Nonmelanoma Skin Cancer

Individuals with skin of color (SOC) are disproportionately affected by hyperpigmentation disorders such as melasma and postinflammatory hyperpigmentation following sun exposure. Although epidermal melanin provides UVB protection, susceptibility to pigmentary responses from longer UVA wavelengths and visible light (VL) remains, particularly the highest energy wavelengths of blue light (BL) between 400 and 450 nm.¹ Blue light can induce immediate and persistent pigment darkening in those with Fitzpatrick skin types IV to VI, and trace amounts of near-visible UVA (NV-UVA) between 370 and 400 nm can synergize with VL to amplify pigmentation and erythema responses.²

Current photoprotection recommendations emphasize sun protection factor (SPF) ratings of 30+ and broad-spectrum labeling; however, under the US Food and Drug Administration standards, the ­broad-spectrum designation is based solely on achieving a mean critical wavelength of 370 nm or higher, which does not ensure meaningful attenuation of NV-UVA or VL wavelengths.³ Tinted sunscreens containing iron oxides (FeO) have been shown to improve protection against these ­pigment-inducing wavelengths,⁴ yet quantitative comparisons between tinted and nontinted commercial sunscreen products remain limited.

To address the gap in understanding about tinted vs nontinted commercial sunscreen products, we conducted an in vitro spectrophotometric comparative analysis. The objectives were to quantify NV-UVA and BL attenuation across products and evaluate whether formulation characteristics (eg, SPF rating, filter types and concentration, the presence and depth of tint, antioxidant content) would correlate with improved photoprotection in pigment-sensitive wavelengths. We hypothesized that formulation features such as higher SPF, inorganic filters, and the presence of tint antioxidants would be associated with superior NV-UVA and BL attenuation compared with nontinted formulations.

Methods

Sunscreen Selection—A convenience sample of 23 broad-spectrum sunscreens commercially available at drugstores was selected to reflect easily accessible options. Six sunscreen brands with tinted (n=13) and nontinted (n=10) counterpart formulations were included. Filter category (mineral and/or chemical), SPF, UV filter type and concentration, tint shade (light, medium, medium/deep, deep), number of photoprotective antioxidants (diethylhexyl syringylidenemalonate, vitamin E, vitamin C, licochalcone A, and glycyrrhetinic acid), and presence of FeO were recorded.

Substrate Preparation—Testing was performed using standardized polymethyl methacrylate (PMMA) plates. Sunscreens were mixed prior to application and applied at 1.3 mg/cm² per the European Cosmetic and Perfumery Association (COLIPA) UVA testing guidelines.⁵ Plates were reweighed to confirm dosing and dried in a dark environment for at least 15 minutes prior to testing.

Spectrophotometric Measurements—Spectral transmittance was measured from 250 to 450 nm using a spectrophotometer equipped with a xenon flash lamp (energy <0.2 J/cm²). Baseline transmission was recorded using untreated PMMA plates. Five scans were averaged per plate. Analyses focused on NV-UVA transmittance from 380 to 400 nm and peak BL transmission at 450 nm.

Mean NV-UVA transmittance was calculated as the arithmetic mean of percent transmittance measured at 1-nm increments from 380 to 400 nm (n=21). Because of the steep rise in transmittance between 380 and 400 nm and subsequent plateau into the visible range, this approach was used to approximate the area under the transmittance-wavelength curve over the specified interval, enabling direct comparison of NV-UVA penetration between formulations.

Statistical Analysis—Descriptive statistics were used to summarize transmittance values. Spearman rank correlation was used to assess associations between formulation variables and spectral attenuation. Analysis of covariance was used to evaluate the effect of FeO on transmittance while adjusting for SPF or filter type. The Mann-Whitney U test was used to compare NV-UVA and blue light transmittance between FeO-containing mineral and chemical formulations. Statistical significance was set at P<.05.

Results

Across broad-spectrum sunscreen formulations (N=23), mean SPF values were 40.4 (range, 30-70), and the mean number of antioxidants in the ingredient list was 1.5 (range, 0-4). Mean NV-UVA transmittance was 16.7% (range, 0.1%-55.0%) and mean BL transmittance was 44.3% (range, 0.3%-97.5%)(eTable 1).

The mean labeled zinc oxide (ZnO) concentration among ZnO-containing formulations (n=14) was 10.5% (range, 5.0%-21.6%), with mean NV-UVA and BL transmittance of 12.6% (range, 0.1%-55.0%) and 25.8% (range, 0.3%-67.2%), respectively. Mean NV-UVA and BL transmittance were 26.7% (range, 9.6%-55.0%) and 45.6% (range, 23.0%-67.2%) among ZnO formulations without FeO (n=5), compared with lower transmittance of 4.8% (range, 0.1%-11.5%) and 14.9% (range, 0.3%-29.5%) in ZnO formulations containing FeO (n=9).

The mean labeled titanium dioxide (TiO₂) concentration among TiO₂-containing formulations (n=14) was 9.0% (range, 3.2%-17.0%), with corresponding mean NV-UVA and BL transmittance of 9.5% (range, 0.1%-28.5%) and 22.7% (range, 0.3%-47.6%), respectively. Among TiO₂ formulations without FeO (n=4), mean NV-UVA and BL transmittance was 19.7% (range, 9.6%-28.5%) and 39.8% (range, 23.0%-47.6%), while FeO-containing TiO₂ formulations (n=10) showed lower mean NV-UVA and BL transmittance of 5.4% (range, 0.1%-11.5%) and 15.8% (range, 0.3%-29.5%), respectively. The mean labeled avobenzone concentration among avobenzone-containing formulations (n=8) was 2.9% (range, 2.5%-3%), with mean NV-UVA and BL transmittance of 24.7% (range, 10.2%-46.6%) and 79.2% (range, 53.9%-97.5%). Formulations without FeO (n=5) had mean NV-UVA and BL transmittance of 29.0% (range, 10.2%-46.6%) and 83.2% (range, 61.1%-97.5%), whereas FeO-containing products (n=3) demonstrated lower mean NV-UVA and BL transmittance of 17.5% (range, 12.5%-21.9%) and 72.6% (range, 53.9%-85.1%), respectively.

Among products containing ZnO, TiO₂, and avobenzone, the specific UV filter concentrations showed no statistically significant correlation with NV-UVA or BL transmittance (all P>.05). Iron oxide presence significantly correlated with lower NV-UVA (r=–0.67; P=.00042) and lower BL transmittance (r=–0.57; P=.0046). The number of antioxidants in the ingredient list did not correlate with NV-UVA transmittance (r=–0.28; P=.19) or BL ­transmittance (r=–0.16; P=.47). Sun protection factor was not significantly correlated with either wavelength range (Table 1).

Tint shade was treated as an ordinal variable (light, medium, medium/deep, and deep; medium was considered the universal shade). Increasing tint shade depth was significantly associated with reduced NV-UVA (r=–0.64; P=.045) and BL (r=–0.71; P=.023), suggesting a dose-response relationship wherein darker tints exhibited greater attenuation of pigment-relevant wavelengths. Among mineral filter formulations, tinted products demonstrated lower NV-UVA and BL transmittance compared with their nontinted counterparts, with deeper tints providing the greatest reduction in transmittance (eFigure 1). Similar results were observed for chemical filter formulations with greater attenuation in the NV-UVA and BL range for tinted versus nontinted products with greater variability across shade depths (eFigure 2).

After adjusting for SPF, FeO presence remained significantly associated with reduced NV-UVA (F[1,20]=26.9; P<.001) and BL transmittance (F[1,20]=11.7; P=.003). After adjusting for filter type (mineral vs chemical), FeO remained significantly associated with NV-UVA (F[1,19]=10.1; P=.004) and BL transmittance (F[1,19]=10.4; P=.005)(Table 2).

Among FeO-containing products, mineral filters demonstrated significantly lower NV-UVA transmittance compared with chemical filters (median, 5.58% [interquartile range (IQR), 0.59%-9.35%] vs 18.10% [IQR, 12.47%-21.90%]; U=0.00; P=.007). The same was true for BL transmittance (median, 15.90% [IQR, 5.00%-26.20%] vs 78.70% [IQR, 53.90%-85.10%]; U=0.00; P=.007). The differences in spectral transmittance between ­FeO-containing mineral and chemical filter ­formulations are illustrated in eFigure 3, with mineral-based ­products demonstrating lower transmittance, ­particularly across the upper NV-UVA range and across the BL range. These results indicated greater ­pigment-relevant ­photoprotection with mineral vs chemical filters (eTable 2).

Comment

Our initial hypothesis proposed that tinted sunscreens would provide greater NV-UVA and BL attenuation than nontinted formulations, and that characteristics such as inorganic filter content, SPF rating, and antioxidants would correlate with improved protection in pigment-sensitive wavelengths. Our findings partially supported this hypothesis. In this analysis, substantial variability in the NV-UVA and BL transmittance was observed despite all products meeting broad-spectrum criteria. Nontinted mineral and chemical sunscreens exhibited high transmittance in these pigment-related wavelengths, reaching values as high as 55.0% for NV-UVA and 97.5% for BL. These findings align with prior analysis demonstrating that while broad-spectrum sunscreens available in the United States may meet the current critical wavelength criteria for protection in the UVA range, they still may transmit 30% to 66% of available UVA over 2 hours between formulations with equivalent SPF label values.⁶

Recent analyses show that sunscreen recommendations in lay media rarely incorporate input from board-certified dermatologists for individuals with SOC and disproportionately favor nontinted chemical formulations, despite the high prevalence of pigmentary disorders in this population.⁷ Near-visible UVA and BL have been demonstrated to be biologically relevant pigment-inducing wavelengths, both in vitro and in vivo, particularly in individuals with SOC, yet broad-spectrum labeling does not ensure protection against these spectra.⁸ Pigmentary tints such as FeO have demonstrated enhanced attenuation in this spectral region in vivo and may provide more reliable coverage than products with broad-spectrum designation alone.^4,9 Treatment options for pigmentary disorders such as melasma tend to be palliative and costly, making optimized photoprotection a critical component of care to reduce ongoing pigmentary stimuli.¹⁰

Formulations containing FeO demonstrated significantly lower NV-UVA (P<.001) and BL transmittance (P=.003) on average; however, transmittance values ranged widely (NV-UVA: 0.10%-21.90%, BL: 0.30%-85.10%), indicating that FeO presence alone does not determine the magnitude of attenuation. Notably, among FeO-containing products, mineral filters provided significantly lower NV-UVA and BL transmittance compared with chemical filters (P=.007 for both), suggesting that filter type further modulates pigment-relevant photoprotection. Tinted formulations may improve compliance with product use by reducing the white cast and improve shade matching to find suitable options for deeper skin tones,¹¹ but the highly variable photoprotection offered raises concerns about clinical benefit. Although deeper tints showed greater attenuation, pigment concentrations and combinations are not disclosed by manufacturers as FeO is not considered an active ingredient. Darker shades are not practical across all skin tones in individuals with SOC, which underscores the need for standardized pigment metrics and shade-inclusive options.

While avobenzone and ZnO are the only US Food and Drug Administration–approved sunscreen active ingredients that extend protection beyond 360 nm,¹² both exhibited reduced attenuation beyond the longer end of the UVA spectrum. Formulation characteristics, including the concentration of ZnO, TiO₂, and/or avobenzone as well as SPF, did not correlate with NV-UVA or BL attenuation. In the adjusted analysis, FeO presence remained significantly associated with reduced transmittance after adjusting for SPF (NV-UVA: P<.001, BL: P=.003) or filter type (NV-UVA: P=.004, BL: P=.005). These findings suggest that the presence of FeO, rather than UV filters or SPF ratings, supports attenuation in the 380 to 450–nm range, indicating a functional benefit in addition to improved cosmesis.¹³ 

Although antioxidants in specific combinations have shown promise in vivo, no association was observed between the number of antioxidants present and NV-UVA or BL attenuation compared with added tint.¹⁴ This suggests that specific antioxidant combinations and their concentrations may be more relevant than the total count.

Several study limitations need to be considered in interpreting our results, including a modest number of products, controlled in vitro testing conditions, and an incomplete representation of products with pigment concentrations and shade ranges marketed to individuals with SOC across all price categories, despite our focus on affordable, commercially available options. Moreover, PMMA-based spectrophotometry does not account for skin surface heterogeneity, photodegradation, sweat, oil, friction, or application variability, which may alter real-world performance. Additionally, FeO concentrations could not be quantified beyond labeling of tint shade depth, preventing a true assessment of dose-response effects. These limitations may reduce generalizability and highlight the need for complementary in vivo studies to assess clinically relevant outcomes such as persistent pigment darkening. For this reason, caution is warranted in extrapolating these spectral findings to clinical efficacy.

Conclusion

Given the susceptibility of individuals with SOC to pigmentary disorders driven by NV-UVA and BL, our findings support further development and study of FeO-containing sunscreens that address clinically relevant wavelengths. Wide variability in photo-attenuation among tinted formulations underscores the need for evidence-based recommendations, with further studies needed to guide photoprotection strategies for populations with SOC.

Individuals with skin of color (SOC) are disproportionately affected by hyperpigmentation disorders such as melasma and postinflammatory hyperpigmentation following sun exposure. Although epidermal melanin provides UVB protection, susceptibility to pigmentary responses from longer UVA wavelengths and visible light (VL) remains, particularly the highest energy wavelengths of blue light (BL) between 400 and 450 nm.¹ Blue light can induce immediate and persistent pigment darkening in those with Fitzpatrick skin types IV to VI, and trace amounts of near-visible UVA (NV-UVA) between 370 and 400 nm can synergize with VL to amplify pigmentation and erythema responses.²

Current photoprotection recommendations emphasize sun protection factor (SPF) ratings of 30+ and broad-spectrum labeling; however, under the US Food and Drug Administration standards, the ­broad-spectrum designation is based solely on achieving a mean critical wavelength of 370 nm or higher, which does not ensure meaningful attenuation of NV-UVA or VL wavelengths.³ Tinted sunscreens containing iron oxides (FeO) have been shown to improve protection against these ­pigment-inducing wavelengths,⁴ yet quantitative comparisons between tinted and nontinted commercial sunscreen products remain limited.

To address the gap in understanding about tinted vs nontinted commercial sunscreen products, we conducted an in vitro spectrophotometric comparative analysis. The objectives were to quantify NV-UVA and BL attenuation across products and evaluate whether formulation characteristics (eg, SPF rating, filter types and concentration, the presence and depth of tint, antioxidant content) would correlate with improved photoprotection in pigment-sensitive wavelengths. We hypothesized that formulation features such as higher SPF, inorganic filters, and the presence of tint antioxidants would be associated with superior NV-UVA and BL attenuation compared with nontinted formulations.

Methods

Sunscreen Selection—A convenience sample of 23 broad-spectrum sunscreens commercially available at drugstores was selected to reflect easily accessible options. Six sunscreen brands with tinted (n=13) and nontinted (n=10) counterpart formulations were included. Filter category (mineral and/or chemical), SPF, UV filter type and concentration, tint shade (light, medium, medium/deep, deep), number of photoprotective antioxidants (diethylhexyl syringylidenemalonate, vitamin E, vitamin C, licochalcone A, and glycyrrhetinic acid), and presence of FeO were recorded.

Substrate Preparation—Testing was performed using standardized polymethyl methacrylate (PMMA) plates. Sunscreens were mixed prior to application and applied at 1.3 mg/cm² per the European Cosmetic and Perfumery Association (COLIPA) UVA testing guidelines.⁵ Plates were reweighed to confirm dosing and dried in a dark environment for at least 15 minutes prior to testing.

Spectrophotometric Measurements—Spectral transmittance was measured from 250 to 450 nm using a spectrophotometer equipped with a xenon flash lamp (energy <0.2 J/cm²). Baseline transmission was recorded using untreated PMMA plates. Five scans were averaged per plate. Analyses focused on NV-UVA transmittance from 380 to 400 nm and peak BL transmission at 450 nm.

Mean NV-UVA transmittance was calculated as the arithmetic mean of percent transmittance measured at 1-nm increments from 380 to 400 nm (n=21). Because of the steep rise in transmittance between 380 and 400 nm and subsequent plateau into the visible range, this approach was used to approximate the area under the transmittance-wavelength curve over the specified interval, enabling direct comparison of NV-UVA penetration between formulations.

Statistical Analysis—Descriptive statistics were used to summarize transmittance values. Spearman rank correlation was used to assess associations between formulation variables and spectral attenuation. Analysis of covariance was used to evaluate the effect of FeO on transmittance while adjusting for SPF or filter type. The Mann-Whitney U test was used to compare NV-UVA and blue light transmittance between FeO-containing mineral and chemical formulations. Statistical significance was set at P<.05.

Results

Across broad-spectrum sunscreen formulations (N=23), mean SPF values were 40.4 (range, 30-70), and the mean number of antioxidants in the ingredient list was 1.5 (range, 0-4). Mean NV-UVA transmittance was 16.7% (range, 0.1%-55.0%) and mean BL transmittance was 44.3% (range, 0.3%-97.5%)(eTable 1).

The mean labeled zinc oxide (ZnO) concentration among ZnO-containing formulations (n=14) was 10.5% (range, 5.0%-21.6%), with mean NV-UVA and BL transmittance of 12.6% (range, 0.1%-55.0%) and 25.8% (range, 0.3%-67.2%), respectively. Mean NV-UVA and BL transmittance were 26.7% (range, 9.6%-55.0%) and 45.6% (range, 23.0%-67.2%) among ZnO formulations without FeO (n=5), compared with lower transmittance of 4.8% (range, 0.1%-11.5%) and 14.9% (range, 0.3%-29.5%) in ZnO formulations containing FeO (n=9).

The mean labeled titanium dioxide (TiO₂) concentration among TiO₂-containing formulations (n=14) was 9.0% (range, 3.2%-17.0%), with corresponding mean NV-UVA and BL transmittance of 9.5% (range, 0.1%-28.5%) and 22.7% (range, 0.3%-47.6%), respectively. Among TiO₂ formulations without FeO (n=4), mean NV-UVA and BL transmittance was 19.7% (range, 9.6%-28.5%) and 39.8% (range, 23.0%-47.6%), while FeO-containing TiO₂ formulations (n=10) showed lower mean NV-UVA and BL transmittance of 5.4% (range, 0.1%-11.5%) and 15.8% (range, 0.3%-29.5%), respectively. The mean labeled avobenzone concentration among avobenzone-containing formulations (n=8) was 2.9% (range, 2.5%-3%), with mean NV-UVA and BL transmittance of 24.7% (range, 10.2%-46.6%) and 79.2% (range, 53.9%-97.5%). Formulations without FeO (n=5) had mean NV-UVA and BL transmittance of 29.0% (range, 10.2%-46.6%) and 83.2% (range, 61.1%-97.5%), whereas FeO-containing products (n=3) demonstrated lower mean NV-UVA and BL transmittance of 17.5% (range, 12.5%-21.9%) and 72.6% (range, 53.9%-85.1%), respectively.

Among products containing ZnO, TiO₂, and avobenzone, the specific UV filter concentrations showed no statistically significant correlation with NV-UVA or BL transmittance (all P>.05). Iron oxide presence significantly correlated with lower NV-UVA (r=–0.67; P=.00042) and lower BL transmittance (r=–0.57; P=.0046). The number of antioxidants in the ingredient list did not correlate with NV-UVA transmittance (r=–0.28; P=.19) or BL ­transmittance (r=–0.16; P=.47). Sun protection factor was not significantly correlated with either wavelength range (Table 1).

Tint shade was treated as an ordinal variable (light, medium, medium/deep, and deep; medium was considered the universal shade). Increasing tint shade depth was significantly associated with reduced NV-UVA (r=–0.64; P=.045) and BL (r=–0.71; P=.023), suggesting a dose-response relationship wherein darker tints exhibited greater attenuation of pigment-relevant wavelengths. Among mineral filter formulations, tinted products demonstrated lower NV-UVA and BL transmittance compared with their nontinted counterparts, with deeper tints providing the greatest reduction in transmittance (eFigure 1). Similar results were observed for chemical filter formulations with greater attenuation in the NV-UVA and BL range for tinted versus nontinted products with greater variability across shade depths (eFigure 2).

