for the problem. These companies primarily make money through the sale of prescription drugs, creating a potential COI that may undermine the patient-physician relationship. Although some companies have made it clear that medical care and pharmaceutical sales are provided by legally separate business entities and that they do not pay physicians on commission, a conflict may still exist given the financial importance of physicians prescribing medication to the success of the business.¹⁶

Even as DTC models advertise upon expanded access and choice, the companies largely prohibit patients from choosing their own pharmacy. Instead, they encourage patients to fill prescriptions with the company’s pharmacy network by claiming lower costs compared with competitors. One DTC company, Hims, is launching a prescription-fulfillment center to further consolidate their business.^17,19,25 The inherent COI of issuing and fulfilling prescriptions raises concerns of patient harm.²⁶ For example, when Dermatology.com launched as a DTC prescription skin medication shop backed by Bausch Health Companies Inc, its model included telemedicine consultation. Although consultations were provided by RxDefine, a third party, only Dermatology.com drugs were prescribed. Given the poor quality of care and obvious financial COI, an uproar in the dermatology community and advocacy by the American Academy of Dermatology led to the shutdown of Dermatology.com’s online prescription services.²⁶

The quality of care among DTC telemedicine platforms has been equivocal. Some studies have reported equivalent care in person and online, while others have reported poor adherence to guidelines, overuse of antibiotics, and misdiagnosis.^8,23 A vital portion of the DTC experience is the history questionnaire, which is geared to diagnosis and risk assessment.²⁵ Resneck et al²³ found diagnostic quality to be adequate for simple dermatologic clinical scenarios but poor for scenarios requiring more than basic histories. Although Ro has reported leveraging data from millions of interactions to ask the right questions and streamline visits, it is still unclear whether history questionnaires are adequate.^17,27 Additionally, consultations may lack sufficient counseling on adverse effects, risks, or pregnancy warnings, as well as discussions on alternative treatments and preventative care.^17,23 Finally, patients often are limited in their choice of dermatologist; the lack of a fully developed relationship increases concerns of follow-up and monitoring practices. Although some DTC platforms offer unlimited interactions with physicians for the duration of a prescription, it is unknown how often these services are utilized or how adequate the quality of these interactions is. This potential for lax follow-up is especially concerning for prescriptions that autorenew on a monthly basis and could result in unnecessary overtreatment.

Postpandemic and Future Outlook

The COVID-19 pandemic dramatically impacted the use of telemedicine. To minimize COVID-19 transmission, the Centers for Medicare & Medicaid Services and private payers expanded telehealth coverage and eliminated reimbursement and licensing barriers.²⁸ A decade’s worth of regulatory changes and consumer adoption was accelerated to weeks, resulting in telemedicine companies reaching record-high visit numbers.²⁹ McKinsey & Company estimated that telehealth visit numbers surged 50- to 175-fold compared with pre–COVID-19 numbers. Additionally, 76% of patients were interested in future telehealth use, and 64% of providers were more comfortable using telehealth than before the pandemic.³⁰ For their part, US dermatologists reported an increase in telemedicine use from 14.1% to 96.9% since COVID-19.³¹

Exactly how much DTC pharmaceutical telemedicine companies are growing is unclear, but private investments may be an indication. A record $14.7 billion was invested in the digital health sector in the first half of 2021; the majority went to telehealth companies.³⁰ Ro, which reported $230 million in revenue in 2020 and has served 6 million visits, raised $200 milllion in July 2020 and $500 million in March 2021.³² Although post–COVID-19 health care will certainly involve increased telemedicine, the extent remains unclear, as telehealth vendors saw decreased usage upon reopening of state economies. Ultimately, the postpandemic regulatory landscape is hard to predict.³⁰

Although COVID-19 appears to have caused rapid growth for DTC platforms, it also may have spurred competition. Telemedicine providers have given independent dermatologists and health care systems the infrastructure to implement custom DTC services.³³ Although systems do not directly sell prescription drugs, the target market is essentially the same: patients looking for instant virtual dermatologic care. Therefore, sustained telemedicine services offered by traditional practices and systems may prove detrimental to DTC companies. However, unlike most telemedicine services, DTC models are less affected by certain changes in regulation since they do not rely on insurance. If regulations are tightened and reimbursements for telehealth are not attractive for dermatologists, teledermatology services may see an overall decrease. If so, patients who appreciate teledermatology may shift to using DTC platforms, even if their insurance does not cover them. Still, a nationwide survey found 56% of respondents felt an established relationship with a physician prior to a telemedicine visit is important, which may create a barrier for DTC adoption.³⁴

Conclusion

Direct-to-consumer teledermatology represents a growing for-profit model of health care that provides patients with seemingly affordable and convenient care. However, there is potential for overtreatment, misdiagnosis, and fragmentation of health care. It will be important to monitor and evaluate the quality of care that DTC teledermatology offers and advocate for appropriate regulations and oversight. Eventually, more patients will have medications prescribed and dermatologic care administered through DTC companies. Dermatologists will benefit from this knowledge of DTC models to properly counsel patients on the risks and benefits of their use.

Following the attacks of September 11, 2001, heightened concerns over bioterrorism and the potential use of smallpox as a biological weapon made smallpox vaccination a critical component of military readiness. Therefore, the US Military resumed its smallpox vaccination program in 2002 using the first-generation smallpox vaccine (Dryvax, Wyeth Pharmaceuticals), a live vaccinia virus vaccine created in the late 19th century. This vaccine was developed by pooling vaccinia strains from the skin of infected cows¹ and had previously been used during the worldwide vaccination campaign in the 1970s. Dryvax was associated with various cardiac and cutaneous complications, from benign hypersensitivity reactions to life-threatening eczema vaccinatum and progressive vaccinia.

Due to concerns that the remaining supply of Dryvax was insufficient to vaccinate the US population in the case of a bioterrorism attack, investigators developed the second-generation smallpox vaccine (ACAM2000, Sanofi Pasteur Biologics Co) using advances in vaccine technology.² ACAM2000 is a plaque-purified isolate of vaccinia virus propagated in cell culture, thereby reducing contaminants and lot-to-lot variation.¹ Clinical trials demonstrated comparable immunogenicity and frequency of adverse events compared with Dryvax,² and ACAM2000 replaced Dryvax in 2008. However, these trials focused on serious adverse events, such as cardiac complications and postvaccinal encephalitis, with less specific characterization and description of cutaneous eruptions.³

Since 2008, there have been few reports of cutaneous adverse reactions following vaccination with ACAM2000. Beachkofsky et al⁴ described 7 cases of papulovesicular eruptions and 1 case of generalized vaccinia. Freeman and Lenz⁵ described 4 cases of papulovesicular eruptions, and there has been 1 case of progressive vaccinia reported in a soldier with newly diagnosed acute myelogenous leukemia.⁶ Kramer⁷ described a patient with multiple vesiculopustular lesions secondary to autoinoculation. The distinct pruritic acral papulovesicular eruptions following ACAM2000 vaccination have occurred in healthy military service members at different locations since the introduction of ACAM2000. We describe an additional case of this unique cutaneous eruption, followed by a review of previously described cutaneous adverse events associated with smallpox vaccination.

Case Report

A 21-year-old female soldier who was otherwise healthy presented to the dermatology clinic with a pruritic papular eruption involving the upper and lower extremities of 1 week’s duration. The lesions first appeared 8 days after she received the ACAM2000 vaccine. She received no other concurrent vaccines, had no history of atopic dermatitis, and had no systemic symptoms. Physical examination revealed numerous erythematous indurated papules involving the dorsolateral hands and fingers, as well as the extensor surfaces of the elbows, knees, and thighs (Figures 1 and 2). Based on the clinical presentation, the differential diagnosis included lichen planus, verruca plana, dyshidrotic eczema, and smallpox vaccine reaction. Erythema multiforme was considered; however, the absence of palmoplantar involvement and typical targetoid lesions made this diagnosis less likely.

Biopsies of lesions on the arm and thigh were performed. Histologic findings revealed interface and spongiotic dermatitis with scattered necrotic keratinocytes and extravasated erythrocytes (Figure 3). There was no evidence of viral cytopathic effects. Similar clinical and histologic findings have been reported in the literature as acral papulovesicular eruptions following smallpox vaccination or papular spongiotic dermatitis of smallpox vaccination.⁸ The presence of eosinophils was not conspicuous in the current case and was only a notable finding in 1 of 2 cases previously described by Gaertner et al.⁸ This may simply be due to an idiosyncratic drug reaction. Furthermore, in the cases described by Beachkofsky et al,⁴ there were essentially 2 histologic groups. The first group demonstrated a dermal hypersensitivity-type reaction, and the second group demonstrated a lymphocytic capillaritis.

Based on these findings, the patient was diagnosed with an acral papulovesicular eruption following smallpox vaccination. Of note, the patient’s presentation was not consistent with other described smallpox vaccine reactions, which included eczema vaccinatum, autoinoculation, generalized vaccinia, and progressive vaccinia. The patient was treated supportively with triamcinolone acetonide cream 0.1%, cool compresses, and oral diphenhydramine as needed for pruritus. The lesions notably improved within the first week of treatment.

Comment

Reported cases of acral papulovesicular eruption^4-6 demonstrated an onset of cutaneous symptoms an average of 14 days following vaccination (range, 8–18 days postvaccination). Lesions were benign and self-limited in all cases, with resolution within an average of 25 days (range, 7–71 days). All patients were active-duty military adults with a mean age of 24 years. Supportive treatment varied from topical steroids and oral antihistamines to tapering oral prednisone doses. Of note, all previously reported cases of this reaction occurred in patients who also had received other concurrent or near-concurrent vaccines, including anthrax, hepatitis B, influenza, and typhoid. Our patient represents a unique case of a papulovesicular eruption following smallpox vaccination with no history of concurrent vaccines.

Since the 1970s, smallpox vaccination has been associated with numerous cutaneous reactions, most of which have been reported with the first-generation Dryvax. Minor local reactions occurred in approximately 2% to 6% of vaccinees in clinical trials.⁹ These reactions included local edema involving the upper arm, satellite lesions within 2.5 cm of the vaccination site, local lymphadenopathy, intense inflammation or viral cellulitis surrounding the inoculation site, and viral lymphangitis tracking to axillary lymph nodes. In clinical trials, these reactions were self-limited and required only symptomatic treatment.⁹

Autoinoculation is another cutaneous reaction that can occur because Dryvax and ACAM2000 both contain live-attenuated replicating vaccinia virus. Accidental implantation may occur when the high titers of virus present at the vaccine site are subsequently transferred to other sites, especially abnormal mucosa or skin, resulting in an additional primary inoculation site.¹⁰

Eczema vaccinatum is a potentially life-threatening reaction that may occur in patients with disruptive skin disorders, such as atopic dermatitis. These patients are at risk for massive confluent vaccinia infection of the skin.¹⁰ In patients with atopic dermatitis, the virus rapidly disseminates due to both skin barrier dysfunction and impaired immunomodulation, resulting in large confluent skin lesions and the potential for viremia, septic shock, and death.^10,11 Mortality from eczema vaccinatum may be reduced by administration of vaccinia immune globulin.¹⁰

The vaccinia virus also may spread hematogenously in healthy individuals,¹⁰ resulting in a benign reaction called generalized vaccinia. These patients develop pustules on areas of the skin other than the vaccination site. Although typically benign and self-limited, Beachkofsky et al⁴ described a case of generalized vaccinia in a healthy 34-year-old man resulting in a rapidly progressive vesiculopustular eruption with associated fever and pancytopenia. The patient made a complete recovery over the course of the following month.⁴

Alternatively, progressive vaccinia is a severe complication of smallpox vaccination seen in patients with impaired cell-mediated immunity. It also is known as vaccinia gangrenosum or vaccinia necrosum. These patients develop expanding ulcers due to exaggerated viral replication and cell-to-cell spread of the vaccinia virus.^10,11 Hematogenous spread may result in viral implantation at distant sites of the body. This disease slowly progresses over weeks to months, and it often is resistant to treatment and fatal in patients with severe T-cell deficiency.¹⁰

Acral papulovesicular eruption is a distinct cutaneous adverse event following smallpox vaccination. Although further research is needed to discern the pathogenesis of this reaction, it is benign and self-limited, and patients have fully recovered with supportive care. In addition, a modified vaccinia Ankara vaccine (Bavarian Nordic) was approved by the US Food and Drug Administration in 2019.^12,13 It is a nonreplicating attenuated viral vaccine that had fewer adverse events compared to ACAM2000 in clinical trials.¹³ To date, papulovesicular eruptions have not been reported following vaccination with the modified vaccinia Ankara vaccine; however, continued monitoring will help to further characterize any cutaneous reactions to this newer vaccine.

Following the attacks of September 11, 2001, heightened concerns over bioterrorism and the potential use of smallpox as a biological weapon made smallpox vaccination a critical component of military readiness. Therefore, the US Military resumed its smallpox vaccination program in 2002 using the first-generation smallpox vaccine (Dryvax, Wyeth Pharmaceuticals), a live vaccinia virus vaccine created in the late 19th century. This vaccine was developed by pooling vaccinia strains from the skin of infected cows¹ and had previously been used during the worldwide vaccination campaign in the 1970s. Dryvax was associated with various cardiac and cutaneous complications, from benign hypersensitivity reactions to life-threatening eczema vaccinatum and progressive vaccinia.

Due to concerns that the remaining supply of Dryvax was insufficient to vaccinate the US population in the case of a bioterrorism attack, investigators developed the second-generation smallpox vaccine (ACAM2000, Sanofi Pasteur Biologics Co) using advances in vaccine technology.² ACAM2000 is a plaque-purified isolate of vaccinia virus propagated in cell culture, thereby reducing contaminants and lot-to-lot variation.¹ Clinical trials demonstrated comparable immunogenicity and frequency of adverse events compared with Dryvax,² and ACAM2000 replaced Dryvax in 2008. However, these trials focused on serious adverse events, such as cardiac complications and postvaccinal encephalitis, with less specific characterization and description of cutaneous eruptions.³

Since 2008, there have been few reports of cutaneous adverse reactions following vaccination with ACAM2000. Beachkofsky et al⁴ described 7 cases of papulovesicular eruptions and 1 case of generalized vaccinia. Freeman and Lenz⁵ described 4 cases of papulovesicular eruptions, and there has been 1 case of progressive vaccinia reported in a soldier with newly diagnosed acute myelogenous leukemia.⁶ Kramer⁷ described a patient with multiple vesiculopustular lesions secondary to autoinoculation. The distinct pruritic acral papulovesicular eruptions following ACAM2000 vaccination have occurred in healthy military service members at different locations since the introduction of ACAM2000. We describe an additional case of this unique cutaneous eruption, followed by a review of previously described cutaneous adverse events associated with smallpox vaccination.

Case Report

A 21-year-old female soldier who was otherwise healthy presented to the dermatology clinic with a pruritic papular eruption involving the upper and lower extremities of 1 week’s duration. The lesions first appeared 8 days after she received the ACAM2000 vaccine. She received no other concurrent vaccines, had no history of atopic dermatitis, and had no systemic symptoms. Physical examination revealed numerous erythematous indurated papules involving the dorsolateral hands and fingers, as well as the extensor surfaces of the elbows, knees, and thighs (Figures 1 and 2). Based on the clinical presentation, the differential diagnosis included lichen planus, verruca plana, dyshidrotic eczema, and smallpox vaccine reaction. Erythema multiforme was considered; however, the absence of palmoplantar involvement and typical targetoid lesions made this diagnosis less likely.

Biopsies of lesions on the arm and thigh were performed. Histologic findings revealed interface and spongiotic dermatitis with scattered necrotic keratinocytes and extravasated erythrocytes (Figure 3). There was no evidence of viral cytopathic effects. Similar clinical and histologic findings have been reported in the literature as acral papulovesicular eruptions following smallpox vaccination or papular spongiotic dermatitis of smallpox vaccination.⁸ The presence of eosinophils was not conspicuous in the current case and was only a notable finding in 1 of 2 cases previously described by Gaertner et al.⁸ This may simply be due to an idiosyncratic drug reaction. Furthermore, in the cases described by Beachkofsky et al,⁴ there were essentially 2 histologic groups. The first group demonstrated a dermal hypersensitivity-type reaction, and the second group demonstrated a lymphocytic capillaritis.

Based on these findings, the patient was diagnosed with an acral papulovesicular eruption following smallpox vaccination. Of note, the patient’s presentation was not consistent with other described smallpox vaccine reactions, which included eczema vaccinatum, autoinoculation, generalized vaccinia, and progressive vaccinia. The patient was treated supportively with triamcinolone acetonide cream 0.1%, cool compresses, and oral diphenhydramine as needed for pruritus. The lesions notably improved within the first week of treatment.

Comment

Reported cases of acral papulovesicular eruption^4-6 demonstrated an onset of cutaneous symptoms an average of 14 days following vaccination (range, 8–18 days postvaccination). Lesions were benign and self-limited in all cases, with resolution within an average of 25 days (range, 7–71 days). All patients were active-duty military adults with a mean age of 24 years. Supportive treatment varied from topical steroids and oral antihistamines to tapering oral prednisone doses. Of note, all previously reported cases of this reaction occurred in patients who also had received other concurrent or near-concurrent vaccines, including anthrax, hepatitis B, influenza, and typhoid. Our patient represents a unique case of a papulovesicular eruption following smallpox vaccination with no history of concurrent vaccines.

Since the 1970s, smallpox vaccination has been associated with numerous cutaneous reactions, most of which have been reported with the first-generation Dryvax. Minor local reactions occurred in approximately 2% to 6% of vaccinees in clinical trials.⁹ These reactions included local edema involving the upper arm, satellite lesions within 2.5 cm of the vaccination site, local lymphadenopathy, intense inflammation or viral cellulitis surrounding the inoculation site, and viral lymphangitis tracking to axillary lymph nodes. In clinical trials, these reactions were self-limited and required only symptomatic treatment.⁹

Autoinoculation is another cutaneous reaction that can occur because Dryvax and ACAM2000 both contain live-attenuated replicating vaccinia virus. Accidental implantation may occur when the high titers of virus present at the vaccine site are subsequently transferred to other sites, especially abnormal mucosa or skin, resulting in an additional primary inoculation site.¹⁰

Eczema vaccinatum is a potentially life-threatening reaction that may occur in patients with disruptive skin disorders, such as atopic dermatitis. These patients are at risk for massive confluent vaccinia infection of the skin.¹⁰ In patients with atopic dermatitis, the virus rapidly disseminates due to both skin barrier dysfunction and impaired immunomodulation, resulting in large confluent skin lesions and the potential for viremia, septic shock, and death.^10,11 Mortality from eczema vaccinatum may be reduced by administration of vaccinia immune globulin.¹⁰

The vaccinia virus also may spread hematogenously in healthy individuals,¹⁰ resulting in a benign reaction called generalized vaccinia. These patients develop pustules on areas of the skin other than the vaccination site. Although typically benign and self-limited, Beachkofsky et al⁴ described a case of generalized vaccinia in a healthy 34-year-old man resulting in a rapidly progressive vesiculopustular eruption with associated fever and pancytopenia. The patient made a complete recovery over the course of the following month.⁴

Alternatively, progressive vaccinia is a severe complication of smallpox vaccination seen in patients with impaired cell-mediated immunity. It also is known as vaccinia gangrenosum or vaccinia necrosum. These patients develop expanding ulcers due to exaggerated viral replication and cell-to-cell spread of the vaccinia virus.^10,11 Hematogenous spread may result in viral implantation at distant sites of the body. This disease slowly progresses over weeks to months, and it often is resistant to treatment and fatal in patients with severe T-cell deficiency.¹⁰

Acral papulovesicular eruption is a distinct cutaneous adverse event following smallpox vaccination. Although further research is needed to discern the pathogenesis of this reaction, it is benign and self-limited, and patients have fully recovered with supportive care. In addition, a modified vaccinia Ankara vaccine (Bavarian Nordic) was approved by the US Food and Drug Administration in 2019.^12,13 It is a nonreplicating attenuated viral vaccine that had fewer adverse events compared to ACAM2000 in clinical trials.¹³ To date, papulovesicular eruptions have not been reported following vaccination with the modified vaccinia Ankara vaccine; however, continued monitoring will help to further characterize any cutaneous reactions to this newer vaccine.

Following the attacks of September 11, 2001, heightened concerns over bioterrorism and the potential use of smallpox as a biological weapon made smallpox vaccination a critical component of military readiness. Therefore, the US Military resumed its smallpox vaccination program in 2002 using the first-generation smallpox vaccine (Dryvax, Wyeth Pharmaceuticals), a live vaccinia virus vaccine created in the late 19th century. This vaccine was developed by pooling vaccinia strains from the skin of infected cows¹ and had previously been used during the worldwide vaccination campaign in the 1970s. Dryvax was associated with various cardiac and cutaneous complications, from benign hypersensitivity reactions to life-threatening eczema vaccinatum and progressive vaccinia.

Due to concerns that the remaining supply of Dryvax was insufficient to vaccinate the US population in the case of a bioterrorism attack, investigators developed the second-generation smallpox vaccine (ACAM2000, Sanofi Pasteur Biologics Co) using advances in vaccine technology.² ACAM2000 is a plaque-purified isolate of vaccinia virus propagated in cell culture, thereby reducing contaminants and lot-to-lot variation.¹ Clinical trials demonstrated comparable immunogenicity and frequency of adverse events compared with Dryvax,² and ACAM2000 replaced Dryvax in 2008. However, these trials focused on serious adverse events, such as cardiac complications and postvaccinal encephalitis, with less specific characterization and description of cutaneous eruptions.³

Since 2008, there have been few reports of cutaneous adverse reactions following vaccination with ACAM2000. Beachkofsky et al⁴ described 7 cases of papulovesicular eruptions and 1 case of generalized vaccinia. Freeman and Lenz⁵ described 4 cases of papulovesicular eruptions, and there has been 1 case of progressive vaccinia reported in a soldier with newly diagnosed acute myelogenous leukemia.⁶ Kramer⁷ described a patient with multiple vesiculopustular lesions secondary to autoinoculation. The distinct pruritic acral papulovesicular eruptions following ACAM2000 vaccination have occurred in healthy military service members at different locations since the introduction of ACAM2000. We describe an additional case of this unique cutaneous eruption, followed by a review of previously described cutaneous adverse events associated with smallpox vaccination.

Case Report

A 21-year-old female soldier who was otherwise healthy presented to the dermatology clinic with a pruritic papular eruption involving the upper and lower extremities of 1 week’s duration. The lesions first appeared 8 days after she received the ACAM2000 vaccine. She received no other concurrent vaccines, had no history of atopic dermatitis, and had no systemic symptoms. Physical examination revealed numerous erythematous indurated papules involving the dorsolateral hands and fingers, as well as the extensor surfaces of the elbows, knees, and thighs (Figures 1 and 2). Based on the clinical presentation, the differential diagnosis included lichen planus, verruca plana, dyshidrotic eczema, and smallpox vaccine reaction. Erythema multiforme was considered; however, the absence of palmoplantar involvement and typical targetoid lesions made this diagnosis less likely.

Biopsies of lesions on the arm and thigh were performed. Histologic findings revealed interface and spongiotic dermatitis with scattered necrotic keratinocytes and extravasated erythrocytes (Figure 3). There was no evidence of viral cytopathic effects. Similar clinical and histologic findings have been reported in the literature as acral papulovesicular eruptions following smallpox vaccination or papular spongiotic dermatitis of smallpox vaccination.⁸ The presence of eosinophils was not conspicuous in the current case and was only a notable finding in 1 of 2 cases previously described by Gaertner et al.⁸ This may simply be due to an idiosyncratic drug reaction. Furthermore, in the cases described by Beachkofsky et al,⁴ there were essentially 2 histologic groups. The first group demonstrated a dermal hypersensitivity-type reaction, and the second group demonstrated a lymphocytic capillaritis.

Based on these findings, the patient was diagnosed with an acral papulovesicular eruption following smallpox vaccination. Of note, the patient’s presentation was not consistent with other described smallpox vaccine reactions, which included eczema vaccinatum, autoinoculation, generalized vaccinia, and progressive vaccinia. The patient was treated supportively with triamcinolone acetonide cream 0.1%, cool compresses, and oral diphenhydramine as needed for pruritus. The lesions notably improved within the first week of treatment.

Comment

Reported cases of acral papulovesicular eruption^4-6 demonstrated an onset of cutaneous symptoms an average of 14 days following vaccination (range, 8–18 days postvaccination). Lesions were benign and self-limited in all cases, with resolution within an average of 25 days (range, 7–71 days). All patients were active-duty military adults with a mean age of 24 years. Supportive treatment varied from topical steroids and oral antihistamines to tapering oral prednisone doses. Of note, all previously reported cases of this reaction occurred in patients who also had received other concurrent or near-concurrent vaccines, including anthrax, hepatitis B, influenza, and typhoid. Our patient represents a unique case of a papulovesicular eruption following smallpox vaccination with no history of concurrent vaccines.

Since the 1970s, smallpox vaccination has been associated with numerous cutaneous reactions, most of which have been reported with the first-generation Dryvax. Minor local reactions occurred in approximately 2% to 6% of vaccinees in clinical trials.⁹ These reactions included local edema involving the upper arm, satellite lesions within 2.5 cm of the vaccination site, local lymphadenopathy, intense inflammation or viral cellulitis surrounding the inoculation site, and viral lymphangitis tracking to axillary lymph nodes. In clinical trials, these reactions were self-limited and required only symptomatic treatment.⁹

Autoinoculation is another cutaneous reaction that can occur because Dryvax and ACAM2000 both contain live-attenuated replicating vaccinia virus. Accidental implantation may occur when the high titers of virus present at the vaccine site are subsequently transferred to other sites, especially abnormal mucosa or skin, resulting in an additional primary inoculation site.¹⁰

Eczema vaccinatum is a potentially life-threatening reaction that may occur in patients with disruptive skin disorders, such as atopic dermatitis. These patients are at risk for massive confluent vaccinia infection of the skin.¹⁰ In patients with atopic dermatitis, the virus rapidly disseminates due to both skin barrier dysfunction and impaired immunomodulation, resulting in large confluent skin lesions and the potential for viremia, septic shock, and death.^10,11 Mortality from eczema vaccinatum may be reduced by administration of vaccinia immune globulin.¹⁰

The vaccinia virus also may spread hematogenously in healthy individuals,¹⁰ resulting in a benign reaction called generalized vaccinia. These patients develop pustules on areas of the skin other than the vaccination site. Although typically benign and self-limited, Beachkofsky et al⁴ described a case of generalized vaccinia in a healthy 34-year-old man resulting in a rapidly progressive vesiculopustular eruption with associated fever and pancytopenia. The patient made a complete recovery over the course of the following month.⁴

Alternatively, progressive vaccinia is a severe complication of smallpox vaccination seen in patients with impaired cell-mediated immunity. It also is known as vaccinia gangrenosum or vaccinia necrosum. These patients develop expanding ulcers due to exaggerated viral replication and cell-to-cell spread of the vaccinia virus.^10,11 Hematogenous spread may result in viral implantation at distant sites of the body. This disease slowly progresses over weeks to months, and it often is resistant to treatment and fatal in patients with severe T-cell deficiency.¹⁰

Acral papulovesicular eruption is a distinct cutaneous adverse event following smallpox vaccination. Although further research is needed to discern the pathogenesis of this reaction, it is benign and self-limited, and patients have fully recovered with supportive care. In addition, a modified vaccinia Ankara vaccine (Bavarian Nordic) was approved by the US Food and Drug Administration in 2019.^12,13 It is a nonreplicating attenuated viral vaccine that had fewer adverse events compared to ACAM2000 in clinical trials.¹³ To date, papulovesicular eruptions have not been reported following vaccination with the modified vaccinia Ankara vaccine; however, continued monitoring will help to further characterize any cutaneous reactions to this newer vaccine.

Case Report

A 58-year-old woman presented to the dermatology office with a widespread pruritic eruption of 3 days’ duration that started in the groin and spread to the rest of the body. No treatments had been attempted. She had no notable medical history, and she denied any recent illness, change in personal care products, or new medications or supplements. She reported a camping trip 2 weeks prior to presentation on the east end of Long Island, New York. She later learned that others on the same trip developed a similar, albeit less widespread, eruption.

Physical examination revealed clear vesicles on the arms, legs, trunk, and pubic area (Figure 1). Dermoscopy revealed a small lone star tick larva in the center of one of the vesicles (Figure 2). The type of tick larva was identified using resources from the Centers for Disease Control and Prevention (Figure 3).¹ Careful inspection revealed dark marks on various vesicles, mostly in the perineum, yielding nearly 20 larvae, which were removed with forceps. The patient was counseled to cover herself in petrolatum for 2 to 3 hours with the hope of smothering any remaining tick larvae. She was given triamcinolone cream and was encouraged to take a nonsedating antihistamine for itch. The patient was seen back in clinic 2 weeks later and the eruption had resolved.

Comment

Spread of Tick-Borne Disease—Ticks and tick-borne disease are increasing major health concerns for humans, domesticated animals, and livestock. Reported cases of bacterial and protozoan tick-borne disease doubled in the United States between 2004 and 2016. Ninety percent of the nearly 60,000 cases of nationally notifiable vector-borne diseases reported in 2017 were linked to ticks.² Geographic ranges of multiple tick species continue to expand, which is thought to be secondary to rising global temperatures, ecologic changes, reforestation, and increases in commerce and travel (Figure 4).³ Not only have warming temperatures contributed to geographic range expansion, they also may extend ticks’ active season. The lone star tick (Amblyomma americanum) is widely distributed throughout much of the eastern United States.⁴ The range of A americanum has expanded north in recent years from its prior core range in the southeastern United States.² One study found that from 2006 to 2016, the vector tick species most commonly collected from humans and submitted to a tick surveillance system in New Jersey shifted from Ixodes scapularis to A americanum.⁵

Bites by Amblyomma Ticks—As with most hard ticks, the life cycle of A americanum lasts 2 years and includes the egg, the 6-legged larva or “seed tick,” the 8-legged immature nymph, and the 8-legged reproductively mature adult (Figure 3). Amblyomma americanum can lay several thousand eggs.² Because our patient had numerous bites, it is plausible that she came into contact with a nest of newly hatched tick larvae. Morphogenesis from larva to nymph, then nymph to adult, requires a blood meal.^6,7 The larvae emerge from eggs deposited on the ground and then crawl up low vegetation where they can easily attach to passing hosts. The tick clings to hair or clothing and waits until the host is at rest before moving to a favorable location and then bites.⁸ When attaching, ticks inject an anesthetic akin to lidocaine, making the bite painless. A tick may spend up to 24 hours on the host prior to biting and then feed for 2 hours to 7 days before releasing.⁹ For the majority of tick-borne illnesses, the tick must remain attached for 24 to 48 hours before disease is transmitted.¹⁰

All stages of Amblyomma, excluding the egg, are capable of transmitting disease.^8,11Amblyomma americanum is called the lone star tick because of the prominent white dot on the back of the adult female. It will feed on small or large mammals during any stage of its life cycle. It is known to transmit Ehrlichia chaffeensis and Ehrlichia ewingii, which cause human ehrlichiosis, and Francisella tularensis, which causes tularemia, Heartland virus, Bourbon virus, and Southern tick-associated rash illness. Delayed anaphylaxis to ingestion of red meat has been attributed to the bite of A americanum. Amblyomma americanum ticks are not known to transmit Lyme disease. The Centers for Disease Control and Prevention does not recommend prophylactic treatment to prevent ehrlichiosis.¹² Tularemia prophylaxis is only recommended in cases of laboratory exposure to infectious materials. Doxycycline prophylaxis is only recommended if the tick is identified as an adult or nymphal I scapularis.¹²

Even when the ticks do not transmit disease, tick bites can cause impressive local reactions. Uncomplicated bites can be painful and leave a puncture wound that can take 1 to 2 weeks to heal.¹³ Rarely, bites can cause a delayed hypersensitivity reaction including fever, pruritus, and urticaria. Granulomas can develop if a tick is improperly removed.⁹ Other reports describe prurigo lesions, skin hemorrhage, papular urticaria, diffuse papules, vesicles and bullae, necrotic ulcers, and patchy alopecia.^14,15 A 2015 systematic controlled study of human bite reactions from A americanum demonstrated the development of itchy erythematous papules and vesicles within 48 hours of larval tick attachment to research participants. The study found tissue damage from A americanum mouthparts, and degranulating mast cells may be evident in as little as 15 minutes.¹⁶ The severity of individual skin reaction is hypothesized to depend on several variables, such as the duration of feeding, size of mouthparts, type of tick secretions, changes in secretions during feeding, and prior exposures of the host.¹⁴

Tick Removal—If patients present to clinic with ticks attached, removal can be challenging. Removal recommendations call for use of blunt forceps or tweezers. Ticks should be grasped near the skin with consistent pressure, and the tick should be pulled straight out, perpendicular to the skin. Twisting motions can cause the head to separate from the body and remain in the bite wound. Immediately following removal, the area should be cleansed with a disinfectant.^10,17 After the tick is removed, some studies recommend storing the tick at −20 °C; should the patient develop disease, the tick could be sent for evaluation.^6,17 If there is no clinical or serologic evidence of infection, testing for the presence of antibodies against tick-borne bacteria at presentation and at 3 and 6 weeks is not recommended due to low sensitivity, low positive predictive value, and cost. Clinicians must only observe and treat if disease occurs.¹⁷

Prevention of Tick Bites—Tick bites are best prevented by avoiding tick-infested areas; when these areas are unavoidable, tick bites may be prevented by wearing long pants with the pant legs tucked into boots. In addition, applying topical DEET (N,N-diethyl-m-toluamide) repellent to exposed skin and treating clothing with permethrin can be helpful.¹⁷ When used alone, DEET provides greater than 90% protection for up to 2.7 hours against A americanum.¹⁸ Permethrin-treated clothing alone is 79% to 100% effective at killing A americanum ticks or disabling them for several hours.¹⁹

Conclusion

Tick-borne illness is an increasingly important cause of human infectious disease. In addition to their role as a disease vector, ticks can produce primary skin disorders. This case posed a diagnostic challenge because of the unusually large number and wide distribution of bites as well as the subsequent vesicular reaction that ensued. It is important to keep tick larvae or adult tick bites in the differential when evaluating a patient to expedite tick removal and begin clinical monitoring. Recognition of A americanum larvae as a potential cause of pruritic papules may be helpful in similar cases. In addition, it is important for dermatologists to be aware of the tick species in their area.

Case Report

A 58-year-old woman presented to the dermatology office with a widespread pruritic eruption of 3 days’ duration that started in the groin and spread to the rest of the body. No treatments had been attempted. She had no notable medical history, and she denied any recent illness, change in personal care products, or new medications or supplements. She reported a camping trip 2 weeks prior to presentation on the east end of Long Island, New York. She later learned that others on the same trip developed a similar, albeit less widespread, eruption.

Physical examination revealed clear vesicles on the arms, legs, trunk, and pubic area (Figure 1). Dermoscopy revealed a small lone star tick larva in the center of one of the vesicles (Figure 2). The type of tick larva was identified using resources from the Centers for Disease Control and Prevention (Figure 3).¹ Careful inspection revealed dark marks on various vesicles, mostly in the perineum, yielding nearly 20 larvae, which were removed with forceps. The patient was counseled to cover herself in petrolatum for 2 to 3 hours with the hope of smothering any remaining tick larvae. She was given triamcinolone cream and was encouraged to take a nonsedating antihistamine for itch. The patient was seen back in clinic 2 weeks later and the eruption had resolved.

Comment

Spread of Tick-Borne Disease—Ticks and tick-borne disease are increasing major health concerns for humans, domesticated animals, and livestock. Reported cases of bacterial and protozoan tick-borne disease doubled in the United States between 2004 and 2016. Ninety percent of the nearly 60,000 cases of nationally notifiable vector-borne diseases reported in 2017 were linked to ticks.² Geographic ranges of multiple tick species continue to expand, which is thought to be secondary to rising global temperatures, ecologic changes, reforestation, and increases in commerce and travel (Figure 4).³ Not only have warming temperatures contributed to geographic range expansion, they also may extend ticks’ active season. The lone star tick (Amblyomma americanum) is widely distributed throughout much of the eastern United States.⁴ The range of A americanum has expanded north in recent years from its prior core range in the southeastern United States.² One study found that from 2006 to 2016, the vector tick species most commonly collected from humans and submitted to a tick surveillance system in New Jersey shifted from Ixodes scapularis to A americanum.⁵

Bites by Amblyomma Ticks—As with most hard ticks, the life cycle of A americanum lasts 2 years and includes the egg, the 6-legged larva or “seed tick,” the 8-legged immature nymph, and the 8-legged reproductively mature adult (Figure 3). Amblyomma americanum can lay several thousand eggs.² Because our patient had numerous bites, it is plausible that she came into contact with a nest of newly hatched tick larvae. Morphogenesis from larva to nymph, then nymph to adult, requires a blood meal.^6,7 The larvae emerge from eggs deposited on the ground and then crawl up low vegetation where they can easily attach to passing hosts. The tick clings to hair or clothing and waits until the host is at rest before moving to a favorable location and then bites.⁸ When attaching, ticks inject an anesthetic akin to lidocaine, making the bite painless. A tick may spend up to 24 hours on the host prior to biting and then feed for 2 hours to 7 days before releasing.⁹ For the majority of tick-borne illnesses, the tick must remain attached for 24 to 48 hours before disease is transmitted.¹⁰

All stages of Amblyomma, excluding the egg, are capable of transmitting disease.^8,11Amblyomma americanum is called the lone star tick because of the prominent white dot on the back of the adult female. It will feed on small or large mammals during any stage of its life cycle. It is known to transmit Ehrlichia chaffeensis and Ehrlichia ewingii, which cause human ehrlichiosis, and Francisella tularensis, which causes tularemia, Heartland virus, Bourbon virus, and Southern tick-associated rash illness. Delayed anaphylaxis to ingestion of red meat has been attributed to the bite of A americanum. Amblyomma americanum ticks are not known to transmit Lyme disease. The Centers for Disease Control and Prevention does not recommend prophylactic treatment to prevent ehrlichiosis.¹² Tularemia prophylaxis is only recommended in cases of laboratory exposure to infectious materials. Doxycycline prophylaxis is only recommended if the tick is identified as an adult or nymphal I scapularis.¹²

Even when the ticks do not transmit disease, tick bites can cause impressive local reactions. Uncomplicated bites can be painful and leave a puncture wound that can take 1 to 2 weeks to heal.¹³ Rarely, bites can cause a delayed hypersensitivity reaction including fever, pruritus, and urticaria. Granulomas can develop if a tick is improperly removed.⁹ Other reports describe prurigo lesions, skin hemorrhage, papular urticaria, diffuse papules, vesicles and bullae, necrotic ulcers, and patchy alopecia.^14,15 A 2015 systematic controlled study of human bite reactions from A americanum demonstrated the development of itchy erythematous papules and vesicles within 48 hours of larval tick attachment to research participants. The study found tissue damage from A americanum mouthparts, and degranulating mast cells may be evident in as little as 15 minutes.¹⁶ The severity of individual skin reaction is hypothesized to depend on several variables, such as the duration of feeding, size of mouthparts, type of tick secretions, changes in secretions during feeding, and prior exposures of the host.¹⁴

Tick Removal—If patients present to clinic with ticks attached, removal can be challenging. Removal recommendations call for use of blunt forceps or tweezers. Ticks should be grasped near the skin with consistent pressure, and the tick should be pulled straight out, perpendicular to the skin. Twisting motions can cause the head to separate from the body and remain in the bite wound. Immediately following removal, the area should be cleansed with a disinfectant.^10,17 After the tick is removed, some studies recommend storing the tick at −20 °C; should the patient develop disease, the tick could be sent for evaluation.^6,17 If there is no clinical or serologic evidence of infection, testing for the presence of antibodies against tick-borne bacteria at presentation and at 3 and 6 weeks is not recommended due to low sensitivity, low positive predictive value, and cost. Clinicians must only observe and treat if disease occurs.¹⁷

Prevention of Tick Bites—Tick bites are best prevented by avoiding tick-infested areas; when these areas are unavoidable, tick bites may be prevented by wearing long pants with the pant legs tucked into boots. In addition, applying topical DEET (N,N-diethyl-m-toluamide) repellent to exposed skin and treating clothing with permethrin can be helpful.¹⁷ When used alone, DEET provides greater than 90% protection for up to 2.7 hours against A americanum.¹⁸ Permethrin-treated clothing alone is 79% to 100% effective at killing A americanum ticks or disabling them for several hours.¹⁹

Conclusion

Tick-borne illness is an increasingly important cause of human infectious disease. In addition to their role as a disease vector, ticks can produce primary skin disorders. This case posed a diagnostic challenge because of the unusually large number and wide distribution of bites as well as the subsequent vesicular reaction that ensued. It is important to keep tick larvae or adult tick bites in the differential when evaluating a patient to expedite tick removal and begin clinical monitoring. Recognition of A americanum larvae as a potential cause of pruritic papules may be helpful in similar cases. In addition, it is important for dermatologists to be aware of the tick species in their area.