After adjusting for SPF, FeO presence remained significantly associated with reduced NV-UVA (F[1,20]=26.9; P<.001) and BL transmittance (F[1,20]=11.7; P=.003). After adjusting for filter type (mineral vs chemical), FeO remained significantly associated with NV-UVA (F[1,19]=10.1; P=.004) and BL transmittance (F[1,19]=10.4; P=.005)(Table 2).

Among FeO-containing products, mineral filters demonstrated significantly lower NV-UVA transmittance compared with chemical filters (median, 5.58% [interquartile range (IQR), 0.59%-9.35%] vs 18.10% [IQR, 12.47%-21.90%]; U=0.00; P=.007). The same was true for BL transmittance (median, 15.90% [IQR, 5.00%-26.20%] vs 78.70% [IQR, 53.90%-85.10%]; U=0.00; P=.007). The differences in spectral transmittance between ­FeO-containing mineral and chemical filter ­formulations are illustrated in eFigure 3, with mineral-based ­products demonstrating lower transmittance, ­particularly across the upper NV-UVA range and across the BL range. These results indicated greater ­pigment-relevant ­photoprotection with mineral vs chemical filters (eTable 2).

Comment

Our initial hypothesis proposed that tinted sunscreens would provide greater NV-UVA and BL attenuation than nontinted formulations, and that characteristics such as inorganic filter content, SPF rating, and antioxidants would correlate with improved protection in pigment-sensitive wavelengths. Our findings partially supported this hypothesis. In this analysis, substantial variability in the NV-UVA and BL transmittance was observed despite all products meeting broad-spectrum criteria. Nontinted mineral and chemical sunscreens exhibited high transmittance in these pigment-related wavelengths, reaching values as high as 55.0% for NV-UVA and 97.5% for BL. These findings align with prior analysis demonstrating that while broad-spectrum sunscreens available in the United States may meet the current critical wavelength criteria for protection in the UVA range, they still may transmit 30% to 66% of available UVA over 2 hours between formulations with equivalent SPF label values.⁶

Recent analyses show that sunscreen recommendations in lay media rarely incorporate input from board-certified dermatologists for individuals with SOC and disproportionately favor nontinted chemical formulations, despite the high prevalence of pigmentary disorders in this population.⁷ Near-visible UVA and BL have been demonstrated to be biologically relevant pigment-inducing wavelengths, both in vitro and in vivo, particularly in individuals with SOC, yet broad-spectrum labeling does not ensure protection against these spectra.⁸ Pigmentary tints such as FeO have demonstrated enhanced attenuation in this spectral region in vivo and may provide more reliable coverage than products with broad-spectrum designation alone.^4,9 Treatment options for pigmentary disorders such as melasma tend to be palliative and costly, making optimized photoprotection a critical component of care to reduce ongoing pigmentary stimuli.¹⁰

Formulations containing FeO demonstrated significantly lower NV-UVA (P<.001) and BL transmittance (P=.003) on average; however, transmittance values ranged widely (NV-UVA: 0.10%-21.90%, BL: 0.30%-85.10%), indicating that FeO presence alone does not determine the magnitude of attenuation. Notably, among FeO-containing products, mineral filters provided significantly lower NV-UVA and BL transmittance compared with chemical filters (P=.007 for both), suggesting that filter type further modulates pigment-relevant photoprotection. Tinted formulations may improve compliance with product use by reducing the white cast and improve shade matching to find suitable options for deeper skin tones,¹¹ but the highly variable photoprotection offered raises concerns about clinical benefit. Although deeper tints showed greater attenuation, pigment concentrations and combinations are not disclosed by manufacturers as FeO is not considered an active ingredient. Darker shades are not practical across all skin tones in individuals with SOC, which underscores the need for standardized pigment metrics and shade-inclusive options.

While avobenzone and ZnO are the only US Food and Drug Administration–approved sunscreen active ingredients that extend protection beyond 360 nm,¹² both exhibited reduced attenuation beyond the longer end of the UVA spectrum. Formulation characteristics, including the concentration of ZnO, TiO₂, and/or avobenzone as well as SPF, did not correlate with NV-UVA or BL attenuation. In the adjusted analysis, FeO presence remained significantly associated with reduced transmittance after adjusting for SPF (NV-UVA: P<.001, BL: P=.003) or filter type (NV-UVA: P=.004, BL: P=.005). These findings suggest that the presence of FeO, rather than UV filters or SPF ratings, supports attenuation in the 380 to 450–nm range, indicating a functional benefit in addition to improved cosmesis.¹³ 

Although antioxidants in specific combinations have shown promise in vivo, no association was observed between the number of antioxidants present and NV-UVA or BL attenuation compared with added tint.¹⁴ This suggests that specific antioxidant combinations and their concentrations may be more relevant than the total count.

Several study limitations need to be considered in interpreting our results, including a modest number of products, controlled in vitro testing conditions, and an incomplete representation of products with pigment concentrations and shade ranges marketed to individuals with SOC across all price categories, despite our focus on affordable, commercially available options. Moreover, PMMA-based spectrophotometry does not account for skin surface heterogeneity, photodegradation, sweat, oil, friction, or application variability, which may alter real-world performance. Additionally, FeO concentrations could not be quantified beyond labeling of tint shade depth, preventing a true assessment of dose-response effects. These limitations may reduce generalizability and highlight the need for complementary in vivo studies to assess clinically relevant outcomes such as persistent pigment darkening. For this reason, caution is warranted in extrapolating these spectral findings to clinical efficacy.

Conclusion

Given the susceptibility of individuals with SOC to pigmentary disorders driven by NV-UVA and BL, our findings support further development and study of FeO-containing sunscreens that address clinically relevant wavelengths. Wide variability in photo-attenuation among tinted formulations underscores the need for evidence-based recommendations, with further studies needed to guide photoprotection strategies for populations with SOC.

Individuals with skin of color (SOC) are disproportionately affected by hyperpigmentation disorders such as melasma and postinflammatory hyperpigmentation following sun exposure. Although epidermal melanin provides UVB protection, susceptibility to pigmentary responses from longer UVA wavelengths and visible light (VL) remains, particularly the highest energy wavelengths of blue light (BL) between 400 and 450 nm.¹ Blue light can induce immediate and persistent pigment darkening in those with Fitzpatrick skin types IV to VI, and trace amounts of near-visible UVA (NV-UVA) between 370 and 400 nm can synergize with VL to amplify pigmentation and erythema responses.²

Current photoprotection recommendations emphasize sun protection factor (SPF) ratings of 30+ and broad-spectrum labeling; however, under the US Food and Drug Administration standards, the ­broad-spectrum designation is based solely on achieving a mean critical wavelength of 370 nm or higher, which does not ensure meaningful attenuation of NV-UVA or VL wavelengths.³ Tinted sunscreens containing iron oxides (FeO) have been shown to improve protection against these ­pigment-inducing wavelengths,⁴ yet quantitative comparisons between tinted and nontinted commercial sunscreen products remain limited.

To address the gap in understanding about tinted vs nontinted commercial sunscreen products, we conducted an in vitro spectrophotometric comparative analysis. The objectives were to quantify NV-UVA and BL attenuation across products and evaluate whether formulation characteristics (eg, SPF rating, filter types and concentration, the presence and depth of tint, antioxidant content) would correlate with improved photoprotection in pigment-sensitive wavelengths. We hypothesized that formulation features such as higher SPF, inorganic filters, and the presence of tint antioxidants would be associated with superior NV-UVA and BL attenuation compared with nontinted formulations.

Methods

Sunscreen Selection—A convenience sample of 23 broad-spectrum sunscreens commercially available at drugstores was selected to reflect easily accessible options. Six sunscreen brands with tinted (n=13) and nontinted (n=10) counterpart formulations were included. Filter category (mineral and/or chemical), SPF, UV filter type and concentration, tint shade (light, medium, medium/deep, deep), number of photoprotective antioxidants (diethylhexyl syringylidenemalonate, vitamin E, vitamin C, licochalcone A, and glycyrrhetinic acid), and presence of FeO were recorded.

Substrate Preparation—Testing was performed using standardized polymethyl methacrylate (PMMA) plates. Sunscreens were mixed prior to application and applied at 1.3 mg/cm² per the European Cosmetic and Perfumery Association (COLIPA) UVA testing guidelines.⁵ Plates were reweighed to confirm dosing and dried in a dark environment for at least 15 minutes prior to testing.

Spectrophotometric Measurements—Spectral transmittance was measured from 250 to 450 nm using a spectrophotometer equipped with a xenon flash lamp (energy <0.2 J/cm²). Baseline transmission was recorded using untreated PMMA plates. Five scans were averaged per plate. Analyses focused on NV-UVA transmittance from 380 to 400 nm and peak BL transmission at 450 nm.

Mean NV-UVA transmittance was calculated as the arithmetic mean of percent transmittance measured at 1-nm increments from 380 to 400 nm (n=21). Because of the steep rise in transmittance between 380 and 400 nm and subsequent plateau into the visible range, this approach was used to approximate the area under the transmittance-wavelength curve over the specified interval, enabling direct comparison of NV-UVA penetration between formulations.

Statistical Analysis—Descriptive statistics were used to summarize transmittance values. Spearman rank correlation was used to assess associations between formulation variables and spectral attenuation. Analysis of covariance was used to evaluate the effect of FeO on transmittance while adjusting for SPF or filter type. The Mann-Whitney U test was used to compare NV-UVA and blue light transmittance between FeO-containing mineral and chemical formulations. Statistical significance was set at P<.05.

Results

Across broad-spectrum sunscreen formulations (N=23), mean SPF values were 40.4 (range, 30-70), and the mean number of antioxidants in the ingredient list was 1.5 (range, 0-4). Mean NV-UVA transmittance was 16.7% (range, 0.1%-55.0%) and mean BL transmittance was 44.3% (range, 0.3%-97.5%)(eTable 1).

The mean labeled zinc oxide (ZnO) concentration among ZnO-containing formulations (n=14) was 10.5% (range, 5.0%-21.6%), with mean NV-UVA and BL transmittance of 12.6% (range, 0.1%-55.0%) and 25.8% (range, 0.3%-67.2%), respectively. Mean NV-UVA and BL transmittance were 26.7% (range, 9.6%-55.0%) and 45.6% (range, 23.0%-67.2%) among ZnO formulations without FeO (n=5), compared with lower transmittance of 4.8% (range, 0.1%-11.5%) and 14.9% (range, 0.3%-29.5%) in ZnO formulations containing FeO (n=9).

The mean labeled titanium dioxide (TiO₂) concentration among TiO₂-containing formulations (n=14) was 9.0% (range, 3.2%-17.0%), with corresponding mean NV-UVA and BL transmittance of 9.5% (range, 0.1%-28.5%) and 22.7% (range, 0.3%-47.6%), respectively. Among TiO₂ formulations without FeO (n=4), mean NV-UVA and BL transmittance was 19.7% (range, 9.6%-28.5%) and 39.8% (range, 23.0%-47.6%), while FeO-containing TiO₂ formulations (n=10) showed lower mean NV-UVA and BL transmittance of 5.4% (range, 0.1%-11.5%) and 15.8% (range, 0.3%-29.5%), respectively. The mean labeled avobenzone concentration among avobenzone-containing formulations (n=8) was 2.9% (range, 2.5%-3%), with mean NV-UVA and BL transmittance of 24.7% (range, 10.2%-46.6%) and 79.2% (range, 53.9%-97.5%). Formulations without FeO (n=5) had mean NV-UVA and BL transmittance of 29.0% (range, 10.2%-46.6%) and 83.2% (range, 61.1%-97.5%), whereas FeO-containing products (n=3) demonstrated lower mean NV-UVA and BL transmittance of 17.5% (range, 12.5%-21.9%) and 72.6% (range, 53.9%-85.1%), respectively.

Among products containing ZnO, TiO₂, and avobenzone, the specific UV filter concentrations showed no statistically significant correlation with NV-UVA or BL transmittance (all P>.05). Iron oxide presence significantly correlated with lower NV-UVA (r=–0.67; P=.00042) and lower BL transmittance (r=–0.57; P=.0046). The number of antioxidants in the ingredient list did not correlate with NV-UVA transmittance (r=–0.28; P=.19) or BL ­transmittance (r=–0.16; P=.47). Sun protection factor was not significantly correlated with either wavelength range (Table 1).

Tint shade was treated as an ordinal variable (light, medium, medium/deep, and deep; medium was considered the universal shade). Increasing tint shade depth was significantly associated with reduced NV-UVA (r=–0.64; P=.045) and BL (r=–0.71; P=.023), suggesting a dose-response relationship wherein darker tints exhibited greater attenuation of pigment-relevant wavelengths. Among mineral filter formulations, tinted products demonstrated lower NV-UVA and BL transmittance compared with their nontinted counterparts, with deeper tints providing the greatest reduction in transmittance (eFigure 1). Similar results were observed for chemical filter formulations with greater attenuation in the NV-UVA and BL range for tinted versus nontinted products with greater variability across shade depths (eFigure 2).

After adjusting for SPF, FeO presence remained significantly associated with reduced NV-UVA (F[1,20]=26.9; P<.001) and BL transmittance (F[1,20]=11.7; P=.003). After adjusting for filter type (mineral vs chemical), FeO remained significantly associated with NV-UVA (F[1,19]=10.1; P=.004) and BL transmittance (F[1,19]=10.4; P=.005)(Table 2).

Among FeO-containing products, mineral filters demonstrated significantly lower NV-UVA transmittance compared with chemical filters (median, 5.58% [interquartile range (IQR), 0.59%-9.35%] vs 18.10% [IQR, 12.47%-21.90%]; U=0.00; P=.007). The same was true for BL transmittance (median, 15.90% [IQR, 5.00%-26.20%] vs 78.70% [IQR, 53.90%-85.10%]; U=0.00; P=.007). The differences in spectral transmittance between ­FeO-containing mineral and chemical filter ­formulations are illustrated in eFigure 3, with mineral-based ­products demonstrating lower transmittance, ­particularly across the upper NV-UVA range and across the BL range. These results indicated greater ­pigment-relevant ­photoprotection with mineral vs chemical filters (eTable 2).

Comment

Our initial hypothesis proposed that tinted sunscreens would provide greater NV-UVA and BL attenuation than nontinted formulations, and that characteristics such as inorganic filter content, SPF rating, and antioxidants would correlate with improved protection in pigment-sensitive wavelengths. Our findings partially supported this hypothesis. In this analysis, substantial variability in the NV-UVA and BL transmittance was observed despite all products meeting broad-spectrum criteria. Nontinted mineral and chemical sunscreens exhibited high transmittance in these pigment-related wavelengths, reaching values as high as 55.0% for NV-UVA and 97.5% for BL. These findings align with prior analysis demonstrating that while broad-spectrum sunscreens available in the United States may meet the current critical wavelength criteria for protection in the UVA range, they still may transmit 30% to 66% of available UVA over 2 hours between formulations with equivalent SPF label values.⁶

Recent analyses show that sunscreen recommendations in lay media rarely incorporate input from board-certified dermatologists for individuals with SOC and disproportionately favor nontinted chemical formulations, despite the high prevalence of pigmentary disorders in this population.⁷ Near-visible UVA and BL have been demonstrated to be biologically relevant pigment-inducing wavelengths, both in vitro and in vivo, particularly in individuals with SOC, yet broad-spectrum labeling does not ensure protection against these spectra.⁸ Pigmentary tints such as FeO have demonstrated enhanced attenuation in this spectral region in vivo and may provide more reliable coverage than products with broad-spectrum designation alone.^4,9 Treatment options for pigmentary disorders such as melasma tend to be palliative and costly, making optimized photoprotection a critical component of care to reduce ongoing pigmentary stimuli.¹⁰

Formulations containing FeO demonstrated significantly lower NV-UVA (P<.001) and BL transmittance (P=.003) on average; however, transmittance values ranged widely (NV-UVA: 0.10%-21.90%, BL: 0.30%-85.10%), indicating that FeO presence alone does not determine the magnitude of attenuation. Notably, among FeO-containing products, mineral filters provided significantly lower NV-UVA and BL transmittance compared with chemical filters (P=.007 for both), suggesting that filter type further modulates pigment-relevant photoprotection. Tinted formulations may improve compliance with product use by reducing the white cast and improve shade matching to find suitable options for deeper skin tones,¹¹ but the highly variable photoprotection offered raises concerns about clinical benefit. Although deeper tints showed greater attenuation, pigment concentrations and combinations are not disclosed by manufacturers as FeO is not considered an active ingredient. Darker shades are not practical across all skin tones in individuals with SOC, which underscores the need for standardized pigment metrics and shade-inclusive options.

While avobenzone and ZnO are the only US Food and Drug Administration–approved sunscreen active ingredients that extend protection beyond 360 nm,¹² both exhibited reduced attenuation beyond the longer end of the UVA spectrum. Formulation characteristics, including the concentration of ZnO, TiO₂, and/or avobenzone as well as SPF, did not correlate with NV-UVA or BL attenuation. In the adjusted analysis, FeO presence remained significantly associated with reduced transmittance after adjusting for SPF (NV-UVA: P<.001, BL: P=.003) or filter type (NV-UVA: P=.004, BL: P=.005). These findings suggest that the presence of FeO, rather than UV filters or SPF ratings, supports attenuation in the 380 to 450–nm range, indicating a functional benefit in addition to improved cosmesis.¹³ 

Although antioxidants in specific combinations have shown promise in vivo, no association was observed between the number of antioxidants present and NV-UVA or BL attenuation compared with added tint.¹⁴ This suggests that specific antioxidant combinations and their concentrations may be more relevant than the total count.

Several study limitations need to be considered in interpreting our results, including a modest number of products, controlled in vitro testing conditions, and an incomplete representation of products with pigment concentrations and shade ranges marketed to individuals with SOC across all price categories, despite our focus on affordable, commercially available options. Moreover, PMMA-based spectrophotometry does not account for skin surface heterogeneity, photodegradation, sweat, oil, friction, or application variability, which may alter real-world performance. Additionally, FeO concentrations could not be quantified beyond labeling of tint shade depth, preventing a true assessment of dose-response effects. These limitations may reduce generalizability and highlight the need for complementary in vivo studies to assess clinically relevant outcomes such as persistent pigment darkening. For this reason, caution is warranted in extrapolating these spectral findings to clinical efficacy.

Conclusion

Given the susceptibility of individuals with SOC to pigmentary disorders driven by NV-UVA and BL, our findings support further development and study of FeO-containing sunscreens that address clinically relevant wavelengths. Wide variability in photo-attenuation among tinted formulations underscores the need for evidence-based recommendations, with further studies needed to guide photoprotection strategies for populations with SOC.

Military service members are at high risk for skin cancer due to unique occupational and environmental exposures, particularly in the aviation community, in which high-altitude flying, prolonged outdoor aircraft maintenance, physical training, field exercises, and deployments limit access to shade and opportunities for sunscreen reapplication. During deployment or field operations, service members may operate in environments with limited access to SPF products, particularly if sunscreen is not included among personal items.

Research on sun protection strategies and skin cancer risk factors in military personnel is critical to improving prevention, particularly given the higher incidence of melanoma in this population. A 2010 retrospective tumor registry review from the Department of Defense and the National Cancer Institute found higher melanoma rates in military personnel compared with the general population among individuals aged 45 to 49 years (33.62 vs 27.49), 50 to 54 years (49.76 vs 32.18), and 55 to 59 years (178.48 vs 39.17).¹

This article discusses barriers to sun protection in military populations, evaluates sunscreen availability in military exchanges, and considers implications for policy and prevention.

Barriers to Sun Protection and Sunscreen Use

According to Rosenberg et al,² the cause of higher rates of skin cancer among military service members may be multifactorial, including financial barriers to sunscreen use, limited education on photodamage, and insufficient emphasis on sun protection during demanding operational or training activities. Veterans of Operation Enduring Freedom and Operation Iraqi Freedom who were surveyed about UV exposure and sunscreen indicated that 23% (49/211) received education about skin cancer but less than 30% (60/211) used sunscreen consistently during deployment due to lack of access, which has been reported previously.³ Sunscreen adherence also may be reduced in this population due to factors such as skin irritation, cost, poor cosmetic acceptability, and lower utilization among male service members. In their literature review of 9 publications pertaining to skin cancer risk through December 2016, Riemenschneider et al¹ noted that male service members comprised 85% of the US military in 2014, and men statistically have lower rates of sunscreen use than women.