Case Report

A 58-year-old woman presented to the dermatology office with a widespread pruritic eruption of 3 days’ duration that started in the groin and spread to the rest of the body. No treatments had been attempted. She had no notable medical history, and she denied any recent illness, change in personal care products, or new medications or supplements. She reported a camping trip 2 weeks prior to presentation on the east end of Long Island, New York. She later learned that others on the same trip developed a similar, albeit less widespread, eruption.

Physical examination revealed clear vesicles on the arms, legs, trunk, and pubic area (Figure 1). Dermoscopy revealed a small lone star tick larva in the center of one of the vesicles (Figure 2). The type of tick larva was identified using resources from the Centers for Disease Control and Prevention (Figure 3).¹ Careful inspection revealed dark marks on various vesicles, mostly in the perineum, yielding nearly 20 larvae, which were removed with forceps. The patient was counseled to cover herself in petrolatum for 2 to 3 hours with the hope of smothering any remaining tick larvae. She was given triamcinolone cream and was encouraged to take a nonsedating antihistamine for itch. The patient was seen back in clinic 2 weeks later and the eruption had resolved.

Comment

Spread of Tick-Borne Disease—Ticks and tick-borne disease are increasing major health concerns for humans, domesticated animals, and livestock. Reported cases of bacterial and protozoan tick-borne disease doubled in the United States between 2004 and 2016. Ninety percent of the nearly 60,000 cases of nationally notifiable vector-borne diseases reported in 2017 were linked to ticks.² Geographic ranges of multiple tick species continue to expand, which is thought to be secondary to rising global temperatures, ecologic changes, reforestation, and increases in commerce and travel (Figure 4).³ Not only have warming temperatures contributed to geographic range expansion, they also may extend ticks’ active season. The lone star tick (Amblyomma americanum) is widely distributed throughout much of the eastern United States.⁴ The range of A americanum has expanded north in recent years from its prior core range in the southeastern United States.² One study found that from 2006 to 2016, the vector tick species most commonly collected from humans and submitted to a tick surveillance system in New Jersey shifted from Ixodes scapularis to A americanum.⁵

Bites by Amblyomma Ticks—As with most hard ticks, the life cycle of A americanum lasts 2 years and includes the egg, the 6-legged larva or “seed tick,” the 8-legged immature nymph, and the 8-legged reproductively mature adult (Figure 3). Amblyomma americanum can lay several thousand eggs.² Because our patient had numerous bites, it is plausible that she came into contact with a nest of newly hatched tick larvae. Morphogenesis from larva to nymph, then nymph to adult, requires a blood meal.^6,7 The larvae emerge from eggs deposited on the ground and then crawl up low vegetation where they can easily attach to passing hosts. The tick clings to hair or clothing and waits until the host is at rest before moving to a favorable location and then bites.⁸ When attaching, ticks inject an anesthetic akin to lidocaine, making the bite painless. A tick may spend up to 24 hours on the host prior to biting and then feed for 2 hours to 7 days before releasing.⁹ For the majority of tick-borne illnesses, the tick must remain attached for 24 to 48 hours before disease is transmitted.¹⁰

All stages of Amblyomma, excluding the egg, are capable of transmitting disease.^8,11Amblyomma americanum is called the lone star tick because of the prominent white dot on the back of the adult female. It will feed on small or large mammals during any stage of its life cycle. It is known to transmit Ehrlichia chaffeensis and Ehrlichia ewingii, which cause human ehrlichiosis, and Francisella tularensis, which causes tularemia, Heartland virus, Bourbon virus, and Southern tick-associated rash illness. Delayed anaphylaxis to ingestion of red meat has been attributed to the bite of A americanum. Amblyomma americanum ticks are not known to transmit Lyme disease. The Centers for Disease Control and Prevention does not recommend prophylactic treatment to prevent ehrlichiosis.¹² Tularemia prophylaxis is only recommended in cases of laboratory exposure to infectious materials. Doxycycline prophylaxis is only recommended if the tick is identified as an adult or nymphal I scapularis.¹²

Even when the ticks do not transmit disease, tick bites can cause impressive local reactions. Uncomplicated bites can be painful and leave a puncture wound that can take 1 to 2 weeks to heal.¹³ Rarely, bites can cause a delayed hypersensitivity reaction including fever, pruritus, and urticaria. Granulomas can develop if a tick is improperly removed.⁹ Other reports describe prurigo lesions, skin hemorrhage, papular urticaria, diffuse papules, vesicles and bullae, necrotic ulcers, and patchy alopecia.^14,15 A 2015 systematic controlled study of human bite reactions from A americanum demonstrated the development of itchy erythematous papules and vesicles within 48 hours of larval tick attachment to research participants. The study found tissue damage from A americanum mouthparts, and degranulating mast cells may be evident in as little as 15 minutes.¹⁶ The severity of individual skin reaction is hypothesized to depend on several variables, such as the duration of feeding, size of mouthparts, type of tick secretions, changes in secretions during feeding, and prior exposures of the host.¹⁴

Tick Removal—If patients present to clinic with ticks attached, removal can be challenging. Removal recommendations call for use of blunt forceps or tweezers. Ticks should be grasped near the skin with consistent pressure, and the tick should be pulled straight out, perpendicular to the skin. Twisting motions can cause the head to separate from the body and remain in the bite wound. Immediately following removal, the area should be cleansed with a disinfectant.^10,17 After the tick is removed, some studies recommend storing the tick at −20 °C; should the patient develop disease, the tick could be sent for evaluation.^6,17 If there is no clinical or serologic evidence of infection, testing for the presence of antibodies against tick-borne bacteria at presentation and at 3 and 6 weeks is not recommended due to low sensitivity, low positive predictive value, and cost. Clinicians must only observe and treat if disease occurs.¹⁷

Prevention of Tick Bites—Tick bites are best prevented by avoiding tick-infested areas; when these areas are unavoidable, tick bites may be prevented by wearing long pants with the pant legs tucked into boots. In addition, applying topical DEET (N,N-diethyl-m-toluamide) repellent to exposed skin and treating clothing with permethrin can be helpful.¹⁷ When used alone, DEET provides greater than 90% protection for up to 2.7 hours against A americanum.¹⁸ Permethrin-treated clothing alone is 79% to 100% effective at killing A americanum ticks or disabling them for several hours.¹⁹

Conclusion

Tick-borne illness is an increasingly important cause of human infectious disease. In addition to their role as a disease vector, ticks can produce primary skin disorders. This case posed a diagnostic challenge because of the unusually large number and wide distribution of bites as well as the subsequent vesicular reaction that ensued. It is important to keep tick larvae or adult tick bites in the differential when evaluating a patient to expedite tick removal and begin clinical monitoring. Recognition of A americanum larvae as a potential cause of pruritic papules may be helpful in similar cases. In addition, it is important for dermatologists to be aware of the tick species in their area.

Amid increasing numbers of applications, decreasing match rates, and ongoing lack of diversity in the dermatology trainee workforce, the COVID-19 pandemic introduced additional challenges to the dermatology residency application process and laid bare systemic inequities and inherent problems that must be addressed. Historically, dermatology applicants have excelled in academic metrics, such as US Medical Licensing Examination (USMLE) scores and nomination to the Alpha Omega Alpha honor society. As biases associated with these academic metrics are being elucidated, they have in turn become less available. With the upcoming change in USMLE Step 1 reporting to pass/fail only, as well as the elimination of Alpha Omega Alpha nomination for students, clinical grades, and/or class ranks at many medical schools, other elements of the application, such as volunteer experiences and research publications, may be weighed more heavily in the selection process. This may serve to exacerbate the application arms race, characterized by a steady rise in volunteer experiences, research publications, and research gap years that has already begun and likely will continue, particularly among dermatology applicants.

These issues are not unique to dermatology and are occurring across all medical specialties to varying degrees. The monetary and opportunity costs of the application process have become astronomical for both applicants and faculty. Faculty are overburdened with administrative duties related to resident recruitment and advising, and students are experiencing heightened match-related anxiety earlier and more acutely. These factors may contribute to burnout among trainees and faculty and may have deleterious effects on medical education. It is clear that transformative work must be pursued to ensure an equitable and sustainable residency application process moving forward. In this column, we review the notable work being done within dermatology and across specialties to reform the residency application process.

Coalition Recommendations

In August 2021, the Coalition for Physician Accountability (CoPA) released recommendations for comprehensive improvement of the undergraduate medical education (UME) to graduate medical education transition, which includes residency application. Of the 9 principal themes addressed, 2 focus on the residency application process: (1) equitable mission-driven application review, and (2) optimization of the application, interview, and selection processes, which relates to application volume as well as interview offers and formats.¹

In the area of application review, CoPA recommends replacing all letters of recommendation with structured evaluative letters as a universal tool in the application process.¹ These letters would include specialty-specific questions based on core competencies and would be completed by an evaluator who directly observed the student. Additionally, the group recommends revising the content and structure of the medical student performance evaluation to improve access to longitudinal assessment data about students. Ideally, developing UME competency outcomes to apply across learners would decrease reliance on traditional but potentially problematic application elements, such as licensing examination scores, clinical grades, and narrative evaluations.¹

To optimize residency application processes, CoPA recommends exploring innovative approaches to reduce application volume and maximize applicants interviewing and matching at programs where mutual interest is high.¹ Suggestions to address these issues include preference signaling, application caps, and/or additional rounds of application or matching. Standardization of the interview process also is recommended to improve equity, minimize educational disruption, and improve applicant well-being. Suggestions include the use of common interview offer and scheduling platforms, policies to govern interview offers and scheduling timelines, interview caps, and ongoing study of the impact of virtual interviews.¹

Residency Application Innovations Implemented by Other Specialties

A number of specialties have developed innovations in the residency application process to improve equity and fairness as well as optimize applicant-program fit. Emergency medicine created a now widely adopted, specialty-specific standardized letter of evaluation (SLOE).² It compares applicants across a number of measures that include personal qualities, clinical skills, and a global assessment. The SLOE is designed to assess and compare applicants across institutions rather than provide recommendations. The emergency medicine SLOE also provides useful information about the letter writer, including duration and depth of interaction with the applicant and distribution of rankings of prior applicants.²

In 2019, obstetrics and gynecology launched a standardized application and interview process, which set a specialty-wide application deadline, limited interview invitations to the number of interview positions available, encouraged coordinated release of interview offers, and allowed applicants 72 hours to respond to invitations.³ These measures were implemented to improve fairness, transparency, and applicant well-being, as well as to promote equitable distribution of interviews. Data following this launch suggested that universal offer dates reduced excessive interviewing among competitive applicants.³

Last year, otolaryngology implemented a process known as preference signaling in which applicants were able to signal up to 5 preferred programs at the time of application. A signal allowed applicants to demonstrate interest in specific programs and could be used by programs during their application review process. Most applicants opted to submit signals, and programs received 0 to 71 signals (mean, 22).⁴ Almost all programs received at least 1 signal. The rate of receiving an interview was significantly higher for signaled programs (58%) compared to nonsignaled programs (14%)(P<.001), indicating that preference signaling may be beneficial for both programs and applicants for interview selection.⁴

Residency Application Innovations Implemented by Dermatology

Over the last 2 application cycles, dermatology has implemented several innovations to the residency application process. Initial work included release of guidelines for residency programs to conduct holistic application review,⁵ recommendations for website updates to share program-specific information with prospective trainees,⁶ and informational webinars and statements to update dermatology applicants about changes to the process and to answer application-related questions.^7-9

In 2020, dermatology initiated a coordinated interview invitation release in which interview offers were released on prespecified dates and applicants were given 48 hours prior to scheduling. Approximately 50% of residency programs participated in the first year, yet nearly all programs released on 1 of 2 universal dates in the current cycle. In a recent survey of dermatology applicants, nearly 90% supported coordinated release.¹⁰ Several other specialties also have incorporated universal release dates into their processes.

For the 2021-2022 application cycle, dermatology—along with internal medicine and general surgery—participated in the Association of American Medical Colleges’ pilot supplemental Electronic Residency Application Service (ERAS) application.¹¹ The pilot was designed as a first step to updating the ERAS content by allowing students to share more information about their extracurricular, research, and clinical activities, as well as geographic and program preferences to optimize applicant-program fit. Preference signaling, similar to the otolaryngology process, was included in the supplemental application, with dermatology applicants choosing up to 3 preferred programs to signal, excluding their home programs and any programs where they completed in-person away rotations. Preliminary data suggest that the vast majority of dermatology programs and applicants participated in the supplemental application.¹² Ongoing analysis of survey data from applicants, advisors, and program directors will help inform future directions. Dermatology has been an integral partner in the development, implementation, and evaluation of this pilot.

Proposed Innovations to the Application Process

Given the challenges of the current application process, there has been a long list of proposed innovations to ameliorate applicant, advisor, and program concerns.¹³ Many of these approaches are intended to respond to increasing costs to programs and applicants as well as the lack of equity in the process. Application caps and an early result acceptance program have both been proposed to address the ever-increasing volume of applications.^14,15 Neither of these proposals has been adopted by a specialty yet, but obstetrics and gynecology stakeholders have shown broad support for an early result acceptance program, signaling a possible future pilot.¹⁶

Interview caps also have been proposed to promote more equitable distribution of interview positions.¹⁷ Ophthalmology implemented this approach in the 2021-2022 application cycle, with applicants limited to a maximum of 18 interviews.¹⁸ Data from this pilot will help determine the effect of interview caps as well as the optimal limit, which will vary by specialty.

Changes to the application content itself could better facilitate holistic review and optimize applicant-program fit. This is the principle driving the pilot supplemental ERAS application, but it also has been addressed in other specialties. Ophthalmology replaced the traditional personal statement with a shorter autobiographical statement as well as 2 short personal essay questions. Plastic surgery designed a common supplemental application, currently in its second iteration, that highlights specialty-specific information from applicants to promote holistic review and eventually reduce application costs.¹⁹

 

 

Final Thoughts

The reforms introduced and proposed by dermatology and other specialties represent initial steps to address the issues inherent to the current residency application process. Providing faculty with better tools to holistically assess applicants during the review process and increasing transparency between programs and applicants should help optimize applicant-program fit and increase diversity in the dermatology workforce. Streamlining the application process to allow students to highlight their unique qualities in a user-friendly format as well as addressing potential inequities in interview distribution and access to the application process hopefully will contribute to better outcomes for both programs and applicants. However, many of these steps are likely to create additional administrative burdens on program faculty and are unlikely to allay student fears about matching.

The underlying issue for many specialties, and particularly for dermatology, is that demand far outstrips supply. With stable numbers of residency positions and an ever-increasing number of applicants, the match rate will continue to decrease, leading to increased anxiety among those interested in pursuing dermatology. Although USMLE Step 1 scores have been shown to have racial bias²⁰ and there are no data correlating scores with clinical performance, the elimination of a scoring system may affect the number of applicants entering dermatology with downstream effects on match rates. Heightened anxiety places increased pressure on students to choose a specialty earlier in their training and impacts the activities they pursue during medical school. Overemphasis on specialty choice and the match process can lead to higher rates of burnout among students and trainees, as students may focus on activities designed to increase their chances of matching at the expense of pursuing activities that could lead to greater engagement and passion in their careers—a key protective factor against burnout.

The goal of the residency application process is to optimize fit between candidates and programs by aligning goals, values, and learning environment. Students and programs working together as honest brokers can lead to transformative change in the process, freeing both parties to highlight their unique qualities and contributions. Programs benefit from optimal fit by being able to hone their particular mission and recruit and retain residents and faculty engaged in that mission. Residents will thrive in programs that support their learning and career goals and will ultimately be better positioned to meaningfully contribute to their chosen field in whatever capacity they choose.

Acknowledgments—The views presented in this column reflect those of the 9 elected members of the Association of Professors of Dermatology Residency Program Directors Section steering committee, all of whom are program directors at their institutions (listed in parentheses): Ammar Ahmed, MD (The University of Texas at Austin, Austin, Texas); Yolanda Helfrich, MD (University of Michigan, Ann Arbor, Michigan); Jo-Ann M. Latkowksi, MD (New York University, New York); Kiran Motaparthi, MD (University of Florida, Gainesville, Florida); Adena E. Rosenblatt, MD, PhD (The University of Chicago, Chicago, Illinois); Ilana S. Rosman, MD (Washington University, St. Louis, Missouri); Travis Vandergriff, MD (University of Texas Southwestern, Dallas, Texas); Diane Whitaker-Worth, MD (University of Connecticut, Farmington, Connecticut); Scott Worswick, MD (University of Southern California, Los Angeles, California).

Amid increasing numbers of applications, decreasing match rates, and ongoing lack of diversity in the dermatology trainee workforce, the COVID-19 pandemic introduced additional challenges to the dermatology residency application process and laid bare systemic inequities and inherent problems that must be addressed. Historically, dermatology applicants have excelled in academic metrics, such as US Medical Licensing Examination (USMLE) scores and nomination to the Alpha Omega Alpha honor society. As biases associated with these academic metrics are being elucidated, they have in turn become less available. With the upcoming change in USMLE Step 1 reporting to pass/fail only, as well as the elimination of Alpha Omega Alpha nomination for students, clinical grades, and/or class ranks at many medical schools, other elements of the application, such as volunteer experiences and research publications, may be weighed more heavily in the selection process. This may serve to exacerbate the application arms race, characterized by a steady rise in volunteer experiences, research publications, and research gap years that has already begun and likely will continue, particularly among dermatology applicants.

These issues are not unique to dermatology and are occurring across all medical specialties to varying degrees. The monetary and opportunity costs of the application process have become astronomical for both applicants and faculty. Faculty are overburdened with administrative duties related to resident recruitment and advising, and students are experiencing heightened match-related anxiety earlier and more acutely. These factors may contribute to burnout among trainees and faculty and may have deleterious effects on medical education. It is clear that transformative work must be pursued to ensure an equitable and sustainable residency application process moving forward. In this column, we review the notable work being done within dermatology and across specialties to reform the residency application process.