Sunscreen Availability and Product Analysis in Military Exchanges

Sunscreen is an important component of skin care for skin cancer prevention. More consistent use has been noted in households with annual incomes of $60,000 or higher.⁴ Sunscreen product availability has not been evaluated in the military community. Exchange stores are military equivalents of commercial chain stores where service members can purchase tax-free items. The Marine Corps Exchange (MCX) operates on 18 large active-duty bases worldwide. Patrons include active-duty service members from any branch, veterans, and family members. Officials from the MCX headquarters approve and maintain items sold on base. Although product availability may vary by location, standardization is maintained through vendor agreements influenced by customer demand and includes both exchange-branded and private-label products.⁵

In a review of 96 sunscreen products at Marine Corps Air Station Cherry Point MCX, 62.5% (60/96) met American Academy of Dermatology guideline criteria (SPF ≥30, broad-spectrum UVA/UVB protection, and water resistance of 40-80 minutes).⁶ Of all products, 79.1% (76/96) were SPF 30 or higher, 76.0% (73/96) were water-resistant, and all provided broad-spectrum protection. Lotion formulations comprised 62.5% (60/96), and the mean price per ounce was $11.96. Opportunities for product expansion include increased availability of options for sensitive skin, as mineral sunscreens comprised 14.6% (14/96) of products; greater variety of products marketed to men, which accounted for 5.2% (5/96); and improved representation for service members with skin of color, as tinted formulations comprised 2.1% (2/96).⁶

Implications for Policy and Operational Readiness

Given these data, future studies should evaluate sunscreen purchasing behaviors among US service members to determine MCX utilization and whether product selection is driven by active-duty demand or broader consumer purchasing patterns. If product offerings are driven by the civilian customer base, this may result in a lack of tailored options for military service members who are most at risk for high UV exposure. If the MCX does not meet the needs of service members adequately or is inaccessible due to cost or inventory limitations, it highlights a weakness in skin cancer prevention.

Future research should explore not only sunscreen purchasing behavior among service members but also barriers to access and compliance with sun protection measures, as these insights are critical for informing effective policy that balances personal responsibility with institutional support. This could help with advocacy efforts for more effective, readily available options on base. It also could strengthen the argument for alternative strategies to complement sunscreen use, such as a sunscreen allowance, inclusion of sunscreen with provided uniforms and equipment, patient education, work breaks, sun-protective uniform items, and designated shade areas at work.⁶

Final Thoughts

Policy changes such as routine provision of sunscreen through supply chains, issuing sunscreen with uniforms, or providing a sunscreen stipend could remove financial and logistical barriers to consistent use of sunscreen in military populations. These measures could be impactful during field operations, deployments, and training in austere environments, where commercial purchasing options are limited and UV exposure is high. A proactive approach to sun safety could demonstrate a commitment to preserving the current health and operational readiness of active-duty service members while reducing future financial burdens of skin disease and helping promote wellness in this population during retirement. As with ear protection, uniforms, and eyewear, sunscreen should be considered a standard component of operational readiness.

Military service members are at high risk for skin cancer due to unique occupational and environmental exposures, particularly in the aviation community, in which high-altitude flying, prolonged outdoor aircraft maintenance, physical training, field exercises, and deployments limit access to shade and opportunities for sunscreen reapplication. During deployment or field operations, service members may operate in environments with limited access to SPF products, particularly if sunscreen is not included among personal items.

Research on sun protection strategies and skin cancer risk factors in military personnel is critical to improving prevention, particularly given the higher incidence of melanoma in this population. A 2010 retrospective tumor registry review from the Department of Defense and the National Cancer Institute found higher melanoma rates in military personnel compared with the general population among individuals aged 45 to 49 years (33.62 vs 27.49), 50 to 54 years (49.76 vs 32.18), and 55 to 59 years (178.48 vs 39.17).¹

This article discusses barriers to sun protection in military populations, evaluates sunscreen availability in military exchanges, and considers implications for policy and prevention.

Barriers to Sun Protection and Sunscreen Use

According to Rosenberg et al,² the cause of higher rates of skin cancer among military service members may be multifactorial, including financial barriers to sunscreen use, limited education on photodamage, and insufficient emphasis on sun protection during demanding operational or training activities. Veterans of Operation Enduring Freedom and Operation Iraqi Freedom who were surveyed about UV exposure and sunscreen indicated that 23% (49/211) received education about skin cancer but less than 30% (60/211) used sunscreen consistently during deployment due to lack of access, which has been reported previously.³ Sunscreen adherence also may be reduced in this population due to factors such as skin irritation, cost, poor cosmetic acceptability, and lower utilization among male service members. In their literature review of 9 publications pertaining to skin cancer risk through December 2016, Riemenschneider et al¹ noted that male service members comprised 85% of the US military in 2014, and men statistically have lower rates of sunscreen use than women.

Sunscreen Availability and Product Analysis in Military Exchanges

Sunscreen is an important component of skin care for skin cancer prevention. More consistent use has been noted in households with annual incomes of $60,000 or higher.⁴ Sunscreen product availability has not been evaluated in the military community. Exchange stores are military equivalents of commercial chain stores where service members can purchase tax-free items. The Marine Corps Exchange (MCX) operates on 18 large active-duty bases worldwide. Patrons include active-duty service members from any branch, veterans, and family members. Officials from the MCX headquarters approve and maintain items sold on base. Although product availability may vary by location, standardization is maintained through vendor agreements influenced by customer demand and includes both exchange-branded and private-label products.⁵

In a review of 96 sunscreen products at Marine Corps Air Station Cherry Point MCX, 62.5% (60/96) met American Academy of Dermatology guideline criteria (SPF ≥30, broad-spectrum UVA/UVB protection, and water resistance of 40-80 minutes).⁶ Of all products, 79.1% (76/96) were SPF 30 or higher, 76.0% (73/96) were water-resistant, and all provided broad-spectrum protection. Lotion formulations comprised 62.5% (60/96), and the mean price per ounce was $11.96. Opportunities for product expansion include increased availability of options for sensitive skin, as mineral sunscreens comprised 14.6% (14/96) of products; greater variety of products marketed to men, which accounted for 5.2% (5/96); and improved representation for service members with skin of color, as tinted formulations comprised 2.1% (2/96).⁶

Implications for Policy and Operational Readiness

Given these data, future studies should evaluate sunscreen purchasing behaviors among US service members to determine MCX utilization and whether product selection is driven by active-duty demand or broader consumer purchasing patterns. If product offerings are driven by the civilian customer base, this may result in a lack of tailored options for military service members who are most at risk for high UV exposure. If the MCX does not meet the needs of service members adequately or is inaccessible due to cost or inventory limitations, it highlights a weakness in skin cancer prevention.

Future research should explore not only sunscreen purchasing behavior among service members but also barriers to access and compliance with sun protection measures, as these insights are critical for informing effective policy that balances personal responsibility with institutional support. This could help with advocacy efforts for more effective, readily available options on base. It also could strengthen the argument for alternative strategies to complement sunscreen use, such as a sunscreen allowance, inclusion of sunscreen with provided uniforms and equipment, patient education, work breaks, sun-protective uniform items, and designated shade areas at work.⁶

Final Thoughts

Policy changes such as routine provision of sunscreen through supply chains, issuing sunscreen with uniforms, or providing a sunscreen stipend could remove financial and logistical barriers to consistent use of sunscreen in military populations. These measures could be impactful during field operations, deployments, and training in austere environments, where commercial purchasing options are limited and UV exposure is high. A proactive approach to sun safety could demonstrate a commitment to preserving the current health and operational readiness of active-duty service members while reducing future financial burdens of skin disease and helping promote wellness in this population during retirement. As with ear protection, uniforms, and eyewear, sunscreen should be considered a standard component of operational readiness.

Military service members are at high risk for skin cancer due to unique occupational and environmental exposures, particularly in the aviation community, in which high-altitude flying, prolonged outdoor aircraft maintenance, physical training, field exercises, and deployments limit access to shade and opportunities for sunscreen reapplication. During deployment or field operations, service members may operate in environments with limited access to SPF products, particularly if sunscreen is not included among personal items.

Research on sun protection strategies and skin cancer risk factors in military personnel is critical to improving prevention, particularly given the higher incidence of melanoma in this population. A 2010 retrospective tumor registry review from the Department of Defense and the National Cancer Institute found higher melanoma rates in military personnel compared with the general population among individuals aged 45 to 49 years (33.62 vs 27.49), 50 to 54 years (49.76 vs 32.18), and 55 to 59 years (178.48 vs 39.17).¹

This article discusses barriers to sun protection in military populations, evaluates sunscreen availability in military exchanges, and considers implications for policy and prevention.

Barriers to Sun Protection and Sunscreen Use

According to Rosenberg et al,² the cause of higher rates of skin cancer among military service members may be multifactorial, including financial barriers to sunscreen use, limited education on photodamage, and insufficient emphasis on sun protection during demanding operational or training activities. Veterans of Operation Enduring Freedom and Operation Iraqi Freedom who were surveyed about UV exposure and sunscreen indicated that 23% (49/211) received education about skin cancer but less than 30% (60/211) used sunscreen consistently during deployment due to lack of access, which has been reported previously.³ Sunscreen adherence also may be reduced in this population due to factors such as skin irritation, cost, poor cosmetic acceptability, and lower utilization among male service members. In their literature review of 9 publications pertaining to skin cancer risk through December 2016, Riemenschneider et al¹ noted that male service members comprised 85% of the US military in 2014, and men statistically have lower rates of sunscreen use than women.

Sunscreen Availability and Product Analysis in Military Exchanges

Sunscreen is an important component of skin care for skin cancer prevention. More consistent use has been noted in households with annual incomes of $60,000 or higher.⁴ Sunscreen product availability has not been evaluated in the military community. Exchange stores are military equivalents of commercial chain stores where service members can purchase tax-free items. The Marine Corps Exchange (MCX) operates on 18 large active-duty bases worldwide. Patrons include active-duty service members from any branch, veterans, and family members. Officials from the MCX headquarters approve and maintain items sold on base. Although product availability may vary by location, standardization is maintained through vendor agreements influenced by customer demand and includes both exchange-branded and private-label products.⁵

In a review of 96 sunscreen products at Marine Corps Air Station Cherry Point MCX, 62.5% (60/96) met American Academy of Dermatology guideline criteria (SPF ≥30, broad-spectrum UVA/UVB protection, and water resistance of 40-80 minutes).⁶ Of all products, 79.1% (76/96) were SPF 30 or higher, 76.0% (73/96) were water-resistant, and all provided broad-spectrum protection. Lotion formulations comprised 62.5% (60/96), and the mean price per ounce was $11.96. Opportunities for product expansion include increased availability of options for sensitive skin, as mineral sunscreens comprised 14.6% (14/96) of products; greater variety of products marketed to men, which accounted for 5.2% (5/96); and improved representation for service members with skin of color, as tinted formulations comprised 2.1% (2/96).⁶

Implications for Policy and Operational Readiness

Given these data, future studies should evaluate sunscreen purchasing behaviors among US service members to determine MCX utilization and whether product selection is driven by active-duty demand or broader consumer purchasing patterns. If product offerings are driven by the civilian customer base, this may result in a lack of tailored options for military service members who are most at risk for high UV exposure. If the MCX does not meet the needs of service members adequately or is inaccessible due to cost or inventory limitations, it highlights a weakness in skin cancer prevention.

Future research should explore not only sunscreen purchasing behavior among service members but also barriers to access and compliance with sun protection measures, as these insights are critical for informing effective policy that balances personal responsibility with institutional support. This could help with advocacy efforts for more effective, readily available options on base. It also could strengthen the argument for alternative strategies to complement sunscreen use, such as a sunscreen allowance, inclusion of sunscreen with provided uniforms and equipment, patient education, work breaks, sun-protective uniform items, and designated shade areas at work.⁶

Final Thoughts

Policy changes such as routine provision of sunscreen through supply chains, issuing sunscreen with uniforms, or providing a sunscreen stipend could remove financial and logistical barriers to consistent use of sunscreen in military populations. These measures could be impactful during field operations, deployments, and training in austere environments, where commercial purchasing options are limited and UV exposure is high. A proactive approach to sun safety could demonstrate a commitment to preserving the current health and operational readiness of active-duty service members while reducing future financial burdens of skin disease and helping promote wellness in this population during retirement. As with ear protection, uniforms, and eyewear, sunscreen should be considered a standard component of operational readiness.

Sunscreen continues to be the foundation of successful skin cancer prevention. Daily sunscreen application and reapplication are recommended to prevent all types of skin cancer, with the strongest body of evidence supporting prevention of squamous cell carcinoma.¹ Sunscreens have been used safely for decades; since my last update in 2024,² no evidence of harm has emerged, despite the fact that organic (chemical) sunscreen filters are absorbed systemically.³

So, what’s happening with sunscreen in 2026? Let’s review some hot news and fresh controversies.

Sunscreen Doping Is Pervasive

Sunscreen “doping” signifies the sneaky addition of UV filters that have not been approved by the US Food and Drug Administration (FDA) into sunscreens under the guise of inactive ingredients. Why would a manufacturer do such a thing? To enhance a sunscreen’s UV absorption without having to increase the concentration of zinc oxide/titanium dioxide (which creates an undesirable white cast) or exceeding the maximum permitted concentration of chemical active ingredients.^4,5 In a 2025 analysis of the top 150 sunscreens sold on Amazon, 48.3% contained these covert UV filters, including almost half of those marketed as mineral-only products.⁶ The most prevalent doping ingredient was butyloctyl salicylate, which is chemically and functionally related to the FDA-approved chemical UV filter octisalate (ethylhexyl salicylate).⁵

The practice of sunscreen doping is deceptive. Can a product be accurately marketed as mineral sunscreen if it contains ingredients that function as chemical UV filters but are not classified as active ingredients by the FDA? The bigger picture is that sunscreen doping is a symptom of regulatory malaise specific to the United States. Regulation of sunscreens as over-the-counter drugs plus the FDA’s stringent requirements for UV filters to be generally recognized as safe and effective (GRASE) have stymied the approval process to the extent that no new active ingredients have been approved since 1999.² The FDA allows 16 active ingredients compared to about 30 in Europe and Asia—not for lack of safety evaluations prior to approval in those regions.⁷ In the United States, getting a new active sunscreen ingredient approved is far more onerous and costly than the streamlined processes that are in place abroad. This restricts sunscreen innovation; in particular, the US market lacks the wide variety of international options for protection against long-wave UVA radiation, remaining limited to just avobenzone and zinc oxide. Since long-wave UVA plays a major role in photoaging, this represents a gap in protection compared to international sunscreen offerings.^1,7 Due to domestic sunscreen limitations, some Americans have turned to purchasing non–FDA-approved sunscreens abroad or through online channels.⁸

New Sunscreen Filter Pending Approval, and Hope for Regulatory Changes

Let’s move on to a more positive development. A new sunscreen filter is actually nearing approval in the United States! Bemotrizinol, also known as bis-ethylhexyloxyphenol methoxyphenyl triazine, is a broad-spectrum chemical UVA/UVB blocker that would represent the first new active ingredient to become available in the United States since 1999.⁹ It satisfies the FDA requirement for minimal systemic absorption and GRASE status and has been used with a clean safety record since 2000 in Europe.¹⁰ The icing on top is that bemotrizinol seems to be minimally allergenic, with only a few published reports of contact dermatitis over several decades of use.^11,12

Yes, as I write, the FDA is on the cusp of approving bemotrizinol, a great broad-spectrum sunscreen ingredient, to one day be added to the products on our shelves. The cynic in me can’t help but point out that it took more than 20 years of effort and an estimated $20 million to get us to this point of near-approval of one new sunscreen filter.¹³

Perhaps things won’t be so difficult in the future. In late 2025, the bipartisan Supporting Accessible, Flexible, and Effective (SAFE) Sunscreen Standards Act was signed into law.¹⁴ The SAFE Sunscreen Standards Act calls on the FDA to be more flexible and allow for the use of real-world evidence and observational studies to demonstrate safety and effectiveness of active ingredients used in sunscreens. We can only hope that real change is forthcoming and that future sunscreen approvals won’t require decades of work and millions of dollars, as in the case of bemotrizinol.

Daily Sunscreen Use Linked to Reduction in Vitamin D Levels

The UVB wavelengths that cause sunburn overlap with those that initiate vitamin D production in the skin, generating concerns about sunscreen use reducing vitamin D levels. Nevertheless, in 2019, expert opinion and a systematic literature review determined that routine use of sunscreen was unlikely to be associated with a reduction in vitamin D levels.^15,16 However, a major limitation at that time was a lack of studies examining vitamin D status in individuals using high–sun protection factor (SPF) sunscreens.

Now we have results from the first field study assessing the impact of long-term daily application of higher SPF sunscreen on vitamin D levels. In the Australian Sun-D Trial, Tran et al¹⁷ randomly assigned 639 participants to either an intervention group (routine application of SPF 50+ sunscreen on days forecasted to have a UV index ≥3) or a control group (discretionary sunscreen use). Vitamin D levels were measured at baseline in the winter/spring, at the end of summer, and then at the end of the following winter. At the end of summer, vitamin D levels increased in both groups but less in the intervention group, then decreased similarly in both groups by winter. Routine sunscreen application was associated with a decrease of 5.2 nmol/L (2.1 ng/mL) in vitamin D levels, which the authors rightfully considered to be modest. Additionally, vitamin D deficiency (defined as <50 nmol/L [<20 ng/mL]) was detected in more of the intervention group compared to the control group (45.7% vs 36.9%). The study reasonably concluded that sunscreen continues to be essential in preventing skin cancers but regular users may require vitamin D testing and/or supplementation.¹⁷

Looking Ahead

In this update, I discussed several important pieces of sunscreen news. If you check your favorite mineral sunscreen’s ingredients list, odds are you will find it also contains inactive doping ingredients shown to secretly enhance UV protection. Perhaps manufacturers won’t have to dope sunscreens in the United States forever if regulatory reforms facilitate the approval of active ingredients such as bemotrizinol used safely in other countries without huge investments of time and money. For daily sunscreen users, consider checking and/or empirically supplementing vitamin D.

None of this should discourage us from recommending regular consistent sunscreen application and reapplication to our patients. There continues to be a lack of evidence of harms associated with systemic absorption of chemical UV filters in humans, and sunscreen will continue to function as an indispensable component of skin cancer prevention for the foreseeable future.

Sunscreen continues to be the foundation of successful skin cancer prevention. Daily sunscreen application and reapplication are recommended to prevent all types of skin cancer, with the strongest body of evidence supporting prevention of squamous cell carcinoma.¹ Sunscreens have been used safely for decades; since my last update in 2024,² no evidence of harm has emerged, despite the fact that organic (chemical) sunscreen filters are absorbed systemically.³

So, what’s happening with sunscreen in 2026? Let’s review some hot news and fresh controversies.