Coalition Recommendations

In August 2021, the Coalition for Physician Accountability (CoPA) released recommendations for comprehensive improvement of the undergraduate medical education (UME) to graduate medical education transition, which includes residency application. Of the 9 principal themes addressed, 2 focus on the residency application process: (1) equitable mission-driven application review, and (2) optimization of the application, interview, and selection processes, which relates to application volume as well as interview offers and formats.¹

In the area of application review, CoPA recommends replacing all letters of recommendation with structured evaluative letters as a universal tool in the application process.¹ These letters would include specialty-specific questions based on core competencies and would be completed by an evaluator who directly observed the student. Additionally, the group recommends revising the content and structure of the medical student performance evaluation to improve access to longitudinal assessment data about students. Ideally, developing UME competency outcomes to apply across learners would decrease reliance on traditional but potentially problematic application elements, such as licensing examination scores, clinical grades, and narrative evaluations.¹

To optimize residency application processes, CoPA recommends exploring innovative approaches to reduce application volume and maximize applicants interviewing and matching at programs where mutual interest is high.¹ Suggestions to address these issues include preference signaling, application caps, and/or additional rounds of application or matching. Standardization of the interview process also is recommended to improve equity, minimize educational disruption, and improve applicant well-being. Suggestions include the use of common interview offer and scheduling platforms, policies to govern interview offers and scheduling timelines, interview caps, and ongoing study of the impact of virtual interviews.¹

Residency Application Innovations Implemented by Other Specialties

A number of specialties have developed innovations in the residency application process to improve equity and fairness as well as optimize applicant-program fit. Emergency medicine created a now widely adopted, specialty-specific standardized letter of evaluation (SLOE).² It compares applicants across a number of measures that include personal qualities, clinical skills, and a global assessment. The SLOE is designed to assess and compare applicants across institutions rather than provide recommendations. The emergency medicine SLOE also provides useful information about the letter writer, including duration and depth of interaction with the applicant and distribution of rankings of prior applicants.²

In 2019, obstetrics and gynecology launched a standardized application and interview process, which set a specialty-wide application deadline, limited interview invitations to the number of interview positions available, encouraged coordinated release of interview offers, and allowed applicants 72 hours to respond to invitations.³ These measures were implemented to improve fairness, transparency, and applicant well-being, as well as to promote equitable distribution of interviews. Data following this launch suggested that universal offer dates reduced excessive interviewing among competitive applicants.³

Last year, otolaryngology implemented a process known as preference signaling in which applicants were able to signal up to 5 preferred programs at the time of application. A signal allowed applicants to demonstrate interest in specific programs and could be used by programs during their application review process. Most applicants opted to submit signals, and programs received 0 to 71 signals (mean, 22).⁴ Almost all programs received at least 1 signal. The rate of receiving an interview was significantly higher for signaled programs (58%) compared to nonsignaled programs (14%)(P<.001), indicating that preference signaling may be beneficial for both programs and applicants for interview selection.⁴

Residency Application Innovations Implemented by Dermatology

Over the last 2 application cycles, dermatology has implemented several innovations to the residency application process. Initial work included release of guidelines for residency programs to conduct holistic application review,⁵ recommendations for website updates to share program-specific information with prospective trainees,⁶ and informational webinars and statements to update dermatology applicants about changes to the process and to answer application-related questions.^7-9

In 2020, dermatology initiated a coordinated interview invitation release in which interview offers were released on prespecified dates and applicants were given 48 hours prior to scheduling. Approximately 50% of residency programs participated in the first year, yet nearly all programs released on 1 of 2 universal dates in the current cycle. In a recent survey of dermatology applicants, nearly 90% supported coordinated release.¹⁰ Several other specialties also have incorporated universal release dates into their processes.

For the 2021-2022 application cycle, dermatology—along with internal medicine and general surgery—participated in the Association of American Medical Colleges’ pilot supplemental Electronic Residency Application Service (ERAS) application.¹¹ The pilot was designed as a first step to updating the ERAS content by allowing students to share more information about their extracurricular, research, and clinical activities, as well as geographic and program preferences to optimize applicant-program fit. Preference signaling, similar to the otolaryngology process, was included in the supplemental application, with dermatology applicants choosing up to 3 preferred programs to signal, excluding their home programs and any programs where they completed in-person away rotations. Preliminary data suggest that the vast majority of dermatology programs and applicants participated in the supplemental application.¹² Ongoing analysis of survey data from applicants, advisors, and program directors will help inform future directions. Dermatology has been an integral partner in the development, implementation, and evaluation of this pilot.

Proposed Innovations to the Application Process

Given the challenges of the current application process, there has been a long list of proposed innovations to ameliorate applicant, advisor, and program concerns.¹³ Many of these approaches are intended to respond to increasing costs to programs and applicants as well as the lack of equity in the process. Application caps and an early result acceptance program have both been proposed to address the ever-increasing volume of applications.^14,15 Neither of these proposals has been adopted by a specialty yet, but obstetrics and gynecology stakeholders have shown broad support for an early result acceptance program, signaling a possible future pilot.¹⁶

Interview caps also have been proposed to promote more equitable distribution of interview positions.¹⁷ Ophthalmology implemented this approach in the 2021-2022 application cycle, with applicants limited to a maximum of 18 interviews.¹⁸ Data from this pilot will help determine the effect of interview caps as well as the optimal limit, which will vary by specialty.

Changes to the application content itself could better facilitate holistic review and optimize applicant-program fit. This is the principle driving the pilot supplemental ERAS application, but it also has been addressed in other specialties. Ophthalmology replaced the traditional personal statement with a shorter autobiographical statement as well as 2 short personal essay questions. Plastic surgery designed a common supplemental application, currently in its second iteration, that highlights specialty-specific information from applicants to promote holistic review and eventually reduce application costs.¹⁹

 

 

Final Thoughts

The reforms introduced and proposed by dermatology and other specialties represent initial steps to address the issues inherent to the current residency application process. Providing faculty with better tools to holistically assess applicants during the review process and increasing transparency between programs and applicants should help optimize applicant-program fit and increase diversity in the dermatology workforce. Streamlining the application process to allow students to highlight their unique qualities in a user-friendly format as well as addressing potential inequities in interview distribution and access to the application process hopefully will contribute to better outcomes for both programs and applicants. However, many of these steps are likely to create additional administrative burdens on program faculty and are unlikely to allay student fears about matching.

The underlying issue for many specialties, and particularly for dermatology, is that demand far outstrips supply. With stable numbers of residency positions and an ever-increasing number of applicants, the match rate will continue to decrease, leading to increased anxiety among those interested in pursuing dermatology. Although USMLE Step 1 scores have been shown to have racial bias²⁰ and there are no data correlating scores with clinical performance, the elimination of a scoring system may affect the number of applicants entering dermatology with downstream effects on match rates. Heightened anxiety places increased pressure on students to choose a specialty earlier in their training and impacts the activities they pursue during medical school. Overemphasis on specialty choice and the match process can lead to higher rates of burnout among students and trainees, as students may focus on activities designed to increase their chances of matching at the expense of pursuing activities that could lead to greater engagement and passion in their careers—a key protective factor against burnout.

The goal of the residency application process is to optimize fit between candidates and programs by aligning goals, values, and learning environment. Students and programs working together as honest brokers can lead to transformative change in the process, freeing both parties to highlight their unique qualities and contributions. Programs benefit from optimal fit by being able to hone their particular mission and recruit and retain residents and faculty engaged in that mission. Residents will thrive in programs that support their learning and career goals and will ultimately be better positioned to meaningfully contribute to their chosen field in whatever capacity they choose.

Acknowledgments—The views presented in this column reflect those of the 9 elected members of the Association of Professors of Dermatology Residency Program Directors Section steering committee, all of whom are program directors at their institutions (listed in parentheses): Ammar Ahmed, MD (The University of Texas at Austin, Austin, Texas); Yolanda Helfrich, MD (University of Michigan, Ann Arbor, Michigan); Jo-Ann M. Latkowksi, MD (New York University, New York); Kiran Motaparthi, MD (University of Florida, Gainesville, Florida); Adena E. Rosenblatt, MD, PhD (The University of Chicago, Chicago, Illinois); Ilana S. Rosman, MD (Washington University, St. Louis, Missouri); Travis Vandergriff, MD (University of Texas Southwestern, Dallas, Texas); Diane Whitaker-Worth, MD (University of Connecticut, Farmington, Connecticut); Scott Worswick, MD (University of Southern California, Los Angeles, California).

Amid increasing numbers of applications, decreasing match rates, and ongoing lack of diversity in the dermatology trainee workforce, the COVID-19 pandemic introduced additional challenges to the dermatology residency application process and laid bare systemic inequities and inherent problems that must be addressed. Historically, dermatology applicants have excelled in academic metrics, such as US Medical Licensing Examination (USMLE) scores and nomination to the Alpha Omega Alpha honor society. As biases associated with these academic metrics are being elucidated, they have in turn become less available. With the upcoming change in USMLE Step 1 reporting to pass/fail only, as well as the elimination of Alpha Omega Alpha nomination for students, clinical grades, and/or class ranks at many medical schools, other elements of the application, such as volunteer experiences and research publications, may be weighed more heavily in the selection process. This may serve to exacerbate the application arms race, characterized by a steady rise in volunteer experiences, research publications, and research gap years that has already begun and likely will continue, particularly among dermatology applicants.

These issues are not unique to dermatology and are occurring across all medical specialties to varying degrees. The monetary and opportunity costs of the application process have become astronomical for both applicants and faculty. Faculty are overburdened with administrative duties related to resident recruitment and advising, and students are experiencing heightened match-related anxiety earlier and more acutely. These factors may contribute to burnout among trainees and faculty and may have deleterious effects on medical education. It is clear that transformative work must be pursued to ensure an equitable and sustainable residency application process moving forward. In this column, we review the notable work being done within dermatology and across specialties to reform the residency application process.

Coalition Recommendations

In August 2021, the Coalition for Physician Accountability (CoPA) released recommendations for comprehensive improvement of the undergraduate medical education (UME) to graduate medical education transition, which includes residency application. Of the 9 principal themes addressed, 2 focus on the residency application process: (1) equitable mission-driven application review, and (2) optimization of the application, interview, and selection processes, which relates to application volume as well as interview offers and formats.¹

In the area of application review, CoPA recommends replacing all letters of recommendation with structured evaluative letters as a universal tool in the application process.¹ These letters would include specialty-specific questions based on core competencies and would be completed by an evaluator who directly observed the student. Additionally, the group recommends revising the content and structure of the medical student performance evaluation to improve access to longitudinal assessment data about students. Ideally, developing UME competency outcomes to apply across learners would decrease reliance on traditional but potentially problematic application elements, such as licensing examination scores, clinical grades, and narrative evaluations.¹

To optimize residency application processes, CoPA recommends exploring innovative approaches to reduce application volume and maximize applicants interviewing and matching at programs where mutual interest is high.¹ Suggestions to address these issues include preference signaling, application caps, and/or additional rounds of application or matching. Standardization of the interview process also is recommended to improve equity, minimize educational disruption, and improve applicant well-being. Suggestions include the use of common interview offer and scheduling platforms, policies to govern interview offers and scheduling timelines, interview caps, and ongoing study of the impact of virtual interviews.¹

Residency Application Innovations Implemented by Other Specialties

A number of specialties have developed innovations in the residency application process to improve equity and fairness as well as optimize applicant-program fit. Emergency medicine created a now widely adopted, specialty-specific standardized letter of evaluation (SLOE).² It compares applicants across a number of measures that include personal qualities, clinical skills, and a global assessment. The SLOE is designed to assess and compare applicants across institutions rather than provide recommendations. The emergency medicine SLOE also provides useful information about the letter writer, including duration and depth of interaction with the applicant and distribution of rankings of prior applicants.²

In 2019, obstetrics and gynecology launched a standardized application and interview process, which set a specialty-wide application deadline, limited interview invitations to the number of interview positions available, encouraged coordinated release of interview offers, and allowed applicants 72 hours to respond to invitations.³ These measures were implemented to improve fairness, transparency, and applicant well-being, as well as to promote equitable distribution of interviews. Data following this launch suggested that universal offer dates reduced excessive interviewing among competitive applicants.³

Last year, otolaryngology implemented a process known as preference signaling in which applicants were able to signal up to 5 preferred programs at the time of application. A signal allowed applicants to demonstrate interest in specific programs and could be used by programs during their application review process. Most applicants opted to submit signals, and programs received 0 to 71 signals (mean, 22).⁴ Almost all programs received at least 1 signal. The rate of receiving an interview was significantly higher for signaled programs (58%) compared to nonsignaled programs (14%)(P<.001), indicating that preference signaling may be beneficial for both programs and applicants for interview selection.⁴

Residency Application Innovations Implemented by Dermatology

Over the last 2 application cycles, dermatology has implemented several innovations to the residency application process. Initial work included release of guidelines for residency programs to conduct holistic application review,⁵ recommendations for website updates to share program-specific information with prospective trainees,⁶ and informational webinars and statements to update dermatology applicants about changes to the process and to answer application-related questions.^7-9

In 2020, dermatology initiated a coordinated interview invitation release in which interview offers were released on prespecified dates and applicants were given 48 hours prior to scheduling. Approximately 50% of residency programs participated in the first year, yet nearly all programs released on 1 of 2 universal dates in the current cycle. In a recent survey of dermatology applicants, nearly 90% supported coordinated release.¹⁰ Several other specialties also have incorporated universal release dates into their processes.

For the 2021-2022 application cycle, dermatology—along with internal medicine and general surgery—participated in the Association of American Medical Colleges’ pilot supplemental Electronic Residency Application Service (ERAS) application.¹¹ The pilot was designed as a first step to updating the ERAS content by allowing students to share more information about their extracurricular, research, and clinical activities, as well as geographic and program preferences to optimize applicant-program fit. Preference signaling, similar to the otolaryngology process, was included in the supplemental application, with dermatology applicants choosing up to 3 preferred programs to signal, excluding their home programs and any programs where they completed in-person away rotations. Preliminary data suggest that the vast majority of dermatology programs and applicants participated in the supplemental application.¹² Ongoing analysis of survey data from applicants, advisors, and program directors will help inform future directions. Dermatology has been an integral partner in the development, implementation, and evaluation of this pilot.

Proposed Innovations to the Application Process

Given the challenges of the current application process, there has been a long list of proposed innovations to ameliorate applicant, advisor, and program concerns.¹³ Many of these approaches are intended to respond to increasing costs to programs and applicants as well as the lack of equity in the process. Application caps and an early result acceptance program have both been proposed to address the ever-increasing volume of applications.^14,15 Neither of these proposals has been adopted by a specialty yet, but obstetrics and gynecology stakeholders have shown broad support for an early result acceptance program, signaling a possible future pilot.¹⁶

Interview caps also have been proposed to promote more equitable distribution of interview positions.¹⁷ Ophthalmology implemented this approach in the 2021-2022 application cycle, with applicants limited to a maximum of 18 interviews.¹⁸ Data from this pilot will help determine the effect of interview caps as well as the optimal limit, which will vary by specialty.

Changes to the application content itself could better facilitate holistic review and optimize applicant-program fit. This is the principle driving the pilot supplemental ERAS application, but it also has been addressed in other specialties. Ophthalmology replaced the traditional personal statement with a shorter autobiographical statement as well as 2 short personal essay questions. Plastic surgery designed a common supplemental application, currently in its second iteration, that highlights specialty-specific information from applicants to promote holistic review and eventually reduce application costs.¹⁹

 

 

Final Thoughts

The reforms introduced and proposed by dermatology and other specialties represent initial steps to address the issues inherent to the current residency application process. Providing faculty with better tools to holistically assess applicants during the review process and increasing transparency between programs and applicants should help optimize applicant-program fit and increase diversity in the dermatology workforce. Streamlining the application process to allow students to highlight their unique qualities in a user-friendly format as well as addressing potential inequities in interview distribution and access to the application process hopefully will contribute to better outcomes for both programs and applicants. However, many of these steps are likely to create additional administrative burdens on program faculty and are unlikely to allay student fears about matching.

The underlying issue for many specialties, and particularly for dermatology, is that demand far outstrips supply. With stable numbers of residency positions and an ever-increasing number of applicants, the match rate will continue to decrease, leading to increased anxiety among those interested in pursuing dermatology. Although USMLE Step 1 scores have been shown to have racial bias²⁰ and there are no data correlating scores with clinical performance, the elimination of a scoring system may affect the number of applicants entering dermatology with downstream effects on match rates. Heightened anxiety places increased pressure on students to choose a specialty earlier in their training and impacts the activities they pursue during medical school. Overemphasis on specialty choice and the match process can lead to higher rates of burnout among students and trainees, as students may focus on activities designed to increase their chances of matching at the expense of pursuing activities that could lead to greater engagement and passion in their careers—a key protective factor against burnout.

The goal of the residency application process is to optimize fit between candidates and programs by aligning goals, values, and learning environment. Students and programs working together as honest brokers can lead to transformative change in the process, freeing both parties to highlight their unique qualities and contributions. Programs benefit from optimal fit by being able to hone their particular mission and recruit and retain residents and faculty engaged in that mission. Residents will thrive in programs that support their learning and career goals and will ultimately be better positioned to meaningfully contribute to their chosen field in whatever capacity they choose.

Acknowledgments—The views presented in this column reflect those of the 9 elected members of the Association of Professors of Dermatology Residency Program Directors Section steering committee, all of whom are program directors at their institutions (listed in parentheses): Ammar Ahmed, MD (The University of Texas at Austin, Austin, Texas); Yolanda Helfrich, MD (University of Michigan, Ann Arbor, Michigan); Jo-Ann M. Latkowksi, MD (New York University, New York); Kiran Motaparthi, MD (University of Florida, Gainesville, Florida); Adena E. Rosenblatt, MD, PhD (The University of Chicago, Chicago, Illinois); Ilana S. Rosman, MD (Washington University, St. Louis, Missouri); Travis Vandergriff, MD (University of Texas Southwestern, Dallas, Texas); Diane Whitaker-Worth, MD (University of Connecticut, Farmington, Connecticut); Scott Worswick, MD (University of Southern California, Los Angeles, California).

We are excited to announce a new partnership between Cutis and the Association of Professors of Dermatology Residency Program Directors Section (APD-RPDS). The new APD-RPDS column Residency Roundup will contain quarterly communications and submissions that we hope will facilitate greater dissemination of information that is useful to the dermatology teaching community.

The APD is a group of academic dermatologists whose membership comprises chairs, chiefs, residency and fellowship program directors, and teaching faculty. Each fall, the group convenes in Chicago, Illinois, for a 2-day meeting centered around departmental and program leadership with a focus on education. The APD-RPDS was formed in 2020 and is led by a steering committee of 9 members, including our current Chair, Ilana S. Rosman, MD (Washington University School of Medicine, St. Louis, Missouri), and Vice Chair, Jo-Ann M. Latkowski, MD (New York University, New York). Committee members are elected from and by the APD membership and must serve in program leadership at their home programs. The APD-RPDS helps plan and coordinate breakout sessions and lectures at the annual APD meeting, which typically relate to program director duties, changing policies within the American Board of Dermatology or Accreditation Council for Graduate Medical Education, ideas for future growth, and changes in our specialty and in resident education. Members of the APD-RPDS have access to the APD listserv, a valuable resource for discussing issues affecting residency training. We also have work groups led by our members, which include diversity, equity, and inclusion; resource development; communications; and the annual survey. To join the APD, the RPDS, and/or any of our workgroups, please reach out to us or visit the APD website (https://www.dermatologyprofessors.org).

We look forward to welcoming and expediently reviewing members’ submissions to the new Residency Roundup column falling into 2 principal categories within the scope of dermatologic recruitment, didactic education, and clinical training. The first category will feature novel tools, programs, and platforms to improve dermatology training through collaboration. This could entail a description of a new platform designed for sharing resources among programs and specialties to enhance learning for trainees and faculty alike. For example, if a database is created that contains prerecorded lectures pertaining to alopecia, a potential article submission might introduce the database and provide information on what topics are covered and how to access these lectures for readers worldwide. Likewise, if a new technology emerges that allows for easier collaboration among programs, a possible submission would introduce the technology and discuss its potential benefits to trainees, faculty, and practicing dermatologists.