Sunscreen Doping Is Pervasive

Sunscreen “doping” signifies the sneaky addition of UV filters that have not been approved by the US Food and Drug Administration (FDA) into sunscreens under the guise of inactive ingredients. Why would a manufacturer do such a thing? To enhance a sunscreen’s UV absorption without having to increase the concentration of zinc oxide/titanium dioxide (which creates an undesirable white cast) or exceeding the maximum permitted concentration of chemical active ingredients.^4,5 In a 2025 analysis of the top 150 sunscreens sold on Amazon, 48.3% contained these covert UV filters, including almost half of those marketed as mineral-only products.⁶ The most prevalent doping ingredient was butyloctyl salicylate, which is chemically and functionally related to the FDA-approved chemical UV filter octisalate (ethylhexyl salicylate).⁵

The practice of sunscreen doping is deceptive. Can a product be accurately marketed as mineral sunscreen if it contains ingredients that function as chemical UV filters but are not classified as active ingredients by the FDA? The bigger picture is that sunscreen doping is a symptom of regulatory malaise specific to the United States. Regulation of sunscreens as over-the-counter drugs plus the FDA’s stringent requirements for UV filters to be generally recognized as safe and effective (GRASE) have stymied the approval process to the extent that no new active ingredients have been approved since 1999.² The FDA allows 16 active ingredients compared to about 30 in Europe and Asia—not for lack of safety evaluations prior to approval in those regions.⁷ In the United States, getting a new active sunscreen ingredient approved is far more onerous and costly than the streamlined processes that are in place abroad. This restricts sunscreen innovation; in particular, the US market lacks the wide variety of international options for protection against long-wave UVA radiation, remaining limited to just avobenzone and zinc oxide. Since long-wave UVA plays a major role in photoaging, this represents a gap in protection compared to international sunscreen offerings.^1,7 Due to domestic sunscreen limitations, some Americans have turned to purchasing non–FDA-approved sunscreens abroad or through online channels.⁸

New Sunscreen Filter Pending Approval, and Hope for Regulatory Changes

Let’s move on to a more positive development. A new sunscreen filter is actually nearing approval in the United States! Bemotrizinol, also known as bis-ethylhexyloxyphenol methoxyphenyl triazine, is a broad-spectrum chemical UVA/UVB blocker that would represent the first new active ingredient to become available in the United States since 1999.⁹ It satisfies the FDA requirement for minimal systemic absorption and GRASE status and has been used with a clean safety record since 2000 in Europe.¹⁰ The icing on top is that bemotrizinol seems to be minimally allergenic, with only a few published reports of contact dermatitis over several decades of use.^11,12

Yes, as I write, the FDA is on the cusp of approving bemotrizinol, a great broad-spectrum sunscreen ingredient, to one day be added to the products on our shelves. The cynic in me can’t help but point out that it took more than 20 years of effort and an estimated $20 million to get us to this point of near-approval of one new sunscreen filter.¹³

Perhaps things won’t be so difficult in the future. In late 2025, the bipartisan Supporting Accessible, Flexible, and Effective (SAFE) Sunscreen Standards Act was signed into law.¹⁴ The SAFE Sunscreen Standards Act calls on the FDA to be more flexible and allow for the use of real-world evidence and observational studies to demonstrate safety and effectiveness of active ingredients used in sunscreens. We can only hope that real change is forthcoming and that future sunscreen approvals won’t require decades of work and millions of dollars, as in the case of bemotrizinol.

Daily Sunscreen Use Linked to Reduction in Vitamin D Levels

The UVB wavelengths that cause sunburn overlap with those that initiate vitamin D production in the skin, generating concerns about sunscreen use reducing vitamin D levels. Nevertheless, in 2019, expert opinion and a systematic literature review determined that routine use of sunscreen was unlikely to be associated with a reduction in vitamin D levels.^15,16 However, a major limitation at that time was a lack of studies examining vitamin D status in individuals using high–sun protection factor (SPF) sunscreens.

Now we have results from the first field study assessing the impact of long-term daily application of higher SPF sunscreen on vitamin D levels. In the Australian Sun-D Trial, Tran et al¹⁷ randomly assigned 639 participants to either an intervention group (routine application of SPF 50+ sunscreen on days forecasted to have a UV index ≥3) or a control group (discretionary sunscreen use). Vitamin D levels were measured at baseline in the winter/spring, at the end of summer, and then at the end of the following winter. At the end of summer, vitamin D levels increased in both groups but less in the intervention group, then decreased similarly in both groups by winter. Routine sunscreen application was associated with a decrease of 5.2 nmol/L (2.1 ng/mL) in vitamin D levels, which the authors rightfully considered to be modest. Additionally, vitamin D deficiency (defined as <50 nmol/L [<20 ng/mL]) was detected in more of the intervention group compared to the control group (45.7% vs 36.9%). The study reasonably concluded that sunscreen continues to be essential in preventing skin cancers but regular users may require vitamin D testing and/or supplementation.¹⁷

Looking Ahead

In this update, I discussed several important pieces of sunscreen news. If you check your favorite mineral sunscreen’s ingredients list, odds are you will find it also contains inactive doping ingredients shown to secretly enhance UV protection. Perhaps manufacturers won’t have to dope sunscreens in the United States forever if regulatory reforms facilitate the approval of active ingredients such as bemotrizinol used safely in other countries without huge investments of time and money. For daily sunscreen users, consider checking and/or empirically supplementing vitamin D.

None of this should discourage us from recommending regular consistent sunscreen application and reapplication to our patients. There continues to be a lack of evidence of harms associated with systemic absorption of chemical UV filters in humans, and sunscreen will continue to function as an indispensable component of skin cancer prevention for the foreseeable future.

Sunscreen continues to be the foundation of successful skin cancer prevention. Daily sunscreen application and reapplication are recommended to prevent all types of skin cancer, with the strongest body of evidence supporting prevention of squamous cell carcinoma.¹ Sunscreens have been used safely for decades; since my last update in 2024,² no evidence of harm has emerged, despite the fact that organic (chemical) sunscreen filters are absorbed systemically.³

So, what’s happening with sunscreen in 2026? Let’s review some hot news and fresh controversies.

Sunscreen Doping Is Pervasive

Sunscreen “doping” signifies the sneaky addition of UV filters that have not been approved by the US Food and Drug Administration (FDA) into sunscreens under the guise of inactive ingredients. Why would a manufacturer do such a thing? To enhance a sunscreen’s UV absorption without having to increase the concentration of zinc oxide/titanium dioxide (which creates an undesirable white cast) or exceeding the maximum permitted concentration of chemical active ingredients.^4,5 In a 2025 analysis of the top 150 sunscreens sold on Amazon, 48.3% contained these covert UV filters, including almost half of those marketed as mineral-only products.⁶ The most prevalent doping ingredient was butyloctyl salicylate, which is chemically and functionally related to the FDA-approved chemical UV filter octisalate (ethylhexyl salicylate).⁵

The practice of sunscreen doping is deceptive. Can a product be accurately marketed as mineral sunscreen if it contains ingredients that function as chemical UV filters but are not classified as active ingredients by the FDA? The bigger picture is that sunscreen doping is a symptom of regulatory malaise specific to the United States. Regulation of sunscreens as over-the-counter drugs plus the FDA’s stringent requirements for UV filters to be generally recognized as safe and effective (GRASE) have stymied the approval process to the extent that no new active ingredients have been approved since 1999.² The FDA allows 16 active ingredients compared to about 30 in Europe and Asia—not for lack of safety evaluations prior to approval in those regions.⁷ In the United States, getting a new active sunscreen ingredient approved is far more onerous and costly than the streamlined processes that are in place abroad. This restricts sunscreen innovation; in particular, the US market lacks the wide variety of international options for protection against long-wave UVA radiation, remaining limited to just avobenzone and zinc oxide. Since long-wave UVA plays a major role in photoaging, this represents a gap in protection compared to international sunscreen offerings.^1,7 Due to domestic sunscreen limitations, some Americans have turned to purchasing non–FDA-approved sunscreens abroad or through online channels.⁸

New Sunscreen Filter Pending Approval, and Hope for Regulatory Changes

Let’s move on to a more positive development. A new sunscreen filter is actually nearing approval in the United States! Bemotrizinol, also known as bis-ethylhexyloxyphenol methoxyphenyl triazine, is a broad-spectrum chemical UVA/UVB blocker that would represent the first new active ingredient to become available in the United States since 1999.⁹ It satisfies the FDA requirement for minimal systemic absorption and GRASE status and has been used with a clean safety record since 2000 in Europe.¹⁰ The icing on top is that bemotrizinol seems to be minimally allergenic, with only a few published reports of contact dermatitis over several decades of use.^11,12

Yes, as I write, the FDA is on the cusp of approving bemotrizinol, a great broad-spectrum sunscreen ingredient, to one day be added to the products on our shelves. The cynic in me can’t help but point out that it took more than 20 years of effort and an estimated $20 million to get us to this point of near-approval of one new sunscreen filter.¹³

Perhaps things won’t be so difficult in the future. In late 2025, the bipartisan Supporting Accessible, Flexible, and Effective (SAFE) Sunscreen Standards Act was signed into law.¹⁴ The SAFE Sunscreen Standards Act calls on the FDA to be more flexible and allow for the use of real-world evidence and observational studies to demonstrate safety and effectiveness of active ingredients used in sunscreens. We can only hope that real change is forthcoming and that future sunscreen approvals won’t require decades of work and millions of dollars, as in the case of bemotrizinol.

Daily Sunscreen Use Linked to Reduction in Vitamin D Levels

The UVB wavelengths that cause sunburn overlap with those that initiate vitamin D production in the skin, generating concerns about sunscreen use reducing vitamin D levels. Nevertheless, in 2019, expert opinion and a systematic literature review determined that routine use of sunscreen was unlikely to be associated with a reduction in vitamin D levels.^15,16 However, a major limitation at that time was a lack of studies examining vitamin D status in individuals using high–sun protection factor (SPF) sunscreens.

Now we have results from the first field study assessing the impact of long-term daily application of higher SPF sunscreen on vitamin D levels. In the Australian Sun-D Trial, Tran et al¹⁷ randomly assigned 639 participants to either an intervention group (routine application of SPF 50+ sunscreen on days forecasted to have a UV index ≥3) or a control group (discretionary sunscreen use). Vitamin D levels were measured at baseline in the winter/spring, at the end of summer, and then at the end of the following winter. At the end of summer, vitamin D levels increased in both groups but less in the intervention group, then decreased similarly in both groups by winter. Routine sunscreen application was associated with a decrease of 5.2 nmol/L (2.1 ng/mL) in vitamin D levels, which the authors rightfully considered to be modest. Additionally, vitamin D deficiency (defined as <50 nmol/L [<20 ng/mL]) was detected in more of the intervention group compared to the control group (45.7% vs 36.9%). The study reasonably concluded that sunscreen continues to be essential in preventing skin cancers but regular users may require vitamin D testing and/or supplementation.¹⁷

Looking Ahead

In this update, I discussed several important pieces of sunscreen news. If you check your favorite mineral sunscreen’s ingredients list, odds are you will find it also contains inactive doping ingredients shown to secretly enhance UV protection. Perhaps manufacturers won’t have to dope sunscreens in the United States forever if regulatory reforms facilitate the approval of active ingredients such as bemotrizinol used safely in other countries without huge investments of time and money. For daily sunscreen users, consider checking and/or empirically supplementing vitamin D.

None of this should discourage us from recommending regular consistent sunscreen application and reapplication to our patients. There continues to be a lack of evidence of harms associated with systemic absorption of chemical UV filters in humans, and sunscreen will continue to function as an indispensable component of skin cancer prevention for the foreseeable future.

Chromoblastomycosis is a neglected tropical implantation mycosis caused by dematiaceous fungi that leads to substantial morbidity. This condition is diagnosed microscopically by visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).¹ The main causative fungi varies by geographic region, but most commonly is caused by Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa.^2-4 Standardized treatment guidelines have not been established, but itraconazole typically is considered first-line regardless of causative fungi.⁵ Terbinafine, other azoles, and topical immunomodulators, either as monotherapy or in combination, may be appropriate alternative or adjunctive options for refractory disease, although supporting data are limited.^6-9

Complications from chromoblastomycosis are common, particularly in long-standing, severe, or refractory disease. An analysis using billing codes in the United States found 14% (35/255) of hospitalized patients with chromoblastomycosis had lymphedema.¹⁰ In Mexico, 63% (32/51) of patients with chromoblastomycosis developed secondary bacterial infections.¹¹ Skin fibrosis and ankylosis also can occur and cause mobility issues and decreased quality of life. An infrequent but potentially life-threatening complication¹² is the development of squamous cell carcinoma (SCC) associated with chronic lesions, representing a preventable end-stage complication of delayed diagnosis and treatment (Figure).

In this review, we summarize reported epidemiology and clinical risk factors for SCC complicating chromoblastomycosis. We also discuss plausible inflammatory mechanisms of malignant transformation and propose pragmatic clinical and public health interventions, including decentralized microscopy-based diagnosis, timely antifungal access, and biopsy-triggered surveillance of chronically inflamed lesions, to reduce preventable morbidity.

Epidemiology and Risk Factors

The epidemiology of SCC developing from chromoblastomycosis is not well understood due to gaps in national and global surveillance. Some studies have found that 2% to 13% of patients with chromoblastomycosis developed SCC.^4,11,13-15 Based on case reports and case series, a symptom duration of more than 10 years appears to be the most substantial risk factor for the development of SCC rather than host immune status.^16-18 Severity, specifically the size of the injury, and vegetating lesions also have been suggested as risk factors for the development of SCC.¹⁶ Additionally, the appearance of new lesions (mainly ulcers not related to secondary infection) that appear during the healing phase should raise the suspicion of SCC and warrant a biopsy for evaluation.¹⁶

Pathophysiology

The exact mechanism of malignant transformation has not been elucidated, but histopathologic features suggest substantial epidermal proliferation. In some cases, this leads to pseudoepitheliomatous hyperplasia, a nonmalignant hyperproliferative state that is an important differential HPV to leishmaniasis and lupus vulgaris.¹⁹ The chronic inflammation from long-standing chromoblastomycosis likely contributes to the further malignant transformation to SCC.

Polymorphonuclear cells and activated macrophages seen in chronic inflammation can promote the release of enzymes and free radicals that has led to malignant transformation in vitro but has not been investigated specifically in chromoblastomycosis.¹⁶ Additionally, chronic inflammation and metabolic products of phagocytosis often are accompanied by excessive production of reactive oxygen and nitrogen species, which can damage DNA, lipoproteins, and cell membranes. Other potential contributors include the expression of cyclooxygenase 2 and release of arachidonic acid metabolites (eg, prostaglandins, leukotrienes), which can damage the cell and promote carcinogenesis. It is not clear whether similar mechanisms account for the development of SCCs in other chronic skin inflammations or infections such as cutaneous tuberculosis or Marjolin ulcers.²⁰

Clinical and Public Health Interventions

Squamous cell carcinoma arising in the setting of chromoblastomycosis warrants prompt oncologic evaluation and definitive surgical management, which may require extensive surgical excision and, in advanced disease, amputation.^14,17,18 Advanced malignant tumors can be difficult to manage and can result in death.^21,22 Additionally, clinicians should maintain a low threshold for biopsy in long-standing chromoblastomycosis, particularly when lesions demonstrate new ulceration, rapid growth, bleeding, pain, malodor, or failure to improve with appropriate antifungal therapy.¹⁶ Recurrent or new lesions after amputation may indicate persistent or recurrent infection and may require continued antifungal management alongside cancer care.¹⁶

Squamous cell carcinoma arising from chromoblastomycosis results after substantial diagnostic delays, allowing chronic inflammation to transform infection into malignancy. Separating benign inflammation-associated epidermal proliferation from transformation to SCC requires histopathologic skill. An assay based on increased expression of chromosome 15 open reading frame 48 (C15orf48), an immune regulatory protein, has been developed to aid in this distinction; however, it is not widely available.²³

Raising awareness of chromoblastomycosis among clinicians and communities, particularly in rural areas where the disease is more common, is critical to improve health care–seeking behaviors and expedite access to care pathways.² Furthermore, access and training on microscopy to diagnose chromoblastomycosis in decentralized areas can facilitate earlier diagnosis in primary health care settings rather than waiting for diagnosis in tertiary care settings, at which point disease usually is advanced. Global implementation of existing programs that use microscopy (eg, malaria in rural areas) can be partnered with frontline health worker cross-training on chromoblastomycosis diagnosis to improve appropriate identification of disease.²⁴ Finally, improving access to affordable antifungals, particularly itraconazole, is necessary along with further research into novel therapeutic strategies. Approaches that utilize local manufacturing and pooled procurement could help expand treatment availability in parallel with diagnostic improvement initiatives.²⁵

Final Thoughts

Squamous cell carcinoma resulting from chromoblastomycosis is a devastating complication, often leading to limb amputation. The true prevalence is unknown, but it occurs more commonly in long-standing disease without appropriate therapy. The appearance of new lesions or ulcers after initial improvement should increase suspicion and lead to biopsy and careful pathologic evaluation. Prevention of SCC requires increased clinical awareness, early diagnosis, and timely initiation of antifungal treatment. Enhanced surveillance among individuals with chromoblastomycosis would help to better understand its prevalence, associated risk factors, and impact on quality of life.

Chromoblastomycosis is a neglected tropical implantation mycosis caused by dematiaceous fungi that leads to substantial morbidity. This condition is diagnosed microscopically by visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).¹ The main causative fungi varies by geographic region, but most commonly is caused by Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa.^2-4 Standardized treatment guidelines have not been established, but itraconazole typically is considered first-line regardless of causative fungi.⁵ Terbinafine, other azoles, and topical immunomodulators, either as monotherapy or in combination, may be appropriate alternative or adjunctive options for refractory disease, although supporting data are limited.^6-9

Complications from chromoblastomycosis are common, particularly in long-standing, severe, or refractory disease. An analysis using billing codes in the United States found 14% (35/255) of hospitalized patients with chromoblastomycosis had lymphedema.¹⁰ In Mexico, 63% (32/51) of patients with chromoblastomycosis developed secondary bacterial infections.¹¹ Skin fibrosis and ankylosis also can occur and cause mobility issues and decreased quality of life. An infrequent but potentially life-threatening complication¹² is the development of squamous cell carcinoma (SCC) associated with chronic lesions, representing a preventable end-stage complication of delayed diagnosis and treatment (Figure).

In this review, we summarize reported epidemiology and clinical risk factors for SCC complicating chromoblastomycosis. We also discuss plausible inflammatory mechanisms of malignant transformation and propose pragmatic clinical and public health interventions, including decentralized microscopy-based diagnosis, timely antifungal access, and biopsy-triggered surveillance of chronically inflamed lesions, to reduce preventable morbidity.

Epidemiology and Risk Factors

The epidemiology of SCC developing from chromoblastomycosis is not well understood due to gaps in national and global surveillance. Some studies have found that 2% to 13% of patients with chromoblastomycosis developed SCC.^4,11,13-15 Based on case reports and case series, a symptom duration of more than 10 years appears to be the most substantial risk factor for the development of SCC rather than host immune status.^16-18 Severity, specifically the size of the injury, and vegetating lesions also have been suggested as risk factors for the development of SCC.¹⁶ Additionally, the appearance of new lesions (mainly ulcers not related to secondary infection) that appear during the healing phase should raise the suspicion of SCC and warrant a biopsy for evaluation.¹⁶

Pathophysiology

The exact mechanism of malignant transformation has not been elucidated, but histopathologic features suggest substantial epidermal proliferation. In some cases, this leads to pseudoepitheliomatous hyperplasia, a nonmalignant hyperproliferative state that is an important differential HPV to leishmaniasis and lupus vulgaris.¹⁹ The chronic inflammation from long-standing chromoblastomycosis likely contributes to the further malignant transformation to SCC.

Polymorphonuclear cells and activated macrophages seen in chronic inflammation can promote the release of enzymes and free radicals that has led to malignant transformation in vitro but has not been investigated specifically in chromoblastomycosis.¹⁶ Additionally, chronic inflammation and metabolic products of phagocytosis often are accompanied by excessive production of reactive oxygen and nitrogen species, which can damage DNA, lipoproteins, and cell membranes. Other potential contributors include the expression of cyclooxygenase 2 and release of arachidonic acid metabolites (eg, prostaglandins, leukotrienes), which can damage the cell and promote carcinogenesis. It is not clear whether similar mechanisms account for the development of SCCs in other chronic skin inflammations or infections such as cutaneous tuberculosis or Marjolin ulcers.²⁰

Clinical and Public Health Interventions

Squamous cell carcinoma arising in the setting of chromoblastomycosis warrants prompt oncologic evaluation and definitive surgical management, which may require extensive surgical excision and, in advanced disease, amputation.^14,17,18 Advanced malignant tumors can be difficult to manage and can result in death.^21,22 Additionally, clinicians should maintain a low threshold for biopsy in long-standing chromoblastomycosis, particularly when lesions demonstrate new ulceration, rapid growth, bleeding, pain, malodor, or failure to improve with appropriate antifungal therapy.¹⁶ Recurrent or new lesions after amputation may indicate persistent or recurrent infection and may require continued antifungal management alongside cancer care.¹⁶

Squamous cell carcinoma arising from chromoblastomycosis results after substantial diagnostic delays, allowing chronic inflammation to transform infection into malignancy. Separating benign inflammation-associated epidermal proliferation from transformation to SCC requires histopathologic skill. An assay based on increased expression of chromosome 15 open reading frame 48 (C15orf48), an immune regulatory protein, has been developed to aid in this distinction; however, it is not widely available.²³

Raising awareness of chromoblastomycosis among clinicians and communities, particularly in rural areas where the disease is more common, is critical to improve health care–seeking behaviors and expedite access to care pathways.² Furthermore, access and training on microscopy to diagnose chromoblastomycosis in decentralized areas can facilitate earlier diagnosis in primary health care settings rather than waiting for diagnosis in tertiary care settings, at which point disease usually is advanced. Global implementation of existing programs that use microscopy (eg, malaria in rural areas) can be partnered with frontline health worker cross-training on chromoblastomycosis diagnosis to improve appropriate identification of disease.²⁴ Finally, improving access to affordable antifungals, particularly itraconazole, is necessary along with further research into novel therapeutic strategies. Approaches that utilize local manufacturing and pooled procurement could help expand treatment availability in parallel with diagnostic improvement initiatives.²⁵

Final Thoughts

Squamous cell carcinoma resulting from chromoblastomycosis is a devastating complication, often leading to limb amputation. The true prevalence is unknown, but it occurs more commonly in long-standing disease without appropriate therapy. The appearance of new lesions or ulcers after initial improvement should increase suspicion and lead to biopsy and careful pathologic evaluation. Prevention of SCC requires increased clinical awareness, early diagnosis, and timely initiation of antifungal treatment. Enhanced surveillance among individuals with chromoblastomycosis would help to better understand its prevalence, associated risk factors, and impact on quality of life.

Chromoblastomycosis is a neglected tropical implantation mycosis caused by dematiaceous fungi that leads to substantial morbidity. This condition is diagnosed microscopically by visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).¹ The main causative fungi varies by geographic region, but most commonly is caused by Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa.^2-4 Standardized treatment guidelines have not been established, but itraconazole typically is considered first-line regardless of causative fungi.⁵ Terbinafine, other azoles, and topical immunomodulators, either as monotherapy or in combination, may be appropriate alternative or adjunctive options for refractory disease, although supporting data are limited.^6-9

Complications from chromoblastomycosis are common, particularly in long-standing, severe, or refractory disease. An analysis using billing codes in the United States found 14% (35/255) of hospitalized patients with chromoblastomycosis had lymphedema.¹⁰ In Mexico, 63% (32/51) of patients with chromoblastomycosis developed secondary bacterial infections.¹¹ Skin fibrosis and ankylosis also can occur and cause mobility issues and decreased quality of life. An infrequent but potentially life-threatening complication¹² is the development of squamous cell carcinoma (SCC) associated with chronic lesions, representing a preventable end-stage complication of delayed diagnosis and treatment (Figure).

In this review, we summarize reported epidemiology and clinical risk factors for SCC complicating chromoblastomycosis. We also discuss plausible inflammatory mechanisms of malignant transformation and propose pragmatic clinical and public health interventions, including decentralized microscopy-based diagnosis, timely antifungal access, and biopsy-triggered surveillance of chronically inflamed lesions, to reduce preventable morbidity.

Epidemiology and Risk Factors

The epidemiology of SCC developing from chromoblastomycosis is not well understood due to gaps in national and global surveillance. Some studies have found that 2% to 13% of patients with chromoblastomycosis developed SCC.^4,11,13-15 Based on case reports and case series, a symptom duration of more than 10 years appears to be the most substantial risk factor for the development of SCC rather than host immune status.^16-18 Severity, specifically the size of the injury, and vegetating lesions also have been suggested as risk factors for the development of SCC.¹⁶ Additionally, the appearance of new lesions (mainly ulcers not related to secondary infection) that appear during the healing phase should raise the suspicion of SCC and warrant a biopsy for evaluation.¹⁶

Pathophysiology

The exact mechanism of malignant transformation has not been elucidated, but histopathologic features suggest substantial epidermal proliferation. In some cases, this leads to pseudoepitheliomatous hyperplasia, a nonmalignant hyperproliferative state that is an important differential HPV to leishmaniasis and lupus vulgaris.¹⁹ The chronic inflammation from long-standing chromoblastomycosis likely contributes to the further malignant transformation to SCC.

Polymorphonuclear cells and activated macrophages seen in chronic inflammation can promote the release of enzymes and free radicals that has led to malignant transformation in vitro but has not been investigated specifically in chromoblastomycosis.¹⁶ Additionally, chronic inflammation and metabolic products of phagocytosis often are accompanied by excessive production of reactive oxygen and nitrogen species, which can damage DNA, lipoproteins, and cell membranes. Other potential contributors include the expression of cyclooxygenase 2 and release of arachidonic acid metabolites (eg, prostaglandins, leukotrienes), which can damage the cell and promote carcinogenesis. It is not clear whether similar mechanisms account for the development of SCCs in other chronic skin inflammations or infections such as cutaneous tuberculosis or Marjolin ulcers.²⁰

Clinical and Public Health Interventions

Squamous cell carcinoma arising in the setting of chromoblastomycosis warrants prompt oncologic evaluation and definitive surgical management, which may require extensive surgical excision and, in advanced disease, amputation.^14,17,18 Advanced malignant tumors can be difficult to manage and can result in death.^21,22 Additionally, clinicians should maintain a low threshold for biopsy in long-standing chromoblastomycosis, particularly when lesions demonstrate new ulceration, rapid growth, bleeding, pain, malodor, or failure to improve with appropriate antifungal therapy.¹⁶ Recurrent or new lesions after amputation may indicate persistent or recurrent infection and may require continued antifungal management alongside cancer care.¹⁶

Squamous cell carcinoma arising from chromoblastomycosis results after substantial diagnostic delays, allowing chronic inflammation to transform infection into malignancy. Separating benign inflammation-associated epidermal proliferation from transformation to SCC requires histopathologic skill. An assay based on increased expression of chromosome 15 open reading frame 48 (C15orf48), an immune regulatory protein, has been developed to aid in this distinction; however, it is not widely available.²³

Raising awareness of chromoblastomycosis among clinicians and communities, particularly in rural areas where the disease is more common, is critical to improve health care–seeking behaviors and expedite access to care pathways.² Furthermore, access and training on microscopy to diagnose chromoblastomycosis in decentralized areas can facilitate earlier diagnosis in primary health care settings rather than waiting for diagnosis in tertiary care settings, at which point disease usually is advanced. Global implementation of existing programs that use microscopy (eg, malaria in rural areas) can be partnered with frontline health worker cross-training on chromoblastomycosis diagnosis to improve appropriate identification of disease.²⁴ Finally, improving access to affordable antifungals, particularly itraconazole, is necessary along with further research into novel therapeutic strategies. Approaches that utilize local manufacturing and pooled procurement could help expand treatment availability in parallel with diagnostic improvement initiatives.²⁵

Final Thoughts

Squamous cell carcinoma resulting from chromoblastomycosis is a devastating complication, often leading to limb amputation. The true prevalence is unknown, but it occurs more commonly in long-standing disease without appropriate therapy. The appearance of new lesions or ulcers after initial improvement should increase suspicion and lead to biopsy and careful pathologic evaluation. Prevention of SCC requires increased clinical awareness, early diagnosis, and timely initiation of antifungal treatment. Enhanced surveillance among individuals with chromoblastomycosis would help to better understand its prevalence, associated risk factors, and impact on quality of life.

THE DIAGNOSIS: Malignant Proliferating Trichilemmal Tumor

Histologic examination revealed atypical keratinocytes, nuclear pleomorphism, and lobulating epithelial masses with trichilemmal keratinization (Figure). The presence of CD34 positivity, a marker of outer follicular root sheath–derived cells, supported the diagnosis of a malignant proliferating trichilemmal tumor (MPTT). Imaging also revealed signs of bone invasion, further supporting a malignant process. Based on these findings, the patient underwent complete excision of the mass with scalp reconstruction, lymph node dissection, and systemic evaluation for metastases. Final pathology confirmed negative surgical margins and no lymph node involvement. Adjuvant radiation was not required, given the absence of skull invasion or confirmed distant metastasis.

The differential diagnosis for rapidly enlarging scalp tumors can be broad and includes both benign and malignant processes. In this patient, the differential diagnoses included trichilemmal carcinoma, cutaneous squamous cell carcinoma (SCC), sebaceous carcinoma (SC), proliferating trichilemmal tumor (PTT), and MPTT. Due to the notable clinical and histologic overlap among these lesions, definitive diagnosis required histopathologic evaluation in our patient.

Proliferating trichilemmal tumors were first described in 1966 by Wilson-Jones,¹ who used the term proliferating epidermoid cysts, noting their distinct histologic features and resemblance to SCC.² These tumors generally are benign and arise from the isthmus of the outer root sheath of the hair follicle; however, malignant transformation can occur, resulting in a rare entity known as MPTT. This malignant variant was first described in 1983 by Saida et al,³ who emphasized its distinct clinical behavior, including infiltrative growth, high mitotic activity, and potential for local recurrence and metastasis.

A recent literature review identified 60 reported cases of MPTT, with an average patient age of 57 years and a female predominance.⁴ Clinically, MPTTs often manifest as large (>5 cm) lobulated masses located on sun-exposed, hair-bearing areas of the skin, especially the scalp. These lesions may be flesh-colored to pink and often exhibit ulceration, necrosis, or calcification.⁵ Typically, MPTTs follow a biphasic course, beginning with a slow-growing phase followed by a period of rapid growth. Due to their aggressive behavior and resemblance to other cutaneous malignancies, accurate differentiation of MPTT from benign PTTs, cutaneous SCCs, SCs, and trichilemmal carcinomas is critical.

Malignant proliferating trichilemmal tumors demonstrate a substantially higher metastatic potential than either benign PTTs or cutaneous SCCs. While cutaneous SCCs carry a metastasis rate of approximately 1.9% to 2.6%, MPTTs carry a considerably higher rate of approximately 25.0%.⁶ Regional lymphatic spread is the most common route of dissemination, making comprehensive lymph node assessment—both radiographic and clinical—an important component of tumor staging. When lymph node involvement is suspected, surgical dissection may be indicated, along with consideration of adjuvant therapies.

Histopathologically, MPTT is characterized by nuclear atypia, mitotic figures, and lobulated masses of proliferating epithelium showing trichilemmal differentiation and infiltrative growth.⁴ The presence of CD34 positivity, reflecting outer follicular root sheath differentiation, helps distinguish MPTT from cutaneous SCC and SC, which typically lack this marker.^6,7 Immunohistochemistry is therefore a valuable adjunct in differentiating these lesions.

The mainstay of treatment for MPTT is wide local excision with clear margins. Margins of at least 1 cm generally are recommended. Although Mohs micrographic surgery may be used in anatomically sensitive areas, it typically is not preferred due to the potential for skip lesions in MPTT, which may lead to incomplete excision and recurrence.⁸ In cases with evidence of regional or distant metastasis or when clear margins cannot be achieved confidently, adjunctive treatments such as radiation therapy and systemic chemotherapy may be indicated. Preoperative imaging is used to evaluate for local invasion (skull or bone involvement) and regional lymph node status, which may inform adjuvant therapy postoperatively.

The prognosis for MPTT is variable and depends largely on early recognition, accurate histopathologic diagnosis, complete surgical excision with clear margins, and the presence or absence of metastasis. When the tumor is fully excised with negative margins and no lymph node involvement, the risk for recurrence is substantially reduced; however, MPTT is known for its potential aggressive behavior. Delays in diagnosis or incomplete resection can lead to local recurrence, regional spread, or even distant metastasis. In the literature review discussed previously, the mortality rate of patients with MPTT was 11.7%,⁴ which is notably higher than that of more common cutaneous malignancies such as cutaneous SCC, which is reported at 1.2%.⁹

The clinical course of MPTT remains difficult to predict due to its rarity and the limited availability of large-scale studies. Most published data are derived from isolated case reports or small case series, making standardized treatment guidelines challenging. Given this uncertainty, long-term follow-up is strongly recommended to monitor for recurrence or metastatic progression.²

This case highlights the critical role of clinicopathologic correlation in the evaluation of atypical or rapidly growing scalp lesions. The expertise of dermatologists in recognizing atypical presentations, combined with precise histopathologic analysis, including immunohistochemical staining, is vital to ensuring accurate diagnosis and optimal treatment. Early intervention can improve patient outcomes by reducing the risk for local recurrence and metastatic progression as well as the need for more intensive therapies.

THE DIAGNOSIS: Malignant Proliferating Trichilemmal Tumor

Histologic examination revealed atypical keratinocytes, nuclear pleomorphism, and lobulating epithelial masses with trichilemmal keratinization (Figure). The presence of CD34 positivity, a marker of outer follicular root sheath–derived cells, supported the diagnosis of a malignant proliferating trichilemmal tumor (MPTT). Imaging also revealed signs of bone invasion, further supporting a malignant process. Based on these findings, the patient underwent complete excision of the mass with scalp reconstruction, lymph node dissection, and systemic evaluation for metastases. Final pathology confirmed negative surgical margins and no lymph node involvement. Adjuvant radiation was not required, given the absence of skull invasion or confirmed distant metastasis.

The differential diagnosis for rapidly enlarging scalp tumors can be broad and includes both benign and malignant processes. In this patient, the differential diagnoses included trichilemmal carcinoma, cutaneous squamous cell carcinoma (SCC), sebaceous carcinoma (SC), proliferating trichilemmal tumor (PTT), and MPTT. Due to the notable clinical and histologic overlap among these lesions, definitive diagnosis required histopathologic evaluation in our patient.

Proliferating trichilemmal tumors were first described in 1966 by Wilson-Jones,¹ who used the term proliferating epidermoid cysts, noting their distinct histologic features and resemblance to SCC.² These tumors generally are benign and arise from the isthmus of the outer root sheath of the hair follicle; however, malignant transformation can occur, resulting in a rare entity known as MPTT. This malignant variant was first described in 1983 by Saida et al,³ who emphasized its distinct clinical behavior, including infiltrative growth, high mitotic activity, and potential for local recurrence and metastasis.

A recent literature review identified 60 reported cases of MPTT, with an average patient age of 57 years and a female predominance.⁴ Clinically, MPTTs often manifest as large (>5 cm) lobulated masses located on sun-exposed, hair-bearing areas of the skin, especially the scalp. These lesions may be flesh-colored to pink and often exhibit ulceration, necrosis, or calcification.⁵ Typically, MPTTs follow a biphasic course, beginning with a slow-growing phase followed by a period of rapid growth. Due to their aggressive behavior and resemblance to other cutaneous malignancies, accurate differentiation of MPTT from benign PTTs, cutaneous SCCs, SCs, and trichilemmal carcinomas is critical.

Malignant proliferating trichilemmal tumors demonstrate a substantially higher metastatic potential than either benign PTTs or cutaneous SCCs. While cutaneous SCCs carry a metastasis rate of approximately 1.9% to 2.6%, MPTTs carry a considerably higher rate of approximately 25.0%.⁶ Regional lymphatic spread is the most common route of dissemination, making comprehensive lymph node assessment—both radiographic and clinical—an important component of tumor staging. When lymph node involvement is suspected, surgical dissection may be indicated, along with consideration of adjuvant therapies.

Histopathologically, MPTT is characterized by nuclear atypia, mitotic figures, and lobulated masses of proliferating epithelium showing trichilemmal differentiation and infiltrative growth.⁴ The presence of CD34 positivity, reflecting outer follicular root sheath differentiation, helps distinguish MPTT from cutaneous SCC and SC, which typically lack this marker.^6,7 Immunohistochemistry is therefore a valuable adjunct in differentiating these lesions.

The mainstay of treatment for MPTT is wide local excision with clear margins. Margins of at least 1 cm generally are recommended. Although Mohs micrographic surgery may be used in anatomically sensitive areas, it typically is not preferred due to the potential for skip lesions in MPTT, which may lead to incomplete excision and recurrence.⁸ In cases with evidence of regional or distant metastasis or when clear margins cannot be achieved confidently, adjunctive treatments such as radiation therapy and systemic chemotherapy may be indicated. Preoperative imaging is used to evaluate for local invasion (skull or bone involvement) and regional lymph node status, which may inform adjuvant therapy postoperatively.

The prognosis for MPTT is variable and depends largely on early recognition, accurate histopathologic diagnosis, complete surgical excision with clear margins, and the presence or absence of metastasis. When the tumor is fully excised with negative margins and no lymph node involvement, the risk for recurrence is substantially reduced; however, MPTT is known for its potential aggressive behavior. Delays in diagnosis or incomplete resection can lead to local recurrence, regional spread, or even distant metastasis. In the literature review discussed previously, the mortality rate of patients with MPTT was 11.7%,⁴ which is notably higher than that of more common cutaneous malignancies such as cutaneous SCC, which is reported at 1.2%.⁹

The clinical course of MPTT remains difficult to predict due to its rarity and the limited availability of large-scale studies. Most published data are derived from isolated case reports or small case series, making standardized treatment guidelines challenging. Given this uncertainty, long-term follow-up is strongly recommended to monitor for recurrence or metastatic progression.²

This case highlights the critical role of clinicopathologic correlation in the evaluation of atypical or rapidly growing scalp lesions. The expertise of dermatologists in recognizing atypical presentations, combined with precise histopathologic analysis, including immunohistochemical staining, is vital to ensuring accurate diagnosis and optimal treatment. Early intervention can improve patient outcomes by reducing the risk for local recurrence and metastatic progression as well as the need for more intensive therapies.

THE DIAGNOSIS: Malignant Proliferating Trichilemmal Tumor

Histologic examination revealed atypical keratinocytes, nuclear pleomorphism, and lobulating epithelial masses with trichilemmal keratinization (Figure). The presence of CD34 positivity, a marker of outer follicular root sheath–derived cells, supported the diagnosis of a malignant proliferating trichilemmal tumor (MPTT). Imaging also revealed signs of bone invasion, further supporting a malignant process. Based on these findings, the patient underwent complete excision of the mass with scalp reconstruction, lymph node dissection, and systemic evaluation for metastases. Final pathology confirmed negative surgical margins and no lymph node involvement. Adjuvant radiation was not required, given the absence of skull invasion or confirmed distant metastasis.

The differential diagnosis for rapidly enlarging scalp tumors can be broad and includes both benign and malignant processes. In this patient, the differential diagnoses included trichilemmal carcinoma, cutaneous squamous cell carcinoma (SCC), sebaceous carcinoma (SC), proliferating trichilemmal tumor (PTT), and MPTT. Due to the notable clinical and histologic overlap among these lesions, definitive diagnosis required histopathologic evaluation in our patient.

Proliferating trichilemmal tumors were first described in 1966 by Wilson-Jones,¹ who used the term proliferating epidermoid cysts, noting their distinct histologic features and resemblance to SCC.² These tumors generally are benign and arise from the isthmus of the outer root sheath of the hair follicle; however, malignant transformation can occur, resulting in a rare entity known as MPTT. This malignant variant was first described in 1983 by Saida et al,³ who emphasized its distinct clinical behavior, including infiltrative growth, high mitotic activity, and potential for local recurrence and metastasis.

A recent literature review identified 60 reported cases of MPTT, with an average patient age of 57 years and a female predominance.⁴ Clinically, MPTTs often manifest as large (>5 cm) lobulated masses located on sun-exposed, hair-bearing areas of the skin, especially the scalp. These lesions may be flesh-colored to pink and often exhibit ulceration, necrosis, or calcification.⁵ Typically, MPTTs follow a biphasic course, beginning with a slow-growing phase followed by a period of rapid growth. Due to their aggressive behavior and resemblance to other cutaneous malignancies, accurate differentiation of MPTT from benign PTTs, cutaneous SCCs, SCs, and trichilemmal carcinomas is critical.