Secondly and more commonly, we anticipate the Residency Roundup column will feature articles that delve into the critical issues and challenges currently impacting recruitment, training, and administration in dermatology residency programs. Specific topics may include but are not limited to recruitment of underrepresented in medicine applicants to dermatology, technological advances to improve teaching methods within training programs, surveys delving into the dermatology match process, and educational gaps or future directions in the specialty. The column occasionally may be used to disseminate information from our section of the APD, including consensus statements or editorials related to changes implemented in the dermatology residency application process. A prospective editorial on this subject could explore varying viewpoints of implemented and proposed changes as well as the reasons behind the changes.

Our group is collaborative, and our aim is to improve education, equity, management of program director responsibilities, and the dermatology application process for programs and applicants alike. With your input, experience, and varied perspectives, we look forward to moving the field of dermatology to a better future by working together. 

We are excited to announce a new partnership between Cutis and the Association of Professors of Dermatology Residency Program Directors Section (APD-RPDS). The new APD-RPDS column Residency Roundup will contain quarterly communications and submissions that we hope will facilitate greater dissemination of information that is useful to the dermatology teaching community.

The APD is a group of academic dermatologists whose membership comprises chairs, chiefs, residency and fellowship program directors, and teaching faculty. Each fall, the group convenes in Chicago, Illinois, for a 2-day meeting centered around departmental and program leadership with a focus on education. The APD-RPDS was formed in 2020 and is led by a steering committee of 9 members, including our current Chair, Ilana S. Rosman, MD (Washington University School of Medicine, St. Louis, Missouri), and Vice Chair, Jo-Ann M. Latkowski, MD (New York University, New York). Committee members are elected from and by the APD membership and must serve in program leadership at their home programs. The APD-RPDS helps plan and coordinate breakout sessions and lectures at the annual APD meeting, which typically relate to program director duties, changing policies within the American Board of Dermatology or Accreditation Council for Graduate Medical Education, ideas for future growth, and changes in our specialty and in resident education. Members of the APD-RPDS have access to the APD listserv, a valuable resource for discussing issues affecting residency training. We also have work groups led by our members, which include diversity, equity, and inclusion; resource development; communications; and the annual survey. To join the APD, the RPDS, and/or any of our workgroups, please reach out to us or visit the APD website (https://www.dermatologyprofessors.org).

We look forward to welcoming and expediently reviewing members’ submissions to the new Residency Roundup column falling into 2 principal categories within the scope of dermatologic recruitment, didactic education, and clinical training. The first category will feature novel tools, programs, and platforms to improve dermatology training through collaboration. This could entail a description of a new platform designed for sharing resources among programs and specialties to enhance learning for trainees and faculty alike. For example, if a database is created that contains prerecorded lectures pertaining to alopecia, a potential article submission might introduce the database and provide information on what topics are covered and how to access these lectures for readers worldwide. Likewise, if a new technology emerges that allows for easier collaboration among programs, a possible submission would introduce the technology and discuss its potential benefits to trainees, faculty, and practicing dermatologists.

Secondly and more commonly, we anticipate the Residency Roundup column will feature articles that delve into the critical issues and challenges currently impacting recruitment, training, and administration in dermatology residency programs. Specific topics may include but are not limited to recruitment of underrepresented in medicine applicants to dermatology, technological advances to improve teaching methods within training programs, surveys delving into the dermatology match process, and educational gaps or future directions in the specialty. The column occasionally may be used to disseminate information from our section of the APD, including consensus statements or editorials related to changes implemented in the dermatology residency application process. A prospective editorial on this subject could explore varying viewpoints of implemented and proposed changes as well as the reasons behind the changes.

Our group is collaborative, and our aim is to improve education, equity, management of program director responsibilities, and the dermatology application process for programs and applicants alike. With your input, experience, and varied perspectives, we look forward to moving the field of dermatology to a better future by working together. 

We are excited to announce a new partnership between Cutis and the Association of Professors of Dermatology Residency Program Directors Section (APD-RPDS). The new APD-RPDS column Residency Roundup will contain quarterly communications and submissions that we hope will facilitate greater dissemination of information that is useful to the dermatology teaching community.

The APD is a group of academic dermatologists whose membership comprises chairs, chiefs, residency and fellowship program directors, and teaching faculty. Each fall, the group convenes in Chicago, Illinois, for a 2-day meeting centered around departmental and program leadership with a focus on education. The APD-RPDS was formed in 2020 and is led by a steering committee of 9 members, including our current Chair, Ilana S. Rosman, MD (Washington University School of Medicine, St. Louis, Missouri), and Vice Chair, Jo-Ann M. Latkowski, MD (New York University, New York). Committee members are elected from and by the APD membership and must serve in program leadership at their home programs. The APD-RPDS helps plan and coordinate breakout sessions and lectures at the annual APD meeting, which typically relate to program director duties, changing policies within the American Board of Dermatology or Accreditation Council for Graduate Medical Education, ideas for future growth, and changes in our specialty and in resident education. Members of the APD-RPDS have access to the APD listserv, a valuable resource for discussing issues affecting residency training. We also have work groups led by our members, which include diversity, equity, and inclusion; resource development; communications; and the annual survey. To join the APD, the RPDS, and/or any of our workgroups, please reach out to us or visit the APD website (https://www.dermatologyprofessors.org).

We look forward to welcoming and expediently reviewing members’ submissions to the new Residency Roundup column falling into 2 principal categories within the scope of dermatologic recruitment, didactic education, and clinical training. The first category will feature novel tools, programs, and platforms to improve dermatology training through collaboration. This could entail a description of a new platform designed for sharing resources among programs and specialties to enhance learning for trainees and faculty alike. For example, if a database is created that contains prerecorded lectures pertaining to alopecia, a potential article submission might introduce the database and provide information on what topics are covered and how to access these lectures for readers worldwide. Likewise, if a new technology emerges that allows for easier collaboration among programs, a possible submission would introduce the technology and discuss its potential benefits to trainees, faculty, and practicing dermatologists.

Secondly and more commonly, we anticipate the Residency Roundup column will feature articles that delve into the critical issues and challenges currently impacting recruitment, training, and administration in dermatology residency programs. Specific topics may include but are not limited to recruitment of underrepresented in medicine applicants to dermatology, technological advances to improve teaching methods within training programs, surveys delving into the dermatology match process, and educational gaps or future directions in the specialty. The column occasionally may be used to disseminate information from our section of the APD, including consensus statements or editorials related to changes implemented in the dermatology residency application process. A prospective editorial on this subject could explore varying viewpoints of implemented and proposed changes as well as the reasons behind the changes.

Our group is collaborative, and our aim is to improve education, equity, management of program director responsibilities, and the dermatology application process for programs and applicants alike. With your input, experience, and varied perspectives, we look forward to moving the field of dermatology to a better future by working together. 

The Diagnosis: Reactive Perforating Collagenosis

Reactive perforating collagenosis (RPC) may be either acquired or inherited. It is 1 of 4 classical forms of transepithelial elimination, which also includes elastosis perforans serpiginosa (EPS) as well as perforating folliculitis and Kyrle disease. These 4 forms of transepithelial elimination share characteristics of the elimination of altered dermal components through the epidermis.¹ The acquired subtype of RPC frequently occurs in patients with diabetes mellitus and end-stage renal disease,² both present in our patient.

Clinical presentation typically shows pruritic hyperkeratotic papules with a central crater filled with crust that frequently are distributed on the extensor surfaces of the extremities, often in a linear pattern.³ The perforating papules and nodules occasionally may involve the trunk and face.⁴ Histopathologic examination is characterized by the elimination of altered collagen through the epidermis. Established lesions may show a cup-shaped depression of the epidermis filled with a keratin plug. The underlying dermis will show vertically oriented basophilic collagen fibers with focal extrusion through the epidermis, and elastic fibers will be absent.⁵ The exact pathophysiology of this disease is unknown, but it may represent a cutaneous response to superficial trauma caused by intense scratching.⁶

Standard treatment protocols are not well established for this condition, but some evidence shows that a combination of treatments can help ameliorate symptoms, even if they are not curative.⁷ Treatments without strong evidence have included a wide range of topical, systemic, and other therapies. Case series and anecdotal reports have used retinoids, corticosteroids, menthol, antibiotics, allopurinol antihistamines, cryotherapy, and lasers.⁸ One case was treated with a combination of narrowband UVB phototherapy and doxycycline with resolution in approximately 6 weeks.⁹ Other cases have been cured using triple therapy with antihistamines, topical or injected steroids, and emollients or oral antibiotics.⁷ Evidence shows that there may be benefit to combining multiple different treatment types that target pruritus, inflammation, and collagen damage.^7,9 This disease usually cannot be cured, but it may be improved by the available treatments.

The differential diagnosis includes delusional parasitosis, EPS, perforating folliculitis, and prurigo nodularis. Delusional parasitosis also can be characterized by excoriated plaques and a sensation of parasites infesting the skin, as our patient described.¹⁰ However, it can be differentiated from RPC by the fact that it is a diagnosis of exclusion, which would not have the histopathologic findings of the elimination of collagen from the epidermis, as was demonstrated in our patient.¹¹ Elastosis perforans serpiginosa is in the same family of perforating diseases as RPC; however, EPS typically appears in children or young adults and often is associated with other genetic disorders. Physical examination in a patient with EPS would reveal keratotic papules in a serpiginous pattern, whereas our patient had discrete lesions without any serpiginous pattern. The histopathologic appearance of EPS would reveal plugs of elastic fibers rather than collagen fibers, as was demonstrated in our patient.⁸ Perforating folliculitis, while also demonstrating transepithelial elimination similar to RPC, would appear as erythematous follicular papules with small central keratotic plugs and histopathologic findings of a widely dilated follicle with a mass of keratotic debris.¹² Prurigo nodularis would appear as dome-shaped papulonodules with varying degrees of scale, crust, and erosion, with a histopathologic appearance of hyperplasia and thick hyperkeratosis.¹¹

Overall, the histopathology is paramount in differentiating RPC from the alternative diagnoses, with the extrusion of collagen from the epidermis not being seen in these other conditions. The coupling of the medical history (type 2 diabetes mellitus and end-stage renal disease) with the clinical presentation and skin biopsy findings confirmed the diagnosis of RPC.

The Diagnosis: Reactive Perforating Collagenosis

Reactive perforating collagenosis (RPC) may be either acquired or inherited. It is 1 of 4 classical forms of transepithelial elimination, which also includes elastosis perforans serpiginosa (EPS) as well as perforating folliculitis and Kyrle disease. These 4 forms of transepithelial elimination share characteristics of the elimination of altered dermal components through the epidermis.¹ The acquired subtype of RPC frequently occurs in patients with diabetes mellitus and end-stage renal disease,² both present in our patient.

Clinical presentation typically shows pruritic hyperkeratotic papules with a central crater filled with crust that frequently are distributed on the extensor surfaces of the extremities, often in a linear pattern.³ The perforating papules and nodules occasionally may involve the trunk and face.⁴ Histopathologic examination is characterized by the elimination of altered collagen through the epidermis. Established lesions may show a cup-shaped depression of the epidermis filled with a keratin plug. The underlying dermis will show vertically oriented basophilic collagen fibers with focal extrusion through the epidermis, and elastic fibers will be absent.⁵ The exact pathophysiology of this disease is unknown, but it may represent a cutaneous response to superficial trauma caused by intense scratching.⁶

Standard treatment protocols are not well established for this condition, but some evidence shows that a combination of treatments can help ameliorate symptoms, even if they are not curative.⁷ Treatments without strong evidence have included a wide range of topical, systemic, and other therapies. Case series and anecdotal reports have used retinoids, corticosteroids, menthol, antibiotics, allopurinol antihistamines, cryotherapy, and lasers.⁸ One case was treated with a combination of narrowband UVB phototherapy and doxycycline with resolution in approximately 6 weeks.⁹ Other cases have been cured using triple therapy with antihistamines, topical or injected steroids, and emollients or oral antibiotics.⁷ Evidence shows that there may be benefit to combining multiple different treatment types that target pruritus, inflammation, and collagen damage.^7,9 This disease usually cannot be cured, but it may be improved by the available treatments.

The differential diagnosis includes delusional parasitosis, EPS, perforating folliculitis, and prurigo nodularis. Delusional parasitosis also can be characterized by excoriated plaques and a sensation of parasites infesting the skin, as our patient described.¹⁰ However, it can be differentiated from RPC by the fact that it is a diagnosis of exclusion, which would not have the histopathologic findings of the elimination of collagen from the epidermis, as was demonstrated in our patient.¹¹ Elastosis perforans serpiginosa is in the same family of perforating diseases as RPC; however, EPS typically appears in children or young adults and often is associated with other genetic disorders. Physical examination in a patient with EPS would reveal keratotic papules in a serpiginous pattern, whereas our patient had discrete lesions without any serpiginous pattern. The histopathologic appearance of EPS would reveal plugs of elastic fibers rather than collagen fibers, as was demonstrated in our patient.⁸ Perforating folliculitis, while also demonstrating transepithelial elimination similar to RPC, would appear as erythematous follicular papules with small central keratotic plugs and histopathologic findings of a widely dilated follicle with a mass of keratotic debris.¹² Prurigo nodularis would appear as dome-shaped papulonodules with varying degrees of scale, crust, and erosion, with a histopathologic appearance of hyperplasia and thick hyperkeratosis.¹¹

Overall, the histopathology is paramount in differentiating RPC from the alternative diagnoses, with the extrusion of collagen from the epidermis not being seen in these other conditions. The coupling of the medical history (type 2 diabetes mellitus and end-stage renal disease) with the clinical presentation and skin biopsy findings confirmed the diagnosis of RPC.

The Diagnosis: Reactive Perforating Collagenosis

Reactive perforating collagenosis (RPC) may be either acquired or inherited. It is 1 of 4 classical forms of transepithelial elimination, which also includes elastosis perforans serpiginosa (EPS) as well as perforating folliculitis and Kyrle disease. These 4 forms of transepithelial elimination share characteristics of the elimination of altered dermal components through the epidermis.¹ The acquired subtype of RPC frequently occurs in patients with diabetes mellitus and end-stage renal disease,² both present in our patient.

Clinical presentation typically shows pruritic hyperkeratotic papules with a central crater filled with crust that frequently are distributed on the extensor surfaces of the extremities, often in a linear pattern.³ The perforating papules and nodules occasionally may involve the trunk and face.⁴ Histopathologic examination is characterized by the elimination of altered collagen through the epidermis. Established lesions may show a cup-shaped depression of the epidermis filled with a keratin plug. The underlying dermis will show vertically oriented basophilic collagen fibers with focal extrusion through the epidermis, and elastic fibers will be absent.⁵ The exact pathophysiology of this disease is unknown, but it may represent a cutaneous response to superficial trauma caused by intense scratching.⁶

Standard treatment protocols are not well established for this condition, but some evidence shows that a combination of treatments can help ameliorate symptoms, even if they are not curative.⁷ Treatments without strong evidence have included a wide range of topical, systemic, and other therapies. Case series and anecdotal reports have used retinoids, corticosteroids, menthol, antibiotics, allopurinol antihistamines, cryotherapy, and lasers.⁸ One case was treated with a combination of narrowband UVB phototherapy and doxycycline with resolution in approximately 6 weeks.⁹ Other cases have been cured using triple therapy with antihistamines, topical or injected steroids, and emollients or oral antibiotics.⁷ Evidence shows that there may be benefit to combining multiple different treatment types that target pruritus, inflammation, and collagen damage.^7,9 This disease usually cannot be cured, but it may be improved by the available treatments.

The differential diagnosis includes delusional parasitosis, EPS, perforating folliculitis, and prurigo nodularis. Delusional parasitosis also can be characterized by excoriated plaques and a sensation of parasites infesting the skin, as our patient described.¹⁰ However, it can be differentiated from RPC by the fact that it is a diagnosis of exclusion, which would not have the histopathologic findings of the elimination of collagen from the epidermis, as was demonstrated in our patient.¹¹ Elastosis perforans serpiginosa is in the same family of perforating diseases as RPC; however, EPS typically appears in children or young adults and often is associated with other genetic disorders. Physical examination in a patient with EPS would reveal keratotic papules in a serpiginous pattern, whereas our patient had discrete lesions without any serpiginous pattern. The histopathologic appearance of EPS would reveal plugs of elastic fibers rather than collagen fibers, as was demonstrated in our patient.⁸ Perforating folliculitis, while also demonstrating transepithelial elimination similar to RPC, would appear as erythematous follicular papules with small central keratotic plugs and histopathologic findings of a widely dilated follicle with a mass of keratotic debris.¹² Prurigo nodularis would appear as dome-shaped papulonodules with varying degrees of scale, crust, and erosion, with a histopathologic appearance of hyperplasia and thick hyperkeratosis.¹¹

Overall, the histopathology is paramount in differentiating RPC from the alternative diagnoses, with the extrusion of collagen from the epidermis not being seen in these other conditions. The coupling of the medical history (type 2 diabetes mellitus and end-stage renal disease) with the clinical presentation and skin biopsy findings confirmed the diagnosis of RPC.

Verrucous carcinoma is a rare cancer with the greatest predilection for the foot. Multiple case reports with only a few large case series have been published. ^1-3 Plantar verrucous carcinoma is characterized as a slowly but relentlessly enlarging warty tumor with low metastatic potential and high risk for local invasion. The tumor occurs most frequently in patients aged 60 to 70 years, predominantly in White males. ¹ It often is misdiagnosed for years as an ulcer or wart that is highly resistant to therapy. Size typically ranges from 1 to 12 cm in greatest dimension. ¹

The pathogenesis of plantar verrucous carcinoma remains unclear, but some contributing factors have been proposed, including trauma, chronic irritation, infection, and poor local hygiene.² This tumor has been reported to occur in chronic foot ulcerations, particularly in the diabetic population.⁴ It has been proposed that abnormal expression of the p53 tumor suppressor protein and several types of human papillomavirus (HPV) may have a role in the pathogenesis of verrucous carcinoma.⁵

The pathologic hallmarks of this tumor include a verrucous/hyperkeratotic surface with a deeply endophytic, broad, pushing base. Tumor cells are well differentiated, and atypia is either absent or confined to 1 or 2 layers at the base of the tumor. Overt invasion at the base is lacking, except in cases with a component of conventional invasive squamous cell carcinoma. Human papillomavirus viropathic changes are classically absent.^1,3 Studies of the histopathology of verrucous carcinoma have been complicated by similar entities, nomenclatural uncertainty, and variable diagnostic criteria. For example, epithelioma cuniculatum variously has been defined as being synonymous with verrucous carcinoma, a distinct clinical verrucous carcinoma subtype occurring on the soles, a histologic subtype (characterized by prominent burrowing sinuses), or a separate entity entirely.^1,2,6,7 Furthermore, in the genital area, several different types of carcinomas have verruciform features but display distinct microscopic findings and outcomes from verrucous carcinoma.⁸

Verrucous carcinoma represents an unusual variant of squamous cell carcinoma and is treated as such. Treatments have included laser surgery; immunotherapy; retinoid therapy; and chemotherapy by oral, intralesional, or iontophoretic routes in select patients.⁹ Radiotherapy presents another option, though reports have described progression to aggressive squamous cell carcinoma in some cases.⁹ Surgery is the best course of treatment, and as more case reports have been published, a transition from radical resection to wide excision with tumor-free margins is the treatment of choice.^2,3,10,11 To minimize soft-tissue deficits, Mohs micrographic surgery has been discussed as a treatment option for verrucous carcinoma.^11-13

Few studies have described verrucous carcinoma recurrence, and none have systematically examined recurrence rate, risk factors, or prognosis.^3,9,14 In our retrospective review of 19 new cases of verrucous carcinoma of the foot, we examined 5 recurrent tumors despite negative margin surgical resection and report risk factors and surgical management of these lesions.