Malignant proliferating trichilemmal tumors demonstrate a substantially higher metastatic potential than either benign PTTs or cutaneous SCCs. While cutaneous SCCs carry a metastasis rate of approximately 1.9% to 2.6%, MPTTs carry a considerably higher rate of approximately 25.0%.⁶ Regional lymphatic spread is the most common route of dissemination, making comprehensive lymph node assessment—both radiographic and clinical—an important component of tumor staging. When lymph node involvement is suspected, surgical dissection may be indicated, along with consideration of adjuvant therapies.

Histopathologically, MPTT is characterized by nuclear atypia, mitotic figures, and lobulated masses of proliferating epithelium showing trichilemmal differentiation and infiltrative growth.⁴ The presence of CD34 positivity, reflecting outer follicular root sheath differentiation, helps distinguish MPTT from cutaneous SCC and SC, which typically lack this marker.^6,7 Immunohistochemistry is therefore a valuable adjunct in differentiating these lesions.

The mainstay of treatment for MPTT is wide local excision with clear margins. Margins of at least 1 cm generally are recommended. Although Mohs micrographic surgery may be used in anatomically sensitive areas, it typically is not preferred due to the potential for skip lesions in MPTT, which may lead to incomplete excision and recurrence.⁸ In cases with evidence of regional or distant metastasis or when clear margins cannot be achieved confidently, adjunctive treatments such as radiation therapy and systemic chemotherapy may be indicated. Preoperative imaging is used to evaluate for local invasion (skull or bone involvement) and regional lymph node status, which may inform adjuvant therapy postoperatively.

The prognosis for MPTT is variable and depends largely on early recognition, accurate histopathologic diagnosis, complete surgical excision with clear margins, and the presence or absence of metastasis. When the tumor is fully excised with negative margins and no lymph node involvement, the risk for recurrence is substantially reduced; however, MPTT is known for its potential aggressive behavior. Delays in diagnosis or incomplete resection can lead to local recurrence, regional spread, or even distant metastasis. In the literature review discussed previously, the mortality rate of patients with MPTT was 11.7%,⁴ which is notably higher than that of more common cutaneous malignancies such as cutaneous SCC, which is reported at 1.2%.⁹

The clinical course of MPTT remains difficult to predict due to its rarity and the limited availability of large-scale studies. Most published data are derived from isolated case reports or small case series, making standardized treatment guidelines challenging. Given this uncertainty, long-term follow-up is strongly recommended to monitor for recurrence or metastatic progression.²

This case highlights the critical role of clinicopathologic correlation in the evaluation of atypical or rapidly growing scalp lesions. The expertise of dermatologists in recognizing atypical presentations, combined with precise histopathologic analysis, including immunohistochemical staining, is vital to ensuring accurate diagnosis and optimal treatment. Early intervention can improve patient outcomes by reducing the risk for local recurrence and metastatic progression as well as the need for more intensive therapies.

An AI-based skin assessment app may drive up healthcare visits for benign lesions, with unclear benefits for skin cancer detection, a Dutch clinical trial has found.

The trial, of nearly 20,000 patients in one health insurance plan, found that those given free access to the app were no more likely to be diagnosed with skin cancer over 1 year than participants assigned to a control group with no app access. They were, however, more likely to make healthcare visits for benign skin lesions.

The results came as a surprise, lead researcher Marlies Wakkee, MD, PhD, said during a presentation at the European Association of Dermato-Oncology (EADO) Congress 2026, held in Prague, Czech Republic.

“We were a bit flabbergasted,” said Wakkee, of Erasmus MC in Rotterdam, Netherlands. “We were, of course, expecting that those who would use this intervention app would have more skin cancer diagnoses than those who did not.”

She did, however, point to a potential reason for the lack of benefit: A deeper look at the data suggested that participants in the control group might have been particularly motivated to see their doctor for suspicious skin growths.

Can AI Apps Fill a Gap?

Wakkee pointed out that routine skin cancer screening via clinical skin examination is considered infeasible in many countries. Current guidance from the US Preventive Services Task Force says there is insufficient evidence to assess the balance of benefits and harms from widespread screening.

A plethora of AI-based skin assessment apps have entered the market in recent years, Wakkee said, and in theory, they have the potential to aid in earlier skin cancer diagnosis. But, she added, the technology also comes with potential harms, ranging from spurring healthcare visits for benign lesions to missing true cancers.

The current trial focused on the SkinVision app. It relies on a convolutional neural network to analyze images of skin lesions captured by the user’s smartphone and provides risk assessments of low, medium or high; a tele-dermatology team is available for support.

The app has been reimbursed in Netherlands via health insurance companies since 2019, and by 2021, it was available to 2.2 million insurees, with an uptake of about 1%, according to Wakkee.

In a previous study, the researchers used insurance claims data to study 18,960 app users and compare them with 56,880 nonusers. They found that app use was associated with an increased likelihood of being diagnosed with cutaneous malignancies and premalignancies but also benign tumors and nevi.

“So there’s a group in there that just is very worried about their skin,” Wakkee said.

To investigate further, her team conducted the SPOT-study, a randomized controlled trial in which roughly 226,000 adults covered by a Dutch nonprofit health insurance provider were invited to take part.

Of those, just over 19,000 agreed and were randomly assigned to either an intervention group that had free access to the skin app for 12 months or a control group that had no access. They were told that if they had any skin lesions they were worried about, they should visit their general practitioner.

During that period, the study found there was no significant difference in rates of histologically verified melanoma between the intervention and control groups, at 0.26% vs 0.31% — a risk difference of -0.05% (P = .68).

Similarly, the groups showed no difference in rates of any type of skin cancer, including squamous cell and basal cell carcinomas, at 2.66% in the intervention group vs 2.27% in the control group (P = .10). Rates of premalignant lesions were also comparable (6.9% vs 6.3%; P = .23).

The researchers then examined participants’ claims data to look at healthcare visits for benign skin lesions. There, app users did have a significantly higher rate, at 3.9% vs 2.6% (P < .001).

A Case of Inherent Bias?

The lack of benefit for skin cancer detection prompted the researchers to view the data from a different angle. They compared their trial participants with over 200,000 nonresponders from the health insurance plan. And that’s when a difference emerged.

Overall, trial participants were nearly three times more likely to have a skin premalignancy or malignancy diagnosed during that period, at 6.7% vs 2.4% (P < .001).

Wakkee said that because trial participants were told that the study aimed to gauge “the potential impact of this technology” in assessing skin lesions, that might have created an inherent bias. Participants assigned to the control group may have been motivated to have any worrisome skin growth checked out by their general practitioners.

In addition, Wakkee cautioned that the 12-month results are based on a small number of cancer cases, making it difficult to draw firm conclusions about the app’s performance. The trial has a second phase, where both groups were given free access to the app for 12 months, then followed for an additional 24 months.

Longer-term data are needed, Wakkee noted, in part to see whether people’s app usage changes over time.

Future Questions

Audience members at the presentation raised questions about how AI-based apps could be best deployed for skin cancer detection — including whether they might work better in the hands of clinicians rather than patients.

Wakkee said that clinicians would need a more advanced technology than that included in the app used in this trial. But future studies, she said, will look at whether the app can be used in a more targeted way, specifically, as a triage tool for people who are already concerned about something on their skin, to help them decide if they need to visit their doctor.

One presentation attendee wondered whether people given a low-risk result by the app were likely to be reassured or still make an appointment.

Wakkee said her team has begun to dig into that question. In a pilot study, 50 patients who wanted to see their general practitioner for a skin lesion were asked: If you received a low-risk rating on the skin app, would you still visit your doctor?

“Half of them said they would stay at home,” Wakkee said. She added, however, that her team is conducting a follow-up study to see what people actually do.

The trial was supported by SkinVision. The researchers declared having no relevant financial relationships.

This article was previously published by Medscape.

An AI-based skin assessment app may drive up healthcare visits for benign lesions, with unclear benefits for skin cancer detection, a Dutch clinical trial has found.

The trial, of nearly 20,000 patients in one health insurance plan, found that those given free access to the app were no more likely to be diagnosed with skin cancer over 1 year than participants assigned to a control group with no app access. They were, however, more likely to make healthcare visits for benign skin lesions.

The results came as a surprise, lead researcher Marlies Wakkee, MD, PhD, said during a presentation at the European Association of Dermato-Oncology (EADO) Congress 2026, held in Prague, Czech Republic.

“We were a bit flabbergasted,” said Wakkee, of Erasmus MC in Rotterdam, Netherlands. “We were, of course, expecting that those who would use this intervention app would have more skin cancer diagnoses than those who did not.”

She did, however, point to a potential reason for the lack of benefit: A deeper look at the data suggested that participants in the control group might have been particularly motivated to see their doctor for suspicious skin growths.

Can AI Apps Fill a Gap?

Wakkee pointed out that routine skin cancer screening via clinical skin examination is considered infeasible in many countries. Current guidance from the US Preventive Services Task Force says there is insufficient evidence to assess the balance of benefits and harms from widespread screening.

A plethora of AI-based skin assessment apps have entered the market in recent years, Wakkee said, and in theory, they have the potential to aid in earlier skin cancer diagnosis. But, she added, the technology also comes with potential harms, ranging from spurring healthcare visits for benign lesions to missing true cancers.

The current trial focused on the SkinVision app. It relies on a convolutional neural network to analyze images of skin lesions captured by the user’s smartphone and provides risk assessments of low, medium or high; a tele-dermatology team is available for support.

The app has been reimbursed in Netherlands via health insurance companies since 2019, and by 2021, it was available to 2.2 million insurees, with an uptake of about 1%, according to Wakkee.

In a previous study, the researchers used insurance claims data to study 18,960 app users and compare them with 56,880 nonusers. They found that app use was associated with an increased likelihood of being diagnosed with cutaneous malignancies and premalignancies but also benign tumors and nevi.

“So there’s a group in there that just is very worried about their skin,” Wakkee said.

To investigate further, her team conducted the SPOT-study, a randomized controlled trial in which roughly 226,000 adults covered by a Dutch nonprofit health insurance provider were invited to take part.

Of those, just over 19,000 agreed and were randomly assigned to either an intervention group that had free access to the skin app for 12 months or a control group that had no access. They were told that if they had any skin lesions they were worried about, they should visit their general practitioner.

During that period, the study found there was no significant difference in rates of histologically verified melanoma between the intervention and control groups, at 0.26% vs 0.31% — a risk difference of -0.05% (P = .68).

Similarly, the groups showed no difference in rates of any type of skin cancer, including squamous cell and basal cell carcinomas, at 2.66% in the intervention group vs 2.27% in the control group (P = .10). Rates of premalignant lesions were also comparable (6.9% vs 6.3%; P = .23).

The researchers then examined participants’ claims data to look at healthcare visits for benign skin lesions. There, app users did have a significantly higher rate, at 3.9% vs 2.6% (P < .001).

A Case of Inherent Bias?

The lack of benefit for skin cancer detection prompted the researchers to view the data from a different angle. They compared their trial participants with over 200,000 nonresponders from the health insurance plan. And that’s when a difference emerged.

Overall, trial participants were nearly three times more likely to have a skin premalignancy or malignancy diagnosed during that period, at 6.7% vs 2.4% (P < .001).

Wakkee said that because trial participants were told that the study aimed to gauge “the potential impact of this technology” in assessing skin lesions, that might have created an inherent bias. Participants assigned to the control group may have been motivated to have any worrisome skin growth checked out by their general practitioners.

In addition, Wakkee cautioned that the 12-month results are based on a small number of cancer cases, making it difficult to draw firm conclusions about the app’s performance. The trial has a second phase, where both groups were given free access to the app for 12 months, then followed for an additional 24 months.

Longer-term data are needed, Wakkee noted, in part to see whether people’s app usage changes over time.

Future Questions

Audience members at the presentation raised questions about how AI-based apps could be best deployed for skin cancer detection — including whether they might work better in the hands of clinicians rather than patients.

Wakkee said that clinicians would need a more advanced technology than that included in the app used in this trial. But future studies, she said, will look at whether the app can be used in a more targeted way, specifically, as a triage tool for people who are already concerned about something on their skin, to help them decide if they need to visit their doctor.

One presentation attendee wondered whether people given a low-risk result by the app were likely to be reassured or still make an appointment.

Wakkee said her team has begun to dig into that question. In a pilot study, 50 patients who wanted to see their general practitioner for a skin lesion were asked: If you received a low-risk rating on the skin app, would you still visit your doctor?

“Half of them said they would stay at home,” Wakkee said. She added, however, that her team is conducting a follow-up study to see what people actually do.

The trial was supported by SkinVision. The researchers declared having no relevant financial relationships.

This article was previously published by Medscape.

An AI-based skin assessment app may drive up healthcare visits for benign lesions, with unclear benefits for skin cancer detection, a Dutch clinical trial has found.

The trial, of nearly 20,000 patients in one health insurance plan, found that those given free access to the app were no more likely to be diagnosed with skin cancer over 1 year than participants assigned to a control group with no app access. They were, however, more likely to make healthcare visits for benign skin lesions.

The results came as a surprise, lead researcher Marlies Wakkee, MD, PhD, said during a presentation at the European Association of Dermato-Oncology (EADO) Congress 2026, held in Prague, Czech Republic.

“We were a bit flabbergasted,” said Wakkee, of Erasmus MC in Rotterdam, Netherlands. “We were, of course, expecting that those who would use this intervention app would have more skin cancer diagnoses than those who did not.”

She did, however, point to a potential reason for the lack of benefit: A deeper look at the data suggested that participants in the control group might have been particularly motivated to see their doctor for suspicious skin growths.

Can AI Apps Fill a Gap?

Wakkee pointed out that routine skin cancer screening via clinical skin examination is considered infeasible in many countries. Current guidance from the US Preventive Services Task Force says there is insufficient evidence to assess the balance of benefits and harms from widespread screening.

A plethora of AI-based skin assessment apps have entered the market in recent years, Wakkee said, and in theory, they have the potential to aid in earlier skin cancer diagnosis. But, she added, the technology also comes with potential harms, ranging from spurring healthcare visits for benign lesions to missing true cancers.

The current trial focused on the SkinVision app. It relies on a convolutional neural network to analyze images of skin lesions captured by the user’s smartphone and provides risk assessments of low, medium or high; a tele-dermatology team is available for support.

The app has been reimbursed in Netherlands via health insurance companies since 2019, and by 2021, it was available to 2.2 million insurees, with an uptake of about 1%, according to Wakkee.

In a previous study, the researchers used insurance claims data to study 18,960 app users and compare them with 56,880 nonusers. They found that app use was associated with an increased likelihood of being diagnosed with cutaneous malignancies and premalignancies but also benign tumors and nevi.

“So there’s a group in there that just is very worried about their skin,” Wakkee said.

To investigate further, her team conducted the SPOT-study, a randomized controlled trial in which roughly 226,000 adults covered by a Dutch nonprofit health insurance provider were invited to take part.

Of those, just over 19,000 agreed and were randomly assigned to either an intervention group that had free access to the skin app for 12 months or a control group that had no access. They were told that if they had any skin lesions they were worried about, they should visit their general practitioner.

During that period, the study found there was no significant difference in rates of histologically verified melanoma between the intervention and control groups, at 0.26% vs 0.31% — a risk difference of -0.05% (P = .68).

Similarly, the groups showed no difference in rates of any type of skin cancer, including squamous cell and basal cell carcinomas, at 2.66% in the intervention group vs 2.27% in the control group (P = .10). Rates of premalignant lesions were also comparable (6.9% vs 6.3%; P = .23).

The researchers then examined participants’ claims data to look at healthcare visits for benign skin lesions. There, app users did have a significantly higher rate, at 3.9% vs 2.6% (P < .001).

A Case of Inherent Bias?

The lack of benefit for skin cancer detection prompted the researchers to view the data from a different angle. They compared their trial participants with over 200,000 nonresponders from the health insurance plan. And that’s when a difference emerged.

Overall, trial participants were nearly three times more likely to have a skin premalignancy or malignancy diagnosed during that period, at 6.7% vs 2.4% (P < .001).

Wakkee said that because trial participants were told that the study aimed to gauge “the potential impact of this technology” in assessing skin lesions, that might have created an inherent bias. Participants assigned to the control group may have been motivated to have any worrisome skin growth checked out by their general practitioners.

In addition, Wakkee cautioned that the 12-month results are based on a small number of cancer cases, making it difficult to draw firm conclusions about the app’s performance. The trial has a second phase, where both groups were given free access to the app for 12 months, then followed for an additional 24 months.

Longer-term data are needed, Wakkee noted, in part to see whether people’s app usage changes over time.

Future Questions

Audience members at the presentation raised questions about how AI-based apps could be best deployed for skin cancer detection — including whether they might work better in the hands of clinicians rather than patients.

Wakkee said that clinicians would need a more advanced technology than that included in the app used in this trial. But future studies, she said, will look at whether the app can be used in a more targeted way, specifically, as a triage tool for people who are already concerned about something on their skin, to help them decide if they need to visit their doctor.

One presentation attendee wondered whether people given a low-risk result by the app were likely to be reassured or still make an appointment.

Wakkee said her team has begun to dig into that question. In a pilot study, 50 patients who wanted to see their general practitioner for a skin lesion were asked: If you received a low-risk rating on the skin app, would you still visit your doctor?

“Half of them said they would stay at home,” Wakkee said. She added, however, that her team is conducting a follow-up study to see what people actually do.

The trial was supported by SkinVision. The researchers declared having no relevant financial relationships.

This article was previously published by Medscape.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy typically seen in apocrine-rich areas, including the axillae and anogenital region. It presents as a slow-growing, erythematous patch or plaque that commonly is misdiagnosed as an infectious or inflammatory condition.^1,2 Primary EMPD occurs as a intraepithelial neoplasm, whereas secondary EMPD occurs due to epidermotropic metastases or direct extension of an underlying adenocarcinoma into the skin.¹ Most commonly, primary EMPD occurs in situ; however, when present, dermal invasion and metastases from the skin are associated with poorer outcomes.³ Given the rarity of metastatic disease, existing literature is limited to case reports and case series.

We present 2 patients with metastatic primary EMPD who had evidence of invasion on initial biopsy and died secondary to metastatic EMPD. We conducted a comprehensive review of the literature for invasive and metastatic EMPD to highlight key clinicopathologic features, treatment considerations, and the potential for rapid disease progression in cases of invasive EMPD.

Case Series

Patient 1—A 68-year-old White man with a history of breast cancer (in remission) presented to our clinic for further management of biopsy-proven scrotal EMPD. Prior to biopsy, he described a 6-month history of worsening scrotal rash treated with topical antifungals, oral antibiotics, and topical steroids due to presumed diagnosis of intertrigo, cellulitis, and dermatitis, respectively. Clinical examination showed indurated, erythematous, ulcerated plaques involving the bilateral groin, genitalia, and perineum (Figure 1). Skin biopsy confirmed a diagnosis of EMPD with both dermal and lymphovascular invasion. An immunohistochemical profile was positive for CK7 and carcinoembryonic antigen (CEA) and negative for CK20 (Figure 2).

At presentation, the patient had palpable lymphadenopathy and scrotal edema concerning for inguinal and iliac lymph node metastases. Workup for an underlying adenocarcinoma included computed tomography (CT) of the chest, abdomen, and pelvis; urologic consultation with cystoscopy; and a screening colonoscopy. The CT scan revealed multiple enlarged inguinal and external iliac lymph nodes. Fine-needle aspiration revealed CK7- and CEA-positive neoplastic cells consistent with metastatic EMPD. The patient was treated with 6 cycles of carboplatin-paclitaxel, palliative radiation therapy, and pembrolizumab with minimal response to treatment and development of osteolytic vertebral lesions concerning for disease progression. He died 1 year after the initial diagnosis secondary to the disease.

Patient 2—A 79-year-old White man presented for further management of an outside diagnosis of superficially invasive primary EMPD of the bilateral inguinal folds and scrotum that had been present for 5 months prior to biopsy and diagnosis. Clinical examination at initial presentation revealed erythematous patches of the bilateral inguinal folds and scrotum, as well as an erythematous scaling plaque in the right axilla. There was no palpable clinical lymphadenopathy. Biopsy of the axilla and groin were both consistent with invasive EMPD with positive staining for CK7 and negative staining for CK20 and CDX2. Workup for underlying adenocarcinoma with whole-body positron emission tomography/CT, mammography, esophagogastroduodenoscopy, serum CEA, colonoscopy, and cystoscopy were all negative for a metastatic adenocarcinoma. There was no imaging or clinical evidence of lymphadenopathy. Complete circumferential peripheral and deep-margin assessment was performed in a staged manner on both sites, and negative margins were obtained.

Surveillance imaging 6 months after surgery revealed suspicious hepatic lesions. Fine-needle aspiration of the hepatic lesions demonstrated positive staining for CK7 and negative staining for CK20, CDX2, prostate-specific antigen, and thyroid transcription factor 1, consistent with metastatic EMPD. Oncology recommended carboplatin and docetaxel or docetaxel monotherapy chemotherapy. The patient was further managed by an outside oncologist due to ease of travel but died secondary to the disease 15 months following the initial diagnosis.

Comment

Extramammary Paget disease is an uncommon cutaneous malignancy that manifests as pruritic erythematous plaques within apocrine-rich areas such as the genitalia, axillae, or anal region. It most commonly occurs in patients older than 65 years, with White women and Asian men being affected at disproportionately higher rates.^1,4 Delay in diagnosis is common, as EMPD can mimic other benign inflammatory or infectious conditions, including contact dermatitis, seborrheic dermatitis, tinea, candidiasis, and eczema.¹

Metastatic and multifocal cases of primary EMPD are especially rare. According to a search of PubMed articles indexed for MEDLINE published through December 2023 using the terms extramammary Paget disease, EMPD, neoplasm metastasis, invasive extramammary, and neoplasm invasiveness, we identified 5040 cases of invasive EMPD and 477 cases of metastatic EMPD.^5-37 Of the reports that disclosed patient demographic information, 3627 patients were female 1410 were male, and the mean age was 67 years. Sites of metastases included regional lymph nodes, liver, lungs, cervix, bladder, bone, brain, skin, kidney, and adrenal glands

Workup for EMPD—The initial steps for workup of EMPD include a thorough physical examination and lymph node assessment. A skin biopsy also should be performed for patients presenting with refractory, pruritic, and eczematous rashes in apocrine-rich areas to evaluate for EMPD.¹ Characterization of large and complex tumors is better achieved through multiple biopsies with particular focus on nodular or thickened areas, as these may indicate invasive disease.² Primary EMPD is characterized by pagetoid cells with abundant pale cytoplasm proliferating in a single-cell or nested pattern within the epidermis or dermis in invasive disease and often is accompanied by dermal lymphocytic inflammation.¹ Immunohistochemistry demonstrates positive staining for CEA, CK7, and CK8, with negative staining for indicators of secondary EMPD including CK20 and CDX2.^1,2

As part of the workup, it is critical to distinguish between primary disease and secondary EMPD.¹ Beyond skin and clinical lymph node examination, additional workup should be based on age-appropriate and location-directed malignant neoplasm screenings, including colonoscopy, cystoscopy, prostate examination, mammography, and Papanicolaou test. Advanced imaging such as CT, positron emission tomography, or magnetic resonance imaging can be used to assess for metastatic disease if internal malignant neoplasms are present on initial screening or clinical lymphadenopathy is identified.² Additionally, it can be helpful in the evaluation for nodal disease in cases of invasive EMPD.

The likelihood of associated underlying carcinomas varies depending on the site of involvement.^38,39 For example, vulvar involvement constitutes approximately 65% of EMPD cases, with 11% to 20% of cases being associated with underlying gastrointestinal or genitourinary carcinomas. Involvement of the male genitalia, as in our 2 patients, is rare, accounting for approximately 14% of cases, 11% of which are associated with prostate, testicular, and bladder carcinoma. Perianal involvement comprises 20% of EMPD cases and has the greatest risk for underlying malignancy with an incidence of 33% to 86%, the majority of which are rectal or tubo-ovarian cancers.^38,39 Consideration of the frequency and types of underlying carcinoma of respective sites of involvement can be helpful when ruling out secondary EMPD.

In both of our patients, palpable lymphadenopathy at the time of original diagnosis and histologic invasive disease on initial biopsy warranted thorough imaging and laboratory workup; there was no evidence of primary malignancy. Given the absence of an underlying carcinoma, both patients were classified as having metastatic primary EMPD.

Assessment of lymphadenopathy is an essential aspect of disease workup, as it is associated with a statistically higher rate of lymph node metastases. A study by Fujisawa et al²⁰ demonstrated that 80% of patients with lymphadenopathy had regional metastases compared to only 15% of patients without clinical lymphadenopathy. The presence of invasive disease also has been shown to correspond with lymph node metastases.⁴⁰ Ogata et al⁴⁰ showed that 0% of cases with in situ EMPD had a positive sentinel lymph node biopsy (SLNB) compared to 4% and 43% in cases that showed evidence of microinvasion and dermal invasion, respectively. Lymph node metastases are associated with poor prognosis, with increasingly worse prognosis when there are multiple lymph nodes affected.⁴¹ In our case series, patient 1 had lymphadenopathy and both patients had invasive EMPD; they both later developed metastases and died.

Lymphadenopathy should be further investigated with imaging and biopsy or fine-needle aspiration.⁴² Recent expert consensus guidelines recommended this method of investigation over routine use of SLNB, as there is no evidence that a positive SLNB affects treatment that changes disease-specific survival.²

Treatment of EMPD—Surgical excision of the primary lesion is the first-line treatment of EMPD,^1,2 which can be performed by wide local excision; however, studies have demonstrated higher recurrence-free survival with margin-controlled surgery (complete circumferential peripheral and deep margin assessment) or Mohs micrographic surgery (MMS), especially with CK7 immunostaining.^2,37,43 The literature on MMS of invasive EMPD is sparse, accounting for 57 patients.^25,37,44 Other reports describe management with surgical excision, wide local excision, regional resection, or vulvectomy, in addition to lymph node dissection, radiation therapy (RT), and/or chemotherapy.^{1-36,39,43-46} Despite the improved outcomes with MMS, the predominance of other surgical approaches in our search suggests that MMS may be currently underutilized for the treatment of invasive or locally advanced EMPD.

Among patients with unresectable disease or distant metastases, management includes RT with curative intent, chemotherapy, or a combination of both.^1,2 In our review, 267 cases were treated using RT and 77 with chemotherapy. Radiation therapy is an effective therapeutic option with a reported response rate of 62% to 100% and can be employed as either primary or adjuvant treatment.³ For patients with lymph node metastasis the combination of RT and lymph node dissection has been shown to have improved outcomes compared to lymph node dissection alone, with 1 study showing a 5-year survival of 75% for patients who received adjuvant RT compared to 0% for lymph node dissection alone.⁴⁵

There are currently no consensus guidelines on the best chemotherapeutic regimen for metastatic EMPD. Several regimens have been reported, including docetaxel monotherapy; low-dose 5-fluorouracil and cisplatin; combination chemotherapy FECOM (5-fluorouracil, epirubicin, carboplatin, vincristine, mitomycin); or combination therapy with cisplatin, epirubicin, and paclitaxel.¹

Prognosis of Metastatic EMPD—Because invasive and metastatic EMPD is rare, its natural history is hard to predict. Poor prognosis is associated with nodule formation, tumor thickness, perianal or vaginal involvement, lymphovascular invasion, nodal metastasis, and distant metastasis. The 5-year survival for metastatic EMPD has been reported to be less than 10%.⁴⁶ Our cases underscore the poor prognostic risk associated with metastatic EMPD.

For all cases of EMPD, close follow-up is warranted. Guidelines recommend physical examination with lymph node assessment every 3 to 6 months for 3 years and every 6 to 12 months for the subsequent 5 years.² Specific recommendations for follow-up in invasive disease have not yet been described, though the 20% probability of developing an internal malignancy within 5 years after diagnosis and poor prognostic outcomes associated with invasive and metastatic disease support the need for close monitoring.²

Conclusion

Although in situ EMPD often is a slow-growing tumor with good prognosis, invasive disease has high potential to behave aggressively with high morbidity and mortality. Increased awareness and prompt identification of invasive EMPD, expedited comprehensive workup, and early multidisciplinary management might impact patient outcomes.

Acknowledgment—The authors would like to thank Ellen Aaronson, MLIS, AHIP (Mayo Clinic Libraries [Jacksonville, FL]), for creating and conducting the narrative literature search in the MEDLINE database.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy typically seen in apocrine-rich areas, including the axillae and anogenital region. It presents as a slow-growing, erythematous patch or plaque that commonly is misdiagnosed as an infectious or inflammatory condition.^1,2 Primary EMPD occurs as a intraepithelial neoplasm, whereas secondary EMPD occurs due to epidermotropic metastases or direct extension of an underlying adenocarcinoma into the skin.¹ Most commonly, primary EMPD occurs in situ; however, when present, dermal invasion and metastases from the skin are associated with poorer outcomes.³ Given the rarity of metastatic disease, existing literature is limited to case reports and case series.

We present 2 patients with metastatic primary EMPD who had evidence of invasion on initial biopsy and died secondary to metastatic EMPD. We conducted a comprehensive review of the literature for invasive and metastatic EMPD to highlight key clinicopathologic features, treatment considerations, and the potential for rapid disease progression in cases of invasive EMPD.

Case Series

Patient 1—A 68-year-old White man with a history of breast cancer (in remission) presented to our clinic for further management of biopsy-proven scrotal EMPD. Prior to biopsy, he described a 6-month history of worsening scrotal rash treated with topical antifungals, oral antibiotics, and topical steroids due to presumed diagnosis of intertrigo, cellulitis, and dermatitis, respectively. Clinical examination showed indurated, erythematous, ulcerated plaques involving the bilateral groin, genitalia, and perineum (Figure 1). Skin biopsy confirmed a diagnosis of EMPD with both dermal and lymphovascular invasion. An immunohistochemical profile was positive for CK7 and carcinoembryonic antigen (CEA) and negative for CK20 (Figure 2).

At presentation, the patient had palpable lymphadenopathy and scrotal edema concerning for inguinal and iliac lymph node metastases. Workup for an underlying adenocarcinoma included computed tomography (CT) of the chest, abdomen, and pelvis; urologic consultation with cystoscopy; and a screening colonoscopy. The CT scan revealed multiple enlarged inguinal and external iliac lymph nodes. Fine-needle aspiration revealed CK7- and CEA-positive neoplastic cells consistent with metastatic EMPD. The patient was treated with 6 cycles of carboplatin-paclitaxel, palliative radiation therapy, and pembrolizumab with minimal response to treatment and development of osteolytic vertebral lesions concerning for disease progression. He died 1 year after the initial diagnosis secondary to the disease.

Patient 2—A 79-year-old White man presented for further management of an outside diagnosis of superficially invasive primary EMPD of the bilateral inguinal folds and scrotum that had been present for 5 months prior to biopsy and diagnosis. Clinical examination at initial presentation revealed erythematous patches of the bilateral inguinal folds and scrotum, as well as an erythematous scaling plaque in the right axilla. There was no palpable clinical lymphadenopathy. Biopsy of the axilla and groin were both consistent with invasive EMPD with positive staining for CK7 and negative staining for CK20 and CDX2. Workup for underlying adenocarcinoma with whole-body positron emission tomography/CT, mammography, esophagogastroduodenoscopy, serum CEA, colonoscopy, and cystoscopy were all negative for a metastatic adenocarcinoma. There was no imaging or clinical evidence of lymphadenopathy. Complete circumferential peripheral and deep-margin assessment was performed in a staged manner on both sites, and negative margins were obtained.

Surveillance imaging 6 months after surgery revealed suspicious hepatic lesions. Fine-needle aspiration of the hepatic lesions demonstrated positive staining for CK7 and negative staining for CK20, CDX2, prostate-specific antigen, and thyroid transcription factor 1, consistent with metastatic EMPD. Oncology recommended carboplatin and docetaxel or docetaxel monotherapy chemotherapy. The patient was further managed by an outside oncologist due to ease of travel but died secondary to the disease 15 months following the initial diagnosis.

Comment

Extramammary Paget disease is an uncommon cutaneous malignancy that manifests as pruritic erythematous plaques within apocrine-rich areas such as the genitalia, axillae, or anal region. It most commonly occurs in patients older than 65 years, with White women and Asian men being affected at disproportionately higher rates.^1,4 Delay in diagnosis is common, as EMPD can mimic other benign inflammatory or infectious conditions, including contact dermatitis, seborrheic dermatitis, tinea, candidiasis, and eczema.¹

Metastatic and multifocal cases of primary EMPD are especially rare. According to a search of PubMed articles indexed for MEDLINE published through December 2023 using the terms extramammary Paget disease, EMPD, neoplasm metastasis, invasive extramammary, and neoplasm invasiveness, we identified 5040 cases of invasive EMPD and 477 cases of metastatic EMPD.^5-37 Of the reports that disclosed patient demographic information, 3627 patients were female 1410 were male, and the mean age was 67 years. Sites of metastases included regional lymph nodes, liver, lungs, cervix, bladder, bone, brain, skin, kidney, and adrenal glands

Workup for EMPD—The initial steps for workup of EMPD include a thorough physical examination and lymph node assessment. A skin biopsy also should be performed for patients presenting with refractory, pruritic, and eczematous rashes in apocrine-rich areas to evaluate for EMPD.¹ Characterization of large and complex tumors is better achieved through multiple biopsies with particular focus on nodular or thickened areas, as these may indicate invasive disease.² Primary EMPD is characterized by pagetoid cells with abundant pale cytoplasm proliferating in a single-cell or nested pattern within the epidermis or dermis in invasive disease and often is accompanied by dermal lymphocytic inflammation.¹ Immunohistochemistry demonstrates positive staining for CEA, CK7, and CK8, with negative staining for indicators of secondary EMPD including CK20 and CDX2.^1,2

As part of the workup, it is critical to distinguish between primary disease and secondary EMPD.¹ Beyond skin and clinical lymph node examination, additional workup should be based on age-appropriate and location-directed malignant neoplasm screenings, including colonoscopy, cystoscopy, prostate examination, mammography, and Papanicolaou test. Advanced imaging such as CT, positron emission tomography, or magnetic resonance imaging can be used to assess for metastatic disease if internal malignant neoplasms are present on initial screening or clinical lymphadenopathy is identified.² Additionally, it can be helpful in the evaluation for nodal disease in cases of invasive EMPD.

The likelihood of associated underlying carcinomas varies depending on the site of involvement.^38,39 For example, vulvar involvement constitutes approximately 65% of EMPD cases, with 11% to 20% of cases being associated with underlying gastrointestinal or genitourinary carcinomas. Involvement of the male genitalia, as in our 2 patients, is rare, accounting for approximately 14% of cases, 11% of which are associated with prostate, testicular, and bladder carcinoma. Perianal involvement comprises 20% of EMPD cases and has the greatest risk for underlying malignancy with an incidence of 33% to 86%, the majority of which are rectal or tubo-ovarian cancers.^38,39 Consideration of the frequency and types of underlying carcinoma of respective sites of involvement can be helpful when ruling out secondary EMPD.

In both of our patients, palpable lymphadenopathy at the time of original diagnosis and histologic invasive disease on initial biopsy warranted thorough imaging and laboratory workup; there was no evidence of primary malignancy. Given the absence of an underlying carcinoma, both patients were classified as having metastatic primary EMPD.

Assessment of lymphadenopathy is an essential aspect of disease workup, as it is associated with a statistically higher rate of lymph node metastases. A study by Fujisawa et al²⁰ demonstrated that 80% of patients with lymphadenopathy had regional metastases compared to only 15% of patients without clinical lymphadenopathy. The presence of invasive disease also has been shown to correspond with lymph node metastases.⁴⁰ Ogata et al⁴⁰ showed that 0% of cases with in situ EMPD had a positive sentinel lymph node biopsy (SLNB) compared to 4% and 43% in cases that showed evidence of microinvasion and dermal invasion, respectively. Lymph node metastases are associated with poor prognosis, with increasingly worse prognosis when there are multiple lymph nodes affected.⁴¹ In our case series, patient 1 had lymphadenopathy and both patients had invasive EMPD; they both later developed metastases and died.

Lymphadenopathy should be further investigated with imaging and biopsy or fine-needle aspiration.⁴² Recent expert consensus guidelines recommended this method of investigation over routine use of SLNB, as there is no evidence that a positive SLNB affects treatment that changes disease-specific survival.²

Treatment of EMPD—Surgical excision of the primary lesion is the first-line treatment of EMPD,^1,2 which can be performed by wide local excision; however, studies have demonstrated higher recurrence-free survival with margin-controlled surgery (complete circumferential peripheral and deep margin assessment) or Mohs micrographic surgery (MMS), especially with CK7 immunostaining.^2,37,43 The literature on MMS of invasive EMPD is sparse, accounting for 57 patients.^25,37,44 Other reports describe management with surgical excision, wide local excision, regional resection, or vulvectomy, in addition to lymph node dissection, radiation therapy (RT), and/or chemotherapy.^{1-36,39,43-46} Despite the improved outcomes with MMS, the predominance of other surgical approaches in our search suggests that MMS may be currently underutilized for the treatment of invasive or locally advanced EMPD.

Among patients with unresectable disease or distant metastases, management includes RT with curative intent, chemotherapy, or a combination of both.^1,2 In our review, 267 cases were treated using RT and 77 with chemotherapy. Radiation therapy is an effective therapeutic option with a reported response rate of 62% to 100% and can be employed as either primary or adjuvant treatment.³ For patients with lymph node metastasis the combination of RT and lymph node dissection has been shown to have improved outcomes compared to lymph node dissection alone, with 1 study showing a 5-year survival of 75% for patients who received adjuvant RT compared to 0% for lymph node dissection alone.⁴⁵

There are currently no consensus guidelines on the best chemotherapeutic regimen for metastatic EMPD. Several regimens have been reported, including docetaxel monotherapy; low-dose 5-fluorouracil and cisplatin; combination chemotherapy FECOM (5-fluorouracil, epirubicin, carboplatin, vincristine, mitomycin); or combination therapy with cisplatin, epirubicin, and paclitaxel.¹

Prognosis of Metastatic EMPD—Because invasive and metastatic EMPD is rare, its natural history is hard to predict. Poor prognosis is associated with nodule formation, tumor thickness, perianal or vaginal involvement, lymphovascular invasion, nodal metastasis, and distant metastasis. The 5-year survival for metastatic EMPD has been reported to be less than 10%.⁴⁶ Our cases underscore the poor prognostic risk associated with metastatic EMPD.

For all cases of EMPD, close follow-up is warranted. Guidelines recommend physical examination with lymph node assessment every 3 to 6 months for 3 years and every 6 to 12 months for the subsequent 5 years.² Specific recommendations for follow-up in invasive disease have not yet been described, though the 20% probability of developing an internal malignancy within 5 years after diagnosis and poor prognostic outcomes associated with invasive and metastatic disease support the need for close monitoring.²

Conclusion

Although in situ EMPD often is a slow-growing tumor with good prognosis, invasive disease has high potential to behave aggressively with high morbidity and mortality. Increased awareness and prompt identification of invasive EMPD, expedited comprehensive workup, and early multidisciplinary management might impact patient outcomes.

Acknowledgment—The authors would like to thank Ellen Aaronson, MLIS, AHIP (Mayo Clinic Libraries [Jacksonville, FL]), for creating and conducting the narrative literature search in the MEDLINE database.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy typically seen in apocrine-rich areas, including the axillae and anogenital region. It presents as a slow-growing, erythematous patch or plaque that commonly is misdiagnosed as an infectious or inflammatory condition.^1,2 Primary EMPD occurs as a intraepithelial neoplasm, whereas secondary EMPD occurs due to epidermotropic metastases or direct extension of an underlying adenocarcinoma into the skin.¹ Most commonly, primary EMPD occurs in situ; however, when present, dermal invasion and metastases from the skin are associated with poorer outcomes.³ Given the rarity of metastatic disease, existing literature is limited to case reports and case series.