Methods

Patient cases were identified through the University of Michigan (Ann Arbor, Michigan) pathology database from 1995 to 2019 based on the primary diagnosis of verrucous carcinoma located on the foot. Nineteen cases were identified and were included in demographic and clinical presentation analyses. Medical records were reviewed to abstract selected clinical data and outcomes of analysis.

Of the 19 cases, 16 were treated at the University of Michigan and are included in the treatment analyses. Specific attention was then paid to the cases with a clinical recurrence despite negative surgical margins. We compared the clinical and surgical differences between recurrent cases and nonrecurrent cases.

Pathology was rereviewed for selected cases, including 2 cases with recurrence and matched primary, 2 cases with recurrence (for which the matched primary was unavailable for review), and 5 representative primary cases that were not complicated by recurrence. Pathology review was conducted in a blinded manner by one of the authors (P.W.H) who is a board-certified dermatopathologist for approximate depth of invasion from the granular layer, perineural invasion, bone invasion, infiltrative growth, presence of conventional squamous cell carcinoma, and margin status.

Statistical analysis was performed when appropriate using an N1 χ² test or Student t test.

Results

Demographics and Comorbidities—The median age of the patients at the time of diagnosis was 55 years (range, 34–77 years). There were 12 males and 7 females (Table 1). Two patients were Black and 17 were White. Almost all patients had additional comorbidities including tobacco use (68%), alcohol use (47%), and diabetes (47%). Only 1 patient had an autoimmune disease and was on chronic steroids. No significant difference was found between the demographics of patients with recurrent lesions and those without recurrence.

Tumor Location and Clinical Presentation—The most common clinical presentation included a nonhealing ulceration with warty edges, pain, bleeding, and lowered mobility. In most cases, there was history of prior treatment over a duration ranging from 1 to 8 years, with a median of 5 years prior to biopsy-based diagnosis (Table 1). Six patients had a history of osteomyelitis, diagnosed by imaging or biopsy, within a year before tumor diagnosis. The size of the primary tumor ranged from 2.4 to 6 cm, with a mean of 4 cm (P=.20). The clinical presentation, time before diagnosis, and size of the tumors did not differ significantly between recurrent and nonrecurrent cases.

The tumor location for the recurrent cases differed significantly compared to nonrecurrent cases. All 5 of the patients with a recurrence presented with a tumor on the nonglabrous part of the foot. Four patients (80%) had lesions on the dorsal or lateral aspect of the great toe (P=.002), and 1 patient (20%) had a lesion on the low ankle (P=.09)(Table 1). Of the nonrecurrent cases, 1 patient (7%) presented with a tumor on the plantar surface of the great toe (P=.002), 13 patients (93%) presented with tumors on the distal plantar surface of the foot (P=.0002), and 1 patient with a plantar foot tumor (Figure 1) also had verrucous carcinoma on the thumb (Table 1 and Figure 2).

Histopathology—Available pathology slides for recurrent cases of verrucous carcinoma were reviewed alongside representative cases of verrucous carcinomas that did not progress to recurrence. The diagnosis of verrucous carcinoma was confirmed in all cases, with no evidence of conventional squamous cell carcinoma, perineural invasion, extension beyond the dermis, or bone invasion in any case. The median size of the tumors was 4.2 cm and 4 cm for nonrecurrent and recurrent specimens, respectively. Recurrences displayed a trend toward increased depth compared to primary tumors without recurrence (average depth, 5.5 mm vs 3.7 mm); however, this did not reach statistical significance (P=.24). Primary tumors that progressed to recurrence (n=2) displayed similar findings to the other cases, with invasive depths of 3.5 and 5.5 mm, and there was no evidence of conventional squamous cell carcinoma, perineural invasion, or extension beyond the dermis.

Treatment of Nonrecurrent Cases—Of the 16 total cases treated at the University of Michigan, surgery was the primary mode of therapy in every case (Tables 2 and 3). Of the 11 nonrecurrent cases, 7 patients had wide local excision with a dermal regeneration template, and delayed split-thickness graft reconstruction. Three cases had wide local excision with metatarsal resection, dermal regeneration template, and delayed skin grafting. One case had a great toe amputation. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (8/11 [73%] reported). Three cases had positive margins at the time of primary resection; 2 were treated with further resection, and 1 had a below the knee amputation (BKA). Follow-up on average was 12 months, with a range of 3 to 36 months.

Treatment of Recurrent Cases—For the 5 patients with recurrence, surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (4/5 [80%] reported). On average, follow-up for this group of patients was 29 months, with a range of 12 to 60 months (Table 3).

Another patient with recurrence (patient 13) presented with a chronic great toe ulcer of 5 years’ duration that formed on the dorsal aspect of the great toe after a previously excised wart (Figure 4A). This patient underwent mid-proximal metatarsal amputation with 2-cm margins and subsequent skin graft. Pathologic margins were negative. Within 6 months, there was hyperkeratosis and a draining wound (Figure 4B). Biopsy results confirmed recurrent disease that was treated with re-resection, including complete metatarsal amputation with negative margins and skin graft placement. Verrucous carcinoma recurred at the edges of the graft within 8 months, and the patient elected for a BKA. In addition, this patient also presented with a verrucous carcinoma of the contralateral great toe. The tumor presented as a warty ulcer of 4 months’ duration in the setting of osteomyelitis and was resected by great toe amputation that was performed concurrently with the opposite leg BKA; there has been no recurrence. Of note, this was the only patient to have right inguinal sentinel lymph node tissue sampled and HPV testing conducted, which were negative for verrucous carcinoma and high or low strains of HPV.

Another recurrent case (patient 14) presented with a large warty lesion on the dorsal great toe positive for verrucous carcinoma. He underwent a complete great toe amputation with skin graft placement. Verrucous carcinoma recurred on the edges of the graft within 6 months, and the patient was lost to follow-up when a BKA was suggested.

The fourth recurrent case (patient 15) initially had been treated for 1 year as a viral verruca of the dorsal aspect of the great toe. He had an exophytic mass positive for verrucous carcinoma growing on the dorsal aspect of the great toe around the prior excision site. After primary wide excision with negative 1-cm margins and graft placement, the tumor was re-excised twice within the next 2 years with pathologic negative margins. The patient underwent a foot amputation due to a severe osteomyelitis infection at the reconstruction site.

The final recurrent case (patient 16) presented with a mass on the lateral great toe that initially was treated as a viral verruca (for unknown duration) that had begun to ulcerate. The patient underwent wide excision with 1-cm margins and graft placement. Final pathology was consistent with verrucous carcinoma with negative margins. Recurrence occurred within 11 months on the edge of the graft, and a great toe amputation through the metatarsal phalangeal joint was performed.

Comment

Our series of 19 cases of verrucous carcinoma adds to the limited number of reported cases in the literature. We sought to evaluate the potential risk factors for early recurrence. Consistent with prior studies, our series found verrucous carcinoma of the foot to occur most frequently in patients aged 50 to 70 years, predominantly in White men.¹ These tumors grew in the setting of chronic inflammation, tissue regeneration, multiple comorbidities, and poor wound hygiene. Misdiagnosis of verrucous carcinoma often leads to ineffective treatments and local invasion of nerves, muscle, and bone tissue.^9,15,16 Our case series also clearly demonstrated the diagnostic challenge verrucous carcinoma presents, with an average delay in diagnosis of 5 years; correct diagnosis often did not occur until the tumor was 4 cm in size (average) and more than 50% had chronic ulceration. Tissue collection of the raised ulcer borders and the deep dermis layer of warty lesions is imperative for diagnosis. Clinicians should have a high suspicion for verrucous carcinoma in the setting of a chronic ulceration or warty lesion that is resistant to traditional treatment.

The histologic features of the tumors showed striking uniformity. Within the literature, there is confusion regarding the use of the terms verrucous carcinoma and carcinoma (epithelioma) cuniculatum and the possible pathologic differences between the two. The World Health Organization’s classification of skin tumors describes epithelioma cuniculatum as verrucous carcinoma located on the sole of the foot.⁷ Kubik and Rhatigan⁶ pointed out that carcinoma cuniculatum does not have a warty or verrucous surface, which is a defining feature of verrucous carcinoma. Multiple authors have further surmised that the deep burrowing sinus tracts of epithelioma cuniculatum are different than those seen in verrucous carcinoma formed by the undulations extending from the papillomatous and verrucous surface.^1,6 We did not observe these notable pathologic differences in recurrent or nonrecurrent primary tumors or differences between primary and recurrent cases. Although our cohort was small, the findings suggest that standard histologic features do not predict aggressive behavior in verrucous carcinomas. Furthermore, our observations support a model wherein recurrence is an inherent property of certain verrucous carcinomas rather than a consequence of histologic progression to conventional squamous cell carcinoma. The lack of overt malignant features in such cases underscores the need for distinction of verrucous carcinoma from benign mimics such as viral verruca or reactive epidermal hyperplasia.

Our recurrent cases showed a greater predilection for nonplantar surfaces and the great toe (P=.002). Five of 6 cases on the nonplantar surface—1 on the ankle and 5 on the great toe—recurred despite negative pathologic margins. There was no significant difference in demographics, pathogenesis, tumor size, chronicity, phenotype, or metastatic spread in recurrent and nonrecurrent cases in our cohort.

The tumor has only been described in rare instances at extrapedal cutaneous sites including the hand, scalp, and abdomen.^14,17,18 Our series did include a case of synchronous presentation with a verrucous carcinoma on the thumb. Given the rarity of this presentation, thus far there are no data supporting any atypical locations of verrucous carcinoma having greater instances of recurrence. Our recurrent cases displaying atypical location on nonglabrous skin could suggest an underlying pathologic mechanism distinct from tumors on glabrous skin and relevant to increased recurrence risk. Such a mechanism might relate to distinct genetic insults, tumor-microenvironment interactions, or field effects. There are few studies regarding physiologic differences between the plantar surface and the nonglabrous surface and how that influences cancer genesis. Within acral melanoma studies, nonglabrous skin of more sun-exposed surfaces has a higher burden of genetic insults including BRAF mutations.¹⁹ Genetic testing of verrucous carcinoma is highly limited, with abnormal expression of the p53 tumor suppressor protein and possible association with several types of HPV. Verrucous carcinoma in general has been found to contain HPV types 6 and 11, nononcogenic forms, and higher risk from HPV types 16 and 18.^9,20 However, only a few cases of HPV type 16 as well as 1 case each of HPV type 2 and type 11 have been found within verrucous carcinoma of the foot.^21,22 In squamous cell carcinoma of the head and neck, HPV-positive tumors have shown better response to treatment. Further investigation of HPV and genetic contributors in verrucous carcinoma is warranted.

There is notable evidence that surgical resection is the best mode of treatment of verrucous carcinoma.^2,3,10,11 Our case series was treated with wide local excision, with partial metatarsal amputation or great toe amputation, in cases with bone invasion or osteomyelitis. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm with no significant differences between the recurrent and nonrecurrent groups. After excision, closure was conducted by incorporating primary, secondary, and delayed closure techniques, along with skin grafts for larger defects. Lymph node biopsy traditionally has not been recommended due to reported low metastatic potential. In all 5 recurrent cases, the tumors recurred after multiple attempts at wide excision and greater resection of bone and tissue, with negative margins. The tumors regrew quickly, within months, on the edges of the new graft or in the middle of the graft. The sites of recurrent tumor growth would suggest regrowth in the areas of greatest tissue stress and proliferation. We recommend a low threshold for biopsy and aggressive retreatment in the setting of exophytic growth at reconstruction sites.

Recurrence is uncommon in the setting of verrucous carcinoma, with our series being the first to analyze prognostic factors.^3,9,14 Our findings indicate that tumors of the nonglabrous surface of the foot should have a higher suspicion for possible local recurrence. Recurrence occurs within months of treatment, deserves early biopsy, and and warrants aggressive treatment. Our series and review highlight the continual diagnostic challenge of this tumor and the pathologic ambiguity that exists. We encourage earlier detection of verrucous carcinoma by appropriate deep tissue biopsy. Future directions should include more comprehensive examination of pathologic features and genetic markers to improve prognostication and management of recurrent and nonrecurrent verrucous carcinoma of the foot.

Verrucous carcinoma is a rare cancer with the greatest predilection for the foot. Multiple case reports with only a few large case series have been published. ^1-3 Plantar verrucous carcinoma is characterized as a slowly but relentlessly enlarging warty tumor with low metastatic potential and high risk for local invasion. The tumor occurs most frequently in patients aged 60 to 70 years, predominantly in White males. ¹ It often is misdiagnosed for years as an ulcer or wart that is highly resistant to therapy. Size typically ranges from 1 to 12 cm in greatest dimension. ¹

The pathogenesis of plantar verrucous carcinoma remains unclear, but some contributing factors have been proposed, including trauma, chronic irritation, infection, and poor local hygiene.² This tumor has been reported to occur in chronic foot ulcerations, particularly in the diabetic population.⁴ It has been proposed that abnormal expression of the p53 tumor suppressor protein and several types of human papillomavirus (HPV) may have a role in the pathogenesis of verrucous carcinoma.⁵

The pathologic hallmarks of this tumor include a verrucous/hyperkeratotic surface with a deeply endophytic, broad, pushing base. Tumor cells are well differentiated, and atypia is either absent or confined to 1 or 2 layers at the base of the tumor. Overt invasion at the base is lacking, except in cases with a component of conventional invasive squamous cell carcinoma. Human papillomavirus viropathic changes are classically absent.^1,3 Studies of the histopathology of verrucous carcinoma have been complicated by similar entities, nomenclatural uncertainty, and variable diagnostic criteria. For example, epithelioma cuniculatum variously has been defined as being synonymous with verrucous carcinoma, a distinct clinical verrucous carcinoma subtype occurring on the soles, a histologic subtype (characterized by prominent burrowing sinuses), or a separate entity entirely.^1,2,6,7 Furthermore, in the genital area, several different types of carcinomas have verruciform features but display distinct microscopic findings and outcomes from verrucous carcinoma.⁸

Verrucous carcinoma represents an unusual variant of squamous cell carcinoma and is treated as such. Treatments have included laser surgery; immunotherapy; retinoid therapy; and chemotherapy by oral, intralesional, or iontophoretic routes in select patients.⁹ Radiotherapy presents another option, though reports have described progression to aggressive squamous cell carcinoma in some cases.⁹ Surgery is the best course of treatment, and as more case reports have been published, a transition from radical resection to wide excision with tumor-free margins is the treatment of choice.^2,3,10,11 To minimize soft-tissue deficits, Mohs micrographic surgery has been discussed as a treatment option for verrucous carcinoma.^11-13

Few studies have described verrucous carcinoma recurrence, and none have systematically examined recurrence rate, risk factors, or prognosis.^3,9,14 In our retrospective review of 19 new cases of verrucous carcinoma of the foot, we examined 5 recurrent tumors despite negative margin surgical resection and report risk factors and surgical management of these lesions.

Methods

Patient cases were identified through the University of Michigan (Ann Arbor, Michigan) pathology database from 1995 to 2019 based on the primary diagnosis of verrucous carcinoma located on the foot. Nineteen cases were identified and were included in demographic and clinical presentation analyses. Medical records were reviewed to abstract selected clinical data and outcomes of analysis.

Of the 19 cases, 16 were treated at the University of Michigan and are included in the treatment analyses. Specific attention was then paid to the cases with a clinical recurrence despite negative surgical margins. We compared the clinical and surgical differences between recurrent cases and nonrecurrent cases.

Pathology was rereviewed for selected cases, including 2 cases with recurrence and matched primary, 2 cases with recurrence (for which the matched primary was unavailable for review), and 5 representative primary cases that were not complicated by recurrence. Pathology review was conducted in a blinded manner by one of the authors (P.W.H) who is a board-certified dermatopathologist for approximate depth of invasion from the granular layer, perineural invasion, bone invasion, infiltrative growth, presence of conventional squamous cell carcinoma, and margin status.

Statistical analysis was performed when appropriate using an N1 χ² test or Student t test.

Results

Demographics and Comorbidities—The median age of the patients at the time of diagnosis was 55 years (range, 34–77 years). There were 12 males and 7 females (Table 1). Two patients were Black and 17 were White. Almost all patients had additional comorbidities including tobacco use (68%), alcohol use (47%), and diabetes (47%). Only 1 patient had an autoimmune disease and was on chronic steroids. No significant difference was found between the demographics of patients with recurrent lesions and those without recurrence.

Tumor Location and Clinical Presentation—The most common clinical presentation included a nonhealing ulceration with warty edges, pain, bleeding, and lowered mobility. In most cases, there was history of prior treatment over a duration ranging from 1 to 8 years, with a median of 5 years prior to biopsy-based diagnosis (Table 1). Six patients had a history of osteomyelitis, diagnosed by imaging or biopsy, within a year before tumor diagnosis. The size of the primary tumor ranged from 2.4 to 6 cm, with a mean of 4 cm (P=.20). The clinical presentation, time before diagnosis, and size of the tumors did not differ significantly between recurrent and nonrecurrent cases.

The tumor location for the recurrent cases differed significantly compared to nonrecurrent cases. All 5 of the patients with a recurrence presented with a tumor on the nonglabrous part of the foot. Four patients (80%) had lesions on the dorsal or lateral aspect of the great toe (P=.002), and 1 patient (20%) had a lesion on the low ankle (P=.09)(Table 1). Of the nonrecurrent cases, 1 patient (7%) presented with a tumor on the plantar surface of the great toe (P=.002), 13 patients (93%) presented with tumors on the distal plantar surface of the foot (P=.0002), and 1 patient with a plantar foot tumor (Figure 1) also had verrucous carcinoma on the thumb (Table 1 and Figure 2).

Histopathology—Available pathology slides for recurrent cases of verrucous carcinoma were reviewed alongside representative cases of verrucous carcinomas that did not progress to recurrence. The diagnosis of verrucous carcinoma was confirmed in all cases, with no evidence of conventional squamous cell carcinoma, perineural invasion, extension beyond the dermis, or bone invasion in any case. The median size of the tumors was 4.2 cm and 4 cm for nonrecurrent and recurrent specimens, respectively. Recurrences displayed a trend toward increased depth compared to primary tumors without recurrence (average depth, 5.5 mm vs 3.7 mm); however, this did not reach statistical significance (P=.24). Primary tumors that progressed to recurrence (n=2) displayed similar findings to the other cases, with invasive depths of 3.5 and 5.5 mm, and there was no evidence of conventional squamous cell carcinoma, perineural invasion, or extension beyond the dermis.

Treatment of Nonrecurrent Cases—Of the 16 total cases treated at the University of Michigan, surgery was the primary mode of therapy in every case (Tables 2 and 3). Of the 11 nonrecurrent cases, 7 patients had wide local excision with a dermal regeneration template, and delayed split-thickness graft reconstruction. Three cases had wide local excision with metatarsal resection, dermal regeneration template, and delayed skin grafting. One case had a great toe amputation. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (8/11 [73%] reported). Three cases had positive margins at the time of primary resection; 2 were treated with further resection, and 1 had a below the knee amputation (BKA). Follow-up on average was 12 months, with a range of 3 to 36 months.

Treatment of Recurrent Cases—For the 5 patients with recurrence, surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (4/5 [80%] reported). On average, follow-up for this group of patients was 29 months, with a range of 12 to 60 months (Table 3).

Another patient with recurrence (patient 13) presented with a chronic great toe ulcer of 5 years’ duration that formed on the dorsal aspect of the great toe after a previously excised wart (Figure 4A). This patient underwent mid-proximal metatarsal amputation with 2-cm margins and subsequent skin graft. Pathologic margins were negative. Within 6 months, there was hyperkeratosis and a draining wound (Figure 4B). Biopsy results confirmed recurrent disease that was treated with re-resection, including complete metatarsal amputation with negative margins and skin graft placement. Verrucous carcinoma recurred at the edges of the graft within 8 months, and the patient elected for a BKA. In addition, this patient also presented with a verrucous carcinoma of the contralateral great toe. The tumor presented as a warty ulcer of 4 months’ duration in the setting of osteomyelitis and was resected by great toe amputation that was performed concurrently with the opposite leg BKA; there has been no recurrence. Of note, this was the only patient to have right inguinal sentinel lymph node tissue sampled and HPV testing conducted, which were negative for verrucous carcinoma and high or low strains of HPV.