We present 2 patients with metastatic primary EMPD who had evidence of invasion on initial biopsy and died secondary to metastatic EMPD. We conducted a comprehensive review of the literature for invasive and metastatic EMPD to highlight key clinicopathologic features, treatment considerations, and the potential for rapid disease progression in cases of invasive EMPD.

Case Series

Patient 1—A 68-year-old White man with a history of breast cancer (in remission) presented to our clinic for further management of biopsy-proven scrotal EMPD. Prior to biopsy, he described a 6-month history of worsening scrotal rash treated with topical antifungals, oral antibiotics, and topical steroids due to presumed diagnosis of intertrigo, cellulitis, and dermatitis, respectively. Clinical examination showed indurated, erythematous, ulcerated plaques involving the bilateral groin, genitalia, and perineum (Figure 1). Skin biopsy confirmed a diagnosis of EMPD with both dermal and lymphovascular invasion. An immunohistochemical profile was positive for CK7 and carcinoembryonic antigen (CEA) and negative for CK20 (Figure 2).

At presentation, the patient had palpable lymphadenopathy and scrotal edema concerning for inguinal and iliac lymph node metastases. Workup for an underlying adenocarcinoma included computed tomography (CT) of the chest, abdomen, and pelvis; urologic consultation with cystoscopy; and a screening colonoscopy. The CT scan revealed multiple enlarged inguinal and external iliac lymph nodes. Fine-needle aspiration revealed CK7- and CEA-positive neoplastic cells consistent with metastatic EMPD. The patient was treated with 6 cycles of carboplatin-paclitaxel, palliative radiation therapy, and pembrolizumab with minimal response to treatment and development of osteolytic vertebral lesions concerning for disease progression. He died 1 year after the initial diagnosis secondary to the disease.

Patient 2—A 79-year-old White man presented for further management of an outside diagnosis of superficially invasive primary EMPD of the bilateral inguinal folds and scrotum that had been present for 5 months prior to biopsy and diagnosis. Clinical examination at initial presentation revealed erythematous patches of the bilateral inguinal folds and scrotum, as well as an erythematous scaling plaque in the right axilla. There was no palpable clinical lymphadenopathy. Biopsy of the axilla and groin were both consistent with invasive EMPD with positive staining for CK7 and negative staining for CK20 and CDX2. Workup for underlying adenocarcinoma with whole-body positron emission tomography/CT, mammography, esophagogastroduodenoscopy, serum CEA, colonoscopy, and cystoscopy were all negative for a metastatic adenocarcinoma. There was no imaging or clinical evidence of lymphadenopathy. Complete circumferential peripheral and deep-margin assessment was performed in a staged manner on both sites, and negative margins were obtained.

Surveillance imaging 6 months after surgery revealed suspicious hepatic lesions. Fine-needle aspiration of the hepatic lesions demonstrated positive staining for CK7 and negative staining for CK20, CDX2, prostate-specific antigen, and thyroid transcription factor 1, consistent with metastatic EMPD. Oncology recommended carboplatin and docetaxel or docetaxel monotherapy chemotherapy. The patient was further managed by an outside oncologist due to ease of travel but died secondary to the disease 15 months following the initial diagnosis.

Comment

Extramammary Paget disease is an uncommon cutaneous malignancy that manifests as pruritic erythematous plaques within apocrine-rich areas such as the genitalia, axillae, or anal region. It most commonly occurs in patients older than 65 years, with White women and Asian men being affected at disproportionately higher rates.^1,4 Delay in diagnosis is common, as EMPD can mimic other benign inflammatory or infectious conditions, including contact dermatitis, seborrheic dermatitis, tinea, candidiasis, and eczema.¹

Metastatic and multifocal cases of primary EMPD are especially rare. According to a search of PubMed articles indexed for MEDLINE published through December 2023 using the terms extramammary Paget disease, EMPD, neoplasm metastasis, invasive extramammary, and neoplasm invasiveness, we identified 5040 cases of invasive EMPD and 477 cases of metastatic EMPD.^5-37 Of the reports that disclosed patient demographic information, 3627 patients were female 1410 were male, and the mean age was 67 years. Sites of metastases included regional lymph nodes, liver, lungs, cervix, bladder, bone, brain, skin, kidney, and adrenal glands

Workup for EMPD—The initial steps for workup of EMPD include a thorough physical examination and lymph node assessment. A skin biopsy also should be performed for patients presenting with refractory, pruritic, and eczematous rashes in apocrine-rich areas to evaluate for EMPD.¹ Characterization of large and complex tumors is better achieved through multiple biopsies with particular focus on nodular or thickened areas, as these may indicate invasive disease.² Primary EMPD is characterized by pagetoid cells with abundant pale cytoplasm proliferating in a single-cell or nested pattern within the epidermis or dermis in invasive disease and often is accompanied by dermal lymphocytic inflammation.¹ Immunohistochemistry demonstrates positive staining for CEA, CK7, and CK8, with negative staining for indicators of secondary EMPD including CK20 and CDX2.^1,2

As part of the workup, it is critical to distinguish between primary disease and secondary EMPD.¹ Beyond skin and clinical lymph node examination, additional workup should be based on age-appropriate and location-directed malignant neoplasm screenings, including colonoscopy, cystoscopy, prostate examination, mammography, and Papanicolaou test. Advanced imaging such as CT, positron emission tomography, or magnetic resonance imaging can be used to assess for metastatic disease if internal malignant neoplasms are present on initial screening or clinical lymphadenopathy is identified.² Additionally, it can be helpful in the evaluation for nodal disease in cases of invasive EMPD.

The likelihood of associated underlying carcinomas varies depending on the site of involvement.^38,39 For example, vulvar involvement constitutes approximately 65% of EMPD cases, with 11% to 20% of cases being associated with underlying gastrointestinal or genitourinary carcinomas. Involvement of the male genitalia, as in our 2 patients, is rare, accounting for approximately 14% of cases, 11% of which are associated with prostate, testicular, and bladder carcinoma. Perianal involvement comprises 20% of EMPD cases and has the greatest risk for underlying malignancy with an incidence of 33% to 86%, the majority of which are rectal or tubo-ovarian cancers.^38,39 Consideration of the frequency and types of underlying carcinoma of respective sites of involvement can be helpful when ruling out secondary EMPD.

In both of our patients, palpable lymphadenopathy at the time of original diagnosis and histologic invasive disease on initial biopsy warranted thorough imaging and laboratory workup; there was no evidence of primary malignancy. Given the absence of an underlying carcinoma, both patients were classified as having metastatic primary EMPD.

Assessment of lymphadenopathy is an essential aspect of disease workup, as it is associated with a statistically higher rate of lymph node metastases. A study by Fujisawa et al²⁰ demonstrated that 80% of patients with lymphadenopathy had regional metastases compared to only 15% of patients without clinical lymphadenopathy. The presence of invasive disease also has been shown to correspond with lymph node metastases.⁴⁰ Ogata et al⁴⁰ showed that 0% of cases with in situ EMPD had a positive sentinel lymph node biopsy (SLNB) compared to 4% and 43% in cases that showed evidence of microinvasion and dermal invasion, respectively. Lymph node metastases are associated with poor prognosis, with increasingly worse prognosis when there are multiple lymph nodes affected.⁴¹ In our case series, patient 1 had lymphadenopathy and both patients had invasive EMPD; they both later developed metastases and died.

Lymphadenopathy should be further investigated with imaging and biopsy or fine-needle aspiration.⁴² Recent expert consensus guidelines recommended this method of investigation over routine use of SLNB, as there is no evidence that a positive SLNB affects treatment that changes disease-specific survival.²

Treatment of EMPD—Surgical excision of the primary lesion is the first-line treatment of EMPD,^1,2 which can be performed by wide local excision; however, studies have demonstrated higher recurrence-free survival with margin-controlled surgery (complete circumferential peripheral and deep margin assessment) or Mohs micrographic surgery (MMS), especially with CK7 immunostaining.^2,37,43 The literature on MMS of invasive EMPD is sparse, accounting for 57 patients.^25,37,44 Other reports describe management with surgical excision, wide local excision, regional resection, or vulvectomy, in addition to lymph node dissection, radiation therapy (RT), and/or chemotherapy.^{1-36,39,43-46} Despite the improved outcomes with MMS, the predominance of other surgical approaches in our search suggests that MMS may be currently underutilized for the treatment of invasive or locally advanced EMPD.

Among patients with unresectable disease or distant metastases, management includes RT with curative intent, chemotherapy, or a combination of both.^1,2 In our review, 267 cases were treated using RT and 77 with chemotherapy. Radiation therapy is an effective therapeutic option with a reported response rate of 62% to 100% and can be employed as either primary or adjuvant treatment.³ For patients with lymph node metastasis the combination of RT and lymph node dissection has been shown to have improved outcomes compared to lymph node dissection alone, with 1 study showing a 5-year survival of 75% for patients who received adjuvant RT compared to 0% for lymph node dissection alone.⁴⁵

There are currently no consensus guidelines on the best chemotherapeutic regimen for metastatic EMPD. Several regimens have been reported, including docetaxel monotherapy; low-dose 5-fluorouracil and cisplatin; combination chemotherapy FECOM (5-fluorouracil, epirubicin, carboplatin, vincristine, mitomycin); or combination therapy with cisplatin, epirubicin, and paclitaxel.¹

Prognosis of Metastatic EMPD—Because invasive and metastatic EMPD is rare, its natural history is hard to predict. Poor prognosis is associated with nodule formation, tumor thickness, perianal or vaginal involvement, lymphovascular invasion, nodal metastasis, and distant metastasis. The 5-year survival for metastatic EMPD has been reported to be less than 10%.⁴⁶ Our cases underscore the poor prognostic risk associated with metastatic EMPD.

For all cases of EMPD, close follow-up is warranted. Guidelines recommend physical examination with lymph node assessment every 3 to 6 months for 3 years and every 6 to 12 months for the subsequent 5 years.² Specific recommendations for follow-up in invasive disease have not yet been described, though the 20% probability of developing an internal malignancy within 5 years after diagnosis and poor prognostic outcomes associated with invasive and metastatic disease support the need for close monitoring.²

Conclusion

Although in situ EMPD often is a slow-growing tumor with good prognosis, invasive disease has high potential to behave aggressively with high morbidity and mortality. Increased awareness and prompt identification of invasive EMPD, expedited comprehensive workup, and early multidisciplinary management might impact patient outcomes.

Acknowledgment—The authors would like to thank Ellen Aaronson, MLIS, AHIP (Mayo Clinic Libraries [Jacksonville, FL]), for creating and conducting the narrative literature search in the MEDLINE database.

THE DIAGNOSIS: Coexisting Squamous Cell Carcinoma and Basal Cell Carcinoma

Dermoscopy of the plaque showed central ulceration with blood spots surrounded by branched linear vessels, which was suggestive of squamous cell carcinoma (SCC)(Figure 1A). The nodule showed shiny, white-red, structureless areas with small gray spots, bright white crystalline streaks, and short fine telangiectasias suggestive of basal cell carcinoma (BCC)(Figure 1B). Histopathology showed that the plaque had irregular nests, cords, and sheets of neoplastic keratinocytes invading the dermis (Figure 2A) and the nodule had discrete nests of basaloid cells with peripheral palisading in the dermis (Figure 2B), which confirmed the diagnosis of coexisting SCC and BCC. The patient underwent surgical excision of the lesions, which achieved clear margins. At the 2-year follow-up, there was no sign of recurrence.

Squamous cell carcinoma is the second most frequent cancer in humans. Older patients are more susceptible due to chronic UV exposure.¹ Basal cell carcinoma is the most common human cancer worldwide.² These skin cancers have different clinical manifestations, pathologic features, treatment methods, and prognoses. The coexistence of 2 types of skin cancer presents a diagnostic challenge. Possible causes of this phenomenon are not clear. It may simply be a coincidence since the lesions typically occur in sun-exposed areas such as the nose, which may be affected by photodamage.³ According to the field cancerization theory, chronically sun-exposed areas are at higher risk for development of coexisting skin cancers.⁴ A more interesting explanation is the interaction theory, which suggests that one tumor produces epidermal or stromal changes that induce the formation of a second independent tumor via the paracrine effect (ie, growth mediators from nearby cells).⁴

Dermoscopy is an important noninvasive diagnostic tool for the evaluation of skin cancer, particularly early detection. Dermoscopic findings of blood vessels, ulcers, the fiber sign, blood spots, white structureless areas, keratin, and centered vessels indicate a diagnosis of SCC.⁵ In contrast, common dermoscopic findings for BCC include arborizing vessels, ulceration, shiny white structures, and blue-gray ovoid nests or globules.⁶

Irritated seborrheic keratosis is an inflammatory variant of seborrheic keratosis, which often is challenging to identify clinically due to its similar features with SCC; however, SCC is more likely to demonstrate dotted or branched vessels, white structureless areas, white circles around follicles, irregular or peripheral vessel patterns, and central scales on dermoscopy. In contrast, irritated seborrheic keratosis is more likely to have hairpin vessels, regular vessel patterns, and white halos around vessels, which may aid in the differentiation between the two entities.⁶

Due to the higher sensitivity of dermoscopy for detecting pigmented BCC compared to nonpigmented BCC, it holds substantial diagnostic value in Asian populations, in whom pigmented BCC is the most common subtype.^6,8 However, the lack of pigmentation in the nodule in our case posed a diagnostic challenge, as the diagnosis of BCC had to rely on subtle vascular and shiny white structures rather than more obvious pigment clues. This absence of pigment, however, also helped rule out pigmented BCC as a diagnosis for the nodule. Short fine telangiectasias is the second most common vascular pattern in BCC, and bright white structures are highly suggestive of nonpigmented BCC.⁶ Therefore, dermoscopic findings of bright-white structures with fine telangiectasias should be alerted to the possibility of nonpigmented BCC.

Basosquamous carcinoma has clinical and dermoscopic features between SCC and BCC, and the presence of dermatoscopic features from both BCC and SCC should raise suspicion, but the diagnosis is particularly challenging because its presentation is nonspecific.⁹ We need to be vigilant about the possibility of coexistence of 2 types of skin cancer, and that regular physical examination and dermatoscopy are very important for early detection and diagnosis.

THE DIAGNOSIS: Coexisting Squamous Cell Carcinoma and Basal Cell Carcinoma

Dermoscopy of the plaque showed central ulceration with blood spots surrounded by branched linear vessels, which was suggestive of squamous cell carcinoma (SCC)(Figure 1A). The nodule showed shiny, white-red, structureless areas with small gray spots, bright white crystalline streaks, and short fine telangiectasias suggestive of basal cell carcinoma (BCC)(Figure 1B). Histopathology showed that the plaque had irregular nests, cords, and sheets of neoplastic keratinocytes invading the dermis (Figure 2A) and the nodule had discrete nests of basaloid cells with peripheral palisading in the dermis (Figure 2B), which confirmed the diagnosis of coexisting SCC and BCC. The patient underwent surgical excision of the lesions, which achieved clear margins. At the 2-year follow-up, there was no sign of recurrence.

Squamous cell carcinoma is the second most frequent cancer in humans. Older patients are more susceptible due to chronic UV exposure.¹ Basal cell carcinoma is the most common human cancer worldwide.² These skin cancers have different clinical manifestations, pathologic features, treatment methods, and prognoses. The coexistence of 2 types of skin cancer presents a diagnostic challenge. Possible causes of this phenomenon are not clear. It may simply be a coincidence since the lesions typically occur in sun-exposed areas such as the nose, which may be affected by photodamage.³ According to the field cancerization theory, chronically sun-exposed areas are at higher risk for development of coexisting skin cancers.⁴ A more interesting explanation is the interaction theory, which suggests that one tumor produces epidermal or stromal changes that induce the formation of a second independent tumor via the paracrine effect (ie, growth mediators from nearby cells).⁴

Dermoscopy is an important noninvasive diagnostic tool for the evaluation of skin cancer, particularly early detection. Dermoscopic findings of blood vessels, ulcers, the fiber sign, blood spots, white structureless areas, keratin, and centered vessels indicate a diagnosis of SCC.⁵ In contrast, common dermoscopic findings for BCC include arborizing vessels, ulceration, shiny white structures, and blue-gray ovoid nests or globules.⁶

Irritated seborrheic keratosis is an inflammatory variant of seborrheic keratosis, which often is challenging to identify clinically due to its similar features with SCC; however, SCC is more likely to demonstrate dotted or branched vessels, white structureless areas, white circles around follicles, irregular or peripheral vessel patterns, and central scales on dermoscopy. In contrast, irritated seborrheic keratosis is more likely to have hairpin vessels, regular vessel patterns, and white halos around vessels, which may aid in the differentiation between the two entities.⁶

Due to the higher sensitivity of dermoscopy for detecting pigmented BCC compared to nonpigmented BCC, it holds substantial diagnostic value in Asian populations, in whom pigmented BCC is the most common subtype.^6,8 However, the lack of pigmentation in the nodule in our case posed a diagnostic challenge, as the diagnosis of BCC had to rely on subtle vascular and shiny white structures rather than more obvious pigment clues. This absence of pigment, however, also helped rule out pigmented BCC as a diagnosis for the nodule. Short fine telangiectasias is the second most common vascular pattern in BCC, and bright white structures are highly suggestive of nonpigmented BCC.⁶ Therefore, dermoscopic findings of bright-white structures with fine telangiectasias should be alerted to the possibility of nonpigmented BCC.

Basosquamous carcinoma has clinical and dermoscopic features between SCC and BCC, and the presence of dermatoscopic features from both BCC and SCC should raise suspicion, but the diagnosis is particularly challenging because its presentation is nonspecific.⁹ We need to be vigilant about the possibility of coexistence of 2 types of skin cancer, and that regular physical examination and dermatoscopy are very important for early detection and diagnosis.

THE DIAGNOSIS: Coexisting Squamous Cell Carcinoma and Basal Cell Carcinoma

Dermoscopy of the plaque showed central ulceration with blood spots surrounded by branched linear vessels, which was suggestive of squamous cell carcinoma (SCC)(Figure 1A). The nodule showed shiny, white-red, structureless areas with small gray spots, bright white crystalline streaks, and short fine telangiectasias suggestive of basal cell carcinoma (BCC)(Figure 1B). Histopathology showed that the plaque had irregular nests, cords, and sheets of neoplastic keratinocytes invading the dermis (Figure 2A) and the nodule had discrete nests of basaloid cells with peripheral palisading in the dermis (Figure 2B), which confirmed the diagnosis of coexisting SCC and BCC. The patient underwent surgical excision of the lesions, which achieved clear margins. At the 2-year follow-up, there was no sign of recurrence.

Squamous cell carcinoma is the second most frequent cancer in humans. Older patients are more susceptible due to chronic UV exposure.¹ Basal cell carcinoma is the most common human cancer worldwide.² These skin cancers have different clinical manifestations, pathologic features, treatment methods, and prognoses. The coexistence of 2 types of skin cancer presents a diagnostic challenge. Possible causes of this phenomenon are not clear. It may simply be a coincidence since the lesions typically occur in sun-exposed areas such as the nose, which may be affected by photodamage.³ According to the field cancerization theory, chronically sun-exposed areas are at higher risk for development of coexisting skin cancers.⁴ A more interesting explanation is the interaction theory, which suggests that one tumor produces epidermal or stromal changes that induce the formation of a second independent tumor via the paracrine effect (ie, growth mediators from nearby cells).⁴

Dermoscopy is an important noninvasive diagnostic tool for the evaluation of skin cancer, particularly early detection. Dermoscopic findings of blood vessels, ulcers, the fiber sign, blood spots, white structureless areas, keratin, and centered vessels indicate a diagnosis of SCC.⁵ In contrast, common dermoscopic findings for BCC include arborizing vessels, ulceration, shiny white structures, and blue-gray ovoid nests or globules.⁶

Irritated seborrheic keratosis