Another recurrent case (patient 14) presented with a large warty lesion on the dorsal great toe positive for verrucous carcinoma. He underwent a complete great toe amputation with skin graft placement. Verrucous carcinoma recurred on the edges of the graft within 6 months, and the patient was lost to follow-up when a BKA was suggested.

The fourth recurrent case (patient 15) initially had been treated for 1 year as a viral verruca of the dorsal aspect of the great toe. He had an exophytic mass positive for verrucous carcinoma growing on the dorsal aspect of the great toe around the prior excision site. After primary wide excision with negative 1-cm margins and graft placement, the tumor was re-excised twice within the next 2 years with pathologic negative margins. The patient underwent a foot amputation due to a severe osteomyelitis infection at the reconstruction site.

The final recurrent case (patient 16) presented with a mass on the lateral great toe that initially was treated as a viral verruca (for unknown duration) that had begun to ulcerate. The patient underwent wide excision with 1-cm margins and graft placement. Final pathology was consistent with verrucous carcinoma with negative margins. Recurrence occurred within 11 months on the edge of the graft, and a great toe amputation through the metatarsal phalangeal joint was performed.

Comment

Our series of 19 cases of verrucous carcinoma adds to the limited number of reported cases in the literature. We sought to evaluate the potential risk factors for early recurrence. Consistent with prior studies, our series found verrucous carcinoma of the foot to occur most frequently in patients aged 50 to 70 years, predominantly in White men.¹ These tumors grew in the setting of chronic inflammation, tissue regeneration, multiple comorbidities, and poor wound hygiene. Misdiagnosis of verrucous carcinoma often leads to ineffective treatments and local invasion of nerves, muscle, and bone tissue.^9,15,16 Our case series also clearly demonstrated the diagnostic challenge verrucous carcinoma presents, with an average delay in diagnosis of 5 years; correct diagnosis often did not occur until the tumor was 4 cm in size (average) and more than 50% had chronic ulceration. Tissue collection of the raised ulcer borders and the deep dermis layer of warty lesions is imperative for diagnosis. Clinicians should have a high suspicion for verrucous carcinoma in the setting of a chronic ulceration or warty lesion that is resistant to traditional treatment.

The histologic features of the tumors showed striking uniformity. Within the literature, there is confusion regarding the use of the terms verrucous carcinoma and carcinoma (epithelioma) cuniculatum and the possible pathologic differences between the two. The World Health Organization’s classification of skin tumors describes epithelioma cuniculatum as verrucous carcinoma located on the sole of the foot.⁷ Kubik and Rhatigan⁶ pointed out that carcinoma cuniculatum does not have a warty or verrucous surface, which is a defining feature of verrucous carcinoma. Multiple authors have further surmised that the deep burrowing sinus tracts of epithelioma cuniculatum are different than those seen in verrucous carcinoma formed by the undulations extending from the papillomatous and verrucous surface.^1,6 We did not observe these notable pathologic differences in recurrent or nonrecurrent primary tumors or differences between primary and recurrent cases. Although our cohort was small, the findings suggest that standard histologic features do not predict aggressive behavior in verrucous carcinomas. Furthermore, our observations support a model wherein recurrence is an inherent property of certain verrucous carcinomas rather than a consequence of histologic progression to conventional squamous cell carcinoma. The lack of overt malignant features in such cases underscores the need for distinction of verrucous carcinoma from benign mimics such as viral verruca or reactive epidermal hyperplasia.

Our recurrent cases showed a greater predilection for nonplantar surfaces and the great toe (P=.002). Five of 6 cases on the nonplantar surface—1 on the ankle and 5 on the great toe—recurred despite negative pathologic margins. There was no significant difference in demographics, pathogenesis, tumor size, chronicity, phenotype, or metastatic spread in recurrent and nonrecurrent cases in our cohort.

The tumor has only been described in rare instances at extrapedal cutaneous sites including the hand, scalp, and abdomen.^14,17,18 Our series did include a case of synchronous presentation with a verrucous carcinoma on the thumb. Given the rarity of this presentation, thus far there are no data supporting any atypical locations of verrucous carcinoma having greater instances of recurrence. Our recurrent cases displaying atypical location on nonglabrous skin could suggest an underlying pathologic mechanism distinct from tumors on glabrous skin and relevant to increased recurrence risk. Such a mechanism might relate to distinct genetic insults, tumor-microenvironment interactions, or field effects. There are few studies regarding physiologic differences between the plantar surface and the nonglabrous surface and how that influences cancer genesis. Within acral melanoma studies, nonglabrous skin of more sun-exposed surfaces has a higher burden of genetic insults including BRAF mutations.¹⁹ Genetic testing of verrucous carcinoma is highly limited, with abnormal expression of the p53 tumor suppressor protein and possible association with several types of HPV. Verrucous carcinoma in general has been found to contain HPV types 6 and 11, nononcogenic forms, and higher risk from HPV types 16 and 18.^9,20 However, only a few cases of HPV type 16 as well as 1 case each of HPV type 2 and type 11 have been found within verrucous carcinoma of the foot.^21,22 In squamous cell carcinoma of the head and neck, HPV-positive tumors have shown better response to treatment. Further investigation of HPV and genetic contributors in verrucous carcinoma is warranted.

There is notable evidence that surgical resection is the best mode of treatment of verrucous carcinoma.^2,3,10,11 Our case series was treated with wide local excision, with partial metatarsal amputation or great toe amputation, in cases with bone invasion or osteomyelitis. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm with no significant differences between the recurrent and nonrecurrent groups. After excision, closure was conducted by incorporating primary, secondary, and delayed closure techniques, along with skin grafts for larger defects. Lymph node biopsy traditionally has not been recommended due to reported low metastatic potential. In all 5 recurrent cases, the tumors recurred after multiple attempts at wide excision and greater resection of bone and tissue, with negative margins. The tumors regrew quickly, within months, on the edges of the new graft or in the middle of the graft. The sites of recurrent tumor growth would suggest regrowth in the areas of greatest tissue stress and proliferation. We recommend a low threshold for biopsy and aggressive retreatment in the setting of exophytic growth at reconstruction sites.

Recurrence is uncommon in the setting of verrucous carcinoma, with our series being the first to analyze prognostic factors.^3,9,14 Our findings indicate that tumors of the nonglabrous surface of the foot should have a higher suspicion for possible local recurrence. Recurrence occurs within months of treatment, deserves early biopsy, and and warrants aggressive treatment. Our series and review highlight the continual diagnostic challenge of this tumor and the pathologic ambiguity that exists. We encourage earlier detection of verrucous carcinoma by appropriate deep tissue biopsy. Future directions should include more comprehensive examination of pathologic features and genetic markers to improve prognostication and management of recurrent and nonrecurrent verrucous carcinoma of the foot.

Verrucous carcinoma is a rare cancer with the greatest predilection for the foot. Multiple case reports with only a few large case series have been published. ^1-3 Plantar verrucous carcinoma is characterized as a slowly but relentlessly enlarging warty tumor with low metastatic potential and high risk for local invasion. The tumor occurs most frequently in patients aged 60 to 70 years, predominantly in White males. ¹ It often is misdiagnosed for years as an ulcer or wart that is highly resistant to therapy. Size typically ranges from 1 to 12 cm in greatest dimension. ¹

The pathogenesis of plantar verrucous carcinoma remains unclear, but some contributing factors have been proposed, including trauma, chronic irritation, infection, and poor local hygiene.² This tumor has been reported to occur in chronic foot ulcerations, particularly in the diabetic population.⁴ It has been proposed that abnormal expression of the p53 tumor suppressor protein and several types of human papillomavirus (HPV) may have a role in the pathogenesis of verrucous carcinoma.⁵

The pathologic hallmarks of this tumor include a verrucous/hyperkeratotic surface with a deeply endophytic, broad, pushing base. Tumor cells are well differentiated, and atypia is either absent or confined to 1 or 2 layers at the base of the tumor. Overt invasion at the base is lacking, except in cases with a component of conventional invasive squamous cell carcinoma. Human papillomavirus viropathic changes are classically absent.^1,3 Studies of the histopathology of verrucous carcinoma have been complicated by similar entities, nomenclatural uncertainty, and variable diagnostic criteria. For example, epithelioma cuniculatum variously has been defined as being synonymous with verrucous carcinoma, a distinct clinical verrucous carcinoma subtype occurring on the soles, a histologic subtype (characterized by prominent burrowing sinuses), or a separate entity entirely.^1,2,6,7 Furthermore, in the genital area, several different types of carcinomas have verruciform features but display distinct microscopic findings and outcomes from verrucous carcinoma.⁸

Verrucous carcinoma represents an unusual variant of squamous cell carcinoma and is treated as such. Treatments have included laser surgery; immunotherapy; retinoid therapy; and chemotherapy by oral, intralesional, or iontophoretic routes in select patients.⁹ Radiotherapy presents another option, though reports have described progression to aggressive squamous cell carcinoma in some cases.⁹ Surgery is the best course of treatment, and as more case reports have been published, a transition from radical resection to wide excision with tumor-free margins is the treatment of choice.^2,3,10,11 To minimize soft-tissue deficits, Mohs micrographic surgery has been discussed as a treatment option for verrucous carcinoma.^11-13

Few studies have described verrucous carcinoma recurrence, and none have systematically examined recurrence rate, risk factors, or prognosis.^3,9,14 In our retrospective review of 19 new cases of verrucous carcinoma of the foot, we examined 5 recurrent tumors despite negative margin surgical resection and report risk factors and surgical management of these lesions.

Methods

Patient cases were identified through the University of Michigan (Ann Arbor, Michigan) pathology database from 1995 to 2019 based on the primary diagnosis of verrucous carcinoma located on the foot. Nineteen cases were identified and were included in demographic and clinical presentation analyses. Medical records were reviewed to abstract selected clinical data and outcomes of analysis.

Of the 19 cases, 16 were treated at the University of Michigan and are included in the treatment analyses. Specific attention was then paid to the cases with a clinical recurrence despite negative surgical margins. We compared the clinical and surgical differences between recurrent cases and nonrecurrent cases.

Pathology was rereviewed for selected cases, including 2 cases with recurrence and matched primary, 2 cases with recurrence (for which the matched primary was unavailable for review), and 5 representative primary cases that were not complicated by recurrence. Pathology review was conducted in a blinded manner by one of the authors (P.W.H) who is a board-certified dermatopathologist for approximate depth of invasion from the granular layer, perineural invasion, bone invasion, infiltrative growth, presence of conventional squamous cell carcinoma, and margin status.

Statistical analysis was performed when appropriate using an N1 χ² test or Student t test.

Results

Demographics and Comorbidities—The median age of the patients at the time of diagnosis was 55 years (range, 34–77 years). There were 12 males and 7 females (Table 1). Two patients were Black and 17 were White. Almost all patients had additional comorbidities including tobacco use (68%), alcohol use (47%), and diabetes (47%). Only 1 patient had an autoimmune disease and was on chronic steroids. No significant difference was found between the demographics of patients with recurrent lesions and those without recurrence.

Tumor Location and Clinical Presentation—The most common clinical presentation included a nonhealing ulceration with warty edges, pain, bleeding, and lowered mobility. In most cases, there was history of prior treatment over a duration ranging from 1 to 8 years, with a median of 5 years prior to biopsy-based diagnosis (Table 1). Six patients had a history of osteomyelitis, diagnosed by imaging or biopsy, within a year before tumor diagnosis. The size of the primary tumor ranged from 2.4 to 6 cm, with a mean of 4 cm (P=.20). The clinical presentation, time before diagnosis, and size of the tumors did not differ significantly between recurrent and nonrecurrent cases.

The tumor location for the recurrent cases differed significantly compared to nonrecurrent cases. All 5 of the patients with a recurrence presented with a tumor on the nonglabrous part of the foot. Four patients (80%) had lesions on the dorsal or lateral aspect of the great toe (P=.002), and 1 patient (20%) had a lesion on the low ankle (P=.09)(Table 1). Of the nonrecurrent cases, 1 patient (7%) presented with a tumor on the plantar surface of the great toe (P=.002), 13 patients (93%) presented with tumors on the distal plantar surface of the foot (P=.0002), and 1 patient with a plantar foot tumor (Figure 1) also had verrucous carcinoma on the thumb (Table 1 and Figure 2).

Histopathology—Available pathology slides for recurrent cases of verrucous carcinoma were reviewed alongside representative cases of verrucous carcinomas that did not progress to recurrence. The diagnosis of verrucous carcinoma was confirmed in all cases, with no evidence of conventional squamous cell carcinoma, perineural invasion, extension beyond the dermis, or bone invasion in any case. The median size of the tumors was 4.2 cm and 4 cm for nonrecurrent and recurrent specimens, respectively. Recurrences displayed a trend toward increased depth compared to primary tumors without recurrence (average depth, 5.5 mm vs 3.7 mm); however, this did not reach statistical significance (P=.24). Primary tumors that progressed to recurrence (n=2) displayed similar findings to the other cases, with invasive depths of 3.5 and 5.5 mm, and there was no evidence of conventional squamous cell carcinoma, perineural invasion, or extension beyond the dermis.

Treatment of Nonrecurrent Cases—Of the 16 total cases treated at the University of Michigan, surgery was the primary mode of therapy in every case (Tables 2 and 3). Of the 11 nonrecurrent cases, 7 patients had wide local excision with a dermal regeneration template, and delayed split-thickness graft reconstruction. Three cases had wide local excision with metatarsal resection, dermal regeneration template, and delayed skin grafting. One case had a great toe amputation. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (8/11 [73%] reported). Three cases had positive margins at the time of primary resection; 2 were treated with further resection, and 1 had a below the knee amputation (BKA). Follow-up on average was 12 months, with a range of 3 to 36 months.

Treatment of Recurrent Cases—For the 5 patients with recurrence, surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (4/5 [80%] reported). On average, follow-up for this group of patients was 29 months, with a range of 12 to 60 months (Table 3).

Another patient with recurrence (patient 13) presented with a chronic great toe ulcer of 5 years’ duration that formed on the dorsal aspect of the great toe after a previously excised wart (Figure 4A). This patient underwent mid-proximal metatarsal amputation with 2-cm margins and subsequent skin graft. Pathologic margins were negative. Within 6 months, there was hyperkeratosis and a draining wound (Figure 4B). Biopsy results confirmed recurrent disease that was treated with re-resection, including complete metatarsal amputation with negative margins and skin graft placement. Verrucous carcinoma recurred at the edges of the graft within 8 months, and the patient elected for a BKA. In addition, this patient also presented with a verrucous carcinoma of the contralateral great toe. The tumor presented as a warty ulcer of 4 months’ duration in the setting of osteomyelitis and was resected by great toe amputation that was performed concurrently with the opposite leg BKA; there has been no recurrence. Of note, this was the only patient to have right inguinal sentinel lymph node tissue sampled and HPV testing conducted, which were negative for verrucous carcinoma and high or low strains of HPV.

Another recurrent case (patient 14) presented with a large warty lesion on the dorsal great toe positive for verrucous carcinoma. He underwent a complete great toe amputation with skin graft placement. Verrucous carcinoma recurred on the edges of the graft within 6 months, and the patient was lost to follow-up when a BKA was suggested.

The fourth recurrent case (patient 15) initially had been treated for 1 year as a viral verruca of the dorsal aspect of the great toe. He had an exophytic mass positive for verrucous carcinoma growing on the dorsal aspect of the great toe around the prior excision site. After primary wide excision with negative 1-cm margins and graft placement, the tumor was re-excised twice within the next 2 years with pathologic negative margins. The patient underwent a foot amputation due to a severe osteomyelitis infection at the reconstruction site.

The final recurrent case (patient 16) presented with a mass on the lateral great toe that initially was treated as a viral verruca (for unknown duration) that had begun to ulcerate. The patient underwent wide excision with 1-cm margins and graft placement. Final pathology was consistent with verrucous carcinoma with negative margins. Recurrence occurred within 11 months on the edge of the graft, and a great toe amputation through the metatarsal phalangeal joint was performed.

Comment

Our series of 19 cases of verrucous carcinoma adds to the limited number of reported cases in the literature. We sought to evaluate the potential risk factors for early recurrence. Consistent with prior studies, our series found verrucous carcinoma of the foot to occur most frequently in patients aged 50 to 70 years, predominantly in White men.¹ These tumors grew in the setting of chronic inflammation, tissue regeneration, multiple comorbidities, and poor wound hygiene. Misdiagnosis of verrucous carcinoma often leads to ineffective treatments and local invasion of nerves, muscle, and bone tissue.^9,15,16 Our case series also clearly demonstrated the diagnostic challenge verrucous carcinoma presents, with an average delay in diagnosis of 5 years; correct diagnosis often did not occur until the tumor was 4 cm in size (average) and more than 50% had chronic ulceration. Tissue collection of the raised ulcer borders and the deep dermis layer of warty lesions is imperative for diagnosis. Clinicians should have a high suspicion for verrucous carcinoma in the setting of a chronic ulceration or warty lesion that is resistant to traditional treatment.

The histologic features of the tumors showed striking uniformity. Within the literature, there is confusion regarding the use of the terms verrucous carcinoma and carcinoma (epithelioma) cuniculatum and the possible pathologic differences between the two. The World Health Organization’s classification of skin tumors describes epithelioma cuniculatum as verrucous carcinoma located on the sole of the foot.⁷ Kubik and Rhatigan⁶ pointed out that carcinoma cuniculatum does not have a warty or verrucous surface, which is a defining feature of verrucous carcinoma. Multiple authors have further surmised that the deep burrowing sinus tracts of epithelioma cuniculatum are different than those seen in verrucous carcinoma formed by the undulations extending from the papillomatous and verrucous surface.^1,6 We did not observe these notable pathologic differences in recurrent or nonrecurrent primary tumors or differences between primary and recurrent cases. Although our cohort was small, the findings suggest that standard histologic features do not predict aggressive behavior in verrucous carcinomas. Furthermore, our observations support a model wherein recurrence is an inherent property of certain verrucous carcinomas rather than a consequence of histologic progression to conventional squamous cell carcinoma. The lack of overt malignant features in such cases underscores the need for distinction of verrucous carcinoma from benign mimics such as viral verruca or reactive epidermal hyperplasia.

Our recurrent cases showed a greater predilection for nonplantar surfaces and the great toe (P=.002). Five of 6 cases on the nonplantar surface—1 on the ankle and 5 on the great toe—recurred despite negative pathologic margins. There was no significant difference in demographics, pathogenesis, tumor size, chronicity, phenotype, or metastatic spread in recurrent and nonrecurrent cases in our cohort.

The tumor has only been described in rare instances at extrapedal cutaneous sites including the hand, scalp, and abdomen.^14,17,18 Our series did include a case of synchronous presentation with a verrucous carcinoma on the thumb. Given the rarity of this presentation, thus far there are no data supporting any atypical locations of verrucous carcinoma having greater instances of recurrence. Our recurrent cases displaying atypical location on nonglabrous skin could suggest an underlying pathologic mechanism distinct from tumors on glabrous skin and relevant to increased recurrence risk. Such a mechanism might relate to distinct genetic insults, tumor-microenvironment interactions, or field effects. There are few studies regarding physiologic differences between the plantar surface and the nonglabrous surface and how that influences cancer genesis. Within acral melanoma studies, nonglabrous skin of more sun-exposed surfaces has a higher burden of genetic insults including BRAF mutations.¹⁹ Genetic testing of verrucous carcinoma is highly limited, with abnormal expression of the p53 tumor suppressor protein and possible association with several types of HPV. Verrucous carcinoma in general has been found to contain HPV types 6 and 11, nononcogenic forms, and higher risk from HPV types 16 and 18.^9,20 However, only a few cases of HPV type 16 as well as 1 case each of HPV type 2 and type 11 have been found within verrucous carcinoma of the foot.^21,22 In squamous cell carcinoma of the head and neck, HPV-positive tumors have shown better response to treatment. Further investigation of HPV and genetic contributors in verrucous carcinoma is warranted.

There is notable evidence that surgical resection is the best mode of treatment of verrucous carcinoma.^2,3,10,11 Our case series was treated with wide local excision, with partial metatarsal amputation or great toe amputation, in cases with bone invasion or osteomyelitis. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm with no significant differences between the recurrent and nonrecurrent groups. After excision, closure was conducted by incorporating primary, secondary, and delayed closure techniques, along with skin grafts for larger defects. Lymph node biopsy traditionally has not been recommended due to reported low metastatic potential. In all 5 recurrent cases, the tumors recurred after multiple attempts at wide excision and greater resection of bone and tissue, with negative margins. The tumors regrew quickly, within months, on the edges of the new graft or in the middle of the graft. The sites of recurrent tumor growth would suggest regrowth in the areas of greatest tissue stress and proliferation. We recommend a low threshold for biopsy and aggressive retreatment in the setting of exophytic growth at reconstruction sites.

Recurrence is uncommon in the setting of verrucous carcinoma, with our series being the first to analyze prognostic factors.^3,9,14 Our findings indicate that tumors of the nonglabrous surface of the foot should have a higher suspicion for possible local recurrence. Recurrence occurs within months of treatment, deserves early biopsy, and and warrants aggressive treatment. Our series and review highlight the continual diagnostic challenge of this tumor and the pathologic ambiguity that exists. We encourage earlier detection of verrucous carcinoma by appropriate deep tissue biopsy. Future directions should include more comprehensive examination of pathologic features and genetic markers to improve prognostication and management of recurrent and nonrecurrent verrucous carcinoma of the foot.

Isotretinoin is one of the most highly regulated dermatologic medications on the market. The main reason for regulation through the US Food and Drug Administration (FDA)–managed iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) is to minimize the drug’s teratogenic potential, as isotretinoin can cause profound birth defects. The program originally categorized patients into 1 of 3 categories: (1) females of reproductive potential, (2) females not of reproductive potential, and (3) males. Unless the patient commits to abstinence, the program required female patients of childbearing potential to be on 2 forms of birth control and undergo regular pregnancy testing before obtaining refills. Over the last few years, the American Academy of Dermatology Association (AADA) has been advocating for changes to the iPLEDGE system. Proposed changes have included decreasing attestation frequency for patients who cannot get pregnant, increasing contraception counseling and options, and changing enrollment guidelines to encompass all gender and sexual minorities. As of December 13, 2021, the iPLEDGE system changed enrollment categories to reflect the AADA’s wishes and rolled out gender-neutral categories for enrollment in iPLEDGE. This change will simplify and enhance patients’ experience when starting isotretinoin.

Developing Inclusive iPLEDGE Categories

In recent years, dermatologists and patients have viewed these strict gender-based categories as limiting and problematic, especially for their transgender patients and female patients of childbearing potential who exclusively engage in intercourse with cisgender females. The United States has more than 10 million LGBTQIA+ citizens and an estimated 1.4 million adults who identify as transgender individuals, rendering the previously established gender-binary iPLEDGE categories outdated.^1,2

As a result, over the last few years, dermatologists, LGBTQIA+ allies, and patients have urged the FDA to create a gender-neutral registration process for iPLEDGE. With support from the AADA, the new modifications were approved for implementation and include 2 risk categories: (1) people who can get pregnant and (2) people who cannot get pregnant.³

As exciting as these changes are for the future of dermatologic practice, the actual transition to the new iPLEDGE system was described as a “failure, chaotic, and a disaster” due to additional changes made at the same time.⁴ The iPLEDGE system was switched to a new website administered by a different vendor and required providers to confirm each patient online by December 13, 2021. In addition, the new system required pharmacists to obtain risk management authorization via the iPLEDGE REMS website or by calling the iPLEDGE REMS center before dispensing isotretinoin. This overhaul did not work as planned, as the new website was constantly down and it was nearly impossible to reach a contact over the telephone. The complications resulted in major disruptions and delayed prescriptions for thousands of patients nationwide as well as a great disruption in workflow for physicians and pharmacists. The AADA subsequently met with the Isotretinoin Products Manufacturers Group to create workable solutions for these issues.

On January 14, 2022, the FDA posted updates regarding access to the iPLEDGE system. They have worked with the Isotretinoin Products Manufacturers Group to create workable solutions for patients and physicians while transferring the patients’ information to the new database. Their solution includes allowing physicians to send patients login links through their email to access their account instead of waiting for the call center. The majority of iPLEDGE users now have access to their accounts without issues, and the gender-neutral guidelines have been in place since the original change.

Impact of iPLEDGE Categories on Transgender Patients

These changes specifically will improve the experience of transgender men and cisgender women who are at no risk for pregnancy and could be subjected to monthly pregnancy testing when it is not medically necessary.

Consider the following patient scenario. A transgender man presents to your dermatology office seeking treatment of severe nodulocystic acne. He was placed on hormonal replacement therapy with exogenous testosterone—injections, oral pills, topical gel, topical patches, or subdermal pellets—to achieve secondary sex characteristics and promote gender congruence. The patient mentions he has been amenorrheic for several months now. He has tried many topical acne treatments as well as oral antibiotics without much benefit and is now interested in enrolling in iPLEDGE to obtain isotretinoin. With the prior iPLEDGE registration packets, how would this transgender man be classified? As a female with childbearing potential due to his retained ovaries and uterus? What if he did not endorse engaging in sexual intercourse that could result in pregnancy?

Transgender patients have unique and unmet needs that often are overlooked and prevent them from equitable, gender-affirming health care. For example, in a prospective study following 20 transgender men starting hormone replacement therapy, the percentage of patients with facial acne increased from 35% to 82% after 6 months of therapy.⁵ In addition, the increased psychosocial burden of acne may be especially difficult in these patients, as they already report higher rates of depression and suicidal ideation compared with their heterosexual cisgender peers.⁴ Further, the primary patient populations receiving isotretinoin typically are adolescents and young adults who are undergoing major physical, mental, and hormonal changes. Self-discovery and self-actualization develop over time, and our role as physicians is to advocate for all aspects of our patients’ health and eliminate barriers to optimal care.

Inclusive Language in iPLEDGE Categories

It is important to streamline access to care for all patients, and gender-affirming, culturally sensitive language is essential to building trust and understanding between patients and providers. Howa Yeung, MD, MSc, a dermatologist at Emory University (Atlanta, Georgia) who advocated for gender-neutral iPLEDGE registration, welcomes the change and stated it “will make my job easier. I no longer have to struggle between respecting the patient’s gender identity and providing medically necessary care for patients with severe acne.”³

Sanchez et al⁶ provided a list of structured questions providers can ask their patients to assess their risk regarding pregnancy: (1) Do you have a uterus and/or ovaries?, (2) Are you engaging in sexual intercourse with a person who has a penis?, and (3) If yes to these questions, what form(s) of birth control are you using? Providers should preface these questions with the following statement: “It is important that I ask these questions to assess your risk for becoming pregnant on this medication because isotretinoin can cause very serious birth defects.” It is important to review these questions and practice asking them so residents can operate from the same place of openness and understanding when caring for their patients.

Final Thoughts

The landscape of isotretinoin prescribing currently is changing on a day-to-day basis. As residents, it is important we stay up to date with the changes regarding our regularly dispensed medications. The main modification made to the iPLEDGE REMS system was switching the risk categories from 3 (females who can get pregnant, females who cannot get pregnant, males) to 2 (people who can get pregnant, people who cannot get pregnant). This change will make registration for iPLEDGE less complex and more inclusive for all patients. It is important for residents to stay at the forefront of these patient health issues and barriers to equal care, and this change represents a step in the right direction.

Isotretinoin is one of the most highly regulated dermatologic medications on the market. The main reason for regulation through the US Food and Drug Administration (FDA)–managed iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) is to minimize the drug’s teratogenic potential, as isotretinoin can cause profound birth defects. The program originally categorized patients into 1 of 3 categories: (1) females of reproductive potential, (2) females not of reproductive potential, and (3) males. Unless the patient commits to abstinence, the program required female patients of childbearing potential to be on 2 forms of birth control and undergo regular pregnancy testing before obtaining refills. Over the last few years, the American Academy of Dermatology Association (AADA) has been advocating for changes to the iPLEDGE system. Proposed changes have included decreasing attestation frequency for patients who cannot get pregnant, increasing contraception counseling and options, and changing enrollment guidelines to encompass all gender and sexual minorities. As of December 13, 2021, the iPLEDGE system changed enrollment categories to reflect the AADA’s wishes and rolled out gender-neutral categories for enrollment in iPLEDGE. This change will simplify and enhance patients’ experience when starting isotretinoin.

Developing Inclusive iPLEDGE Categories

In recent years, dermatologists and patients have viewed these strict gender-based categories as limiting and problematic, especially for their transgender patients and female patients of childbearing potential who exclusively engage in intercourse with cisgender females. The United States has more than 10 million LGBTQIA+ citizens and an estimated 1.4 million adults who identify as transgender individuals, rendering the previously established gender-binary iPLEDGE categories outdated.^1,2

As a result, over the last few years, dermatologists, LGBTQIA+ allies, and patients have urged the FDA to create a gender-neutral registration process for iPLEDGE. With support from the AADA, the new modifications were approved for implementation and include 2 risk categories: (1) people who can get pregnant and (2) people who cannot get pregnant.³

As exciting as these changes are for the future of dermatologic practice, the actual transition to the new iPLEDGE system was described as a “failure, chaotic, and a disaster” due to additional changes made at the same time.⁴ The iPLEDGE system was switched to a new website administered by a different vendor and required providers to confirm each patient online by December 13, 2021. In addition, the new system required pharmacists to obtain risk management authorization via the iPLEDGE REMS website or by calling the iPLEDGE REMS center before dispensing isotretinoin. This overhaul did not work as planned, as the new website was constantly down and it was nearly impossible to reach a contact over the telephone. The complications resulted in major disruptions and delayed prescriptions for thousands of patients nationwide as well as a great disruption in workflow for physicians and pharmacists. The AADA subsequently met with the Isotretinoin Products Manufacturers Group to create workable solutions for these issues.

On January 14, 2022, the FDA posted updates regarding access to the iPLEDGE system. They have worked with the Isotretinoin Products Manufacturers Group to create workable solutions for patients and physicians while transferring the patients’ information to the new database. Their solution includes allowing physicians to send patients login links through their email to access their account instead of waiting for the call center. The majority of iPLEDGE users now have access to their accounts without issues, and the gender-neutral guidelines have been in place since the original change.

Impact of iPLEDGE Categories on Transgender Patients

These changes specifically will improve the experience of transgender men and cisgender women who are at no risk for pregnancy and could be subjected to monthly pregnancy testing when it is not medically necessary.

Consider the following patient scenario. A transgender man presents to your dermatology office seeking treatment of severe nodulocystic acne. He was placed on hormonal replacement therapy with exogenous testosterone—injections, oral pills, topical gel, topical patches, or subdermal pellets—to achieve secondary sex characteristics and promote gender congruence. The patient mentions he has been amenorrheic for several months now. He has tried many topical acne treatments as well as oral antibiotics without much benefit and is now interested in enrolling in iPLEDGE to obtain isotretinoin. With the prior iPLEDGE registration packets, how would this transgender man be classified? As a female with childbearing potential due to his retained ovaries and uterus? What if he did not endorse engaging in sexual intercourse that could result in pregnancy?

Transgender patients have unique and unmet needs that often are overlooked and prevent them from equitable, gender-affirming health care. For example, in a prospective study following 20 transgender men starting hormone replacement therapy, the percentage of patients with facial acne increased from 35% to 82% after 6 months of therapy.⁵ In addition, the increased psychosocial burden of acne may be especially difficult in these patients, as they already report higher rates of depression and suicidal ideation compared with their heterosexual cisgender peers.⁴ Further, the primary patient populations receiving isotretinoin typically are adolescents and young adults who are undergoing major physical, mental, and hormonal changes. Self-discovery and self-actualization develop over time, and our role as physicians is to advocate for all aspects of our patients’ health and eliminate barriers to optimal care.

Inclusive Language in iPLEDGE Categories

It is important to streamline access to care for all patients, and gender-affirming, culturally sensitive language is essential to building trust and understanding between patients and providers. Howa Yeung, MD, MSc, a dermatologist at Emory University (Atlanta, Georgia) who advocated for gender-neutral iPLEDGE registration, welcomes the change and stated it “will make my job easier. I no longer have to struggle between respecting the patient’s gender identity and providing medically necessary care for patients with severe acne.”³

Sanchez et al⁶ provided a list of structured questions providers can ask their patients to assess their risk regarding pregnancy: (1) Do you have a uterus and/or ovaries?, (2) Are you engaging in sexual intercourse with a person who has a penis?, and (3) If yes to these questions, what form(s) of birth control are you using? Providers should preface these questions with the following statement: “It is important that I ask these questions to assess your risk for becoming pregnant on this medication because isotretinoin can cause very serious birth defects.” It is important to review these questions and practice asking them so residents can operate from the same place of openness and understanding when caring for their patients.

Final Thoughts

The landscape of isotretinoin prescribing currently is changing on a day-to-day basis. As residents, it is important we stay up to date with the changes regarding our regularly dispensed medications. The main modification made to the iPLEDGE REMS system was switching the risk categories from 3 (females who can get pregnant, females who cannot get pregnant, males) to 2 (people who can get pregnant, people who cannot get pregnant). This change will make registration for iPLEDGE less complex and more inclusive for all patients. It is important for residents to stay at the forefront of these patient health issues and barriers to equal care, and this change represents a step in the right direction.

Isotretinoin is one of the most highly regulated dermatologic medications on the market. The main reason for regulation through the US Food and Drug Administration (FDA)–managed iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) is to minimize the drug’s teratogenic potential, as isotretinoin can cause profound birth defects. The program originally categorized patients into 1 of 3 categories: (1) females of reproductive potential, (2) females not of reproductive potential, and (3) males. Unless the patient commits to abstinence, the program required female patients of childbearing potential to be on 2 forms of birth control and undergo regular pregnancy testing before obtaining refills. Over the last few years, the American Academy of Dermatology Association (AADA) has been advocating for changes to the iPLEDGE system. Proposed changes have included decreasing attestation frequency for patients who cannot get pregnant, increasing contraception counseling and options, and changing enrollment guidelines to encompass all gender and sexual minorities. As of December 13, 2021, the iPLEDGE system changed enrollment categories to reflect the AADA’s wishes and rolled out gender-neutral categories for enrollment in iPLEDGE. This change will simplify and enhance patients’ experience when starting isotretinoin.

Developing Inclusive iPLEDGE Categories

In recent years, dermatologists and patients have viewed these strict gender-based categories as limiting and problematic, especially for their transgender patients and female patients of childbearing potential who exclusively engage in intercourse with cisgender females. The United States has more than 10 million LGBTQIA+ citizens and an estimated 1.4 million adults who identify as transgender individuals, rendering the previously established gender-binary iPLEDGE categories outdated.^1,2

As a result, over the last few years, dermatologists, LGBTQIA+ allies, and patients have urged the FDA to create a gender-neutral registration process for iPLEDGE. With support from the AADA, the new modifications were approved for implementation and include 2 risk categories: (1) people who can get pregnant and (2) people who cannot get pregnant.³

As exciting as these changes are for the future of dermatologic practice, the actual transition to the new iPLEDGE system was described as a “failure, chaotic, and a disaster” due to additional changes made at the same time.⁴ The iPLEDGE system was switched to a new website administered by a different vendor and required providers to confirm each patient online by December 13, 2021. In addition, the new system required pharmacists to obtain risk management authorization via the iPLEDGE REMS website or by calling the iPLEDGE REMS center before dispensing isotretinoin. This overhaul did not work as planned, as the new website was constantly down and it was nearly impossible to reach a contact over the telephone. The complications resulted in major disruptions and delayed prescriptions for thousands of patients nationwide as well as a great disruption in workflow for physicians and pharmacists. The AADA subsequently met with the Isotretinoin Products Manufacturers Group to create workable solutions for these issues.

On January 14, 2022, the FDA posted updates regarding access to the iPLEDGE system. They have worked with the Isotretinoin Products Manufacturers Group to create workable solutions for patients and physicians while transferring the patients’ information to the new database. Their solution includes allowing physicians to send patients login links through their email to access their account instead of waiting for the call center. The majority of iPLEDGE users now have access to their accounts without issues, and the gender-neutral guidelines have been in place since the original change.

Impact of iPLEDGE Categories on Transgender Patients

These changes specifically will improve the experience of transgender men and cisgender women who are at no risk for pregnancy and could be subjected to monthly pregnancy testing when it is not medically necessary.

Consider the following patient scenario. A transgender man presents to your dermatology office seeking treatment of severe nodulocystic acne. He was placed on hormonal replacement therapy with exogenous testosterone—injections, oral pills, topical gel, topical patches, or subdermal pellets—to achieve secondary sex characteristics and promote gender congruence. The patient mentions he has been amenorrheic for several months now. He has tried many topical acne treatments as well as oral antibiotics without much benefit and is now interested in enrolling in iPLEDGE to obtain isotretinoin. With the prior iPLEDGE registration packets, how would this transgender man be classified? As a female with childbearing potential due to his retained ovaries and uterus? What if he did not endorse engaging in sexual intercourse that could result in pregnancy?

Transgender patients have unique and unmet needs that often are overlooked and prevent them from equitable, gender-affirming health care. For example, in a prospective study following 20 transgender men starting hormone replacement therapy, the percentage of patients with facial acne increased from 35% to 82% after 6 months of therapy.⁵ In addition, the increased psychosocial burden of acne may be especially difficult in these patients, as they already report higher rates of depression and suicidal ideation compared with their heterosexual cisgender peers.⁴ Further, the primary patient populations receiving isotretinoin typically are adolescents and young adults who are undergoing major physical, mental, and hormonal changes. Self-discovery and self-actualization develop over time, and our role as physicians is to advocate for all aspects of our patients’ health and eliminate barriers to optimal care.

Inclusive Language in iPLEDGE Categories

It is important to streamline access to care for all patients, and gender-affirming, culturally sensitive language is essential to building trust and understanding between patients and providers. Howa Yeung, MD, MSc, a dermatologist at Emory University (Atlanta, Georgia) who advocated for gender-neutral iPLEDGE registration, welcomes the change and stated it “will make my job easier. I no longer have to struggle between respecting the patient’s gender identity and providing medically necessary care for patients with severe acne.”³

Sanchez et al⁶ provided a list of structured questions providers can ask their patients to assess their risk regarding pregnancy: (1) Do you have a uterus and/or ovaries?, (2) Are you engaging in sexual intercourse with a person who has a penis?, and (3) If yes to these questions, what form(s) of birth control are you using? Providers should preface these questions with the following statement: “It is important that I ask these questions to assess your risk for becoming pregnant on this medication because isotretinoin can cause very serious birth defects.” It is important to review these questions and practice asking them so residents can operate from the same place of openness and understanding when caring for their patients.

Final Thoughts

The landscape of isotretinoin prescribing currently is changing on a day-to-day basis. As residents, it is important we stay up to date with the changes regarding our regularly dispensed medications. The main modification made to the iPLEDGE REMS system was switching the risk categories from 3 (females who can get pregnant, females who cannot get pregnant, males) to 2 (people who can get pregnant, people who cannot get pregnant). This change will make registration for iPLEDGE less complex and more inclusive for all patients. It is important for residents to stay at the forefront of these patient health issues and barriers to equal care, and this change represents a step in the right direction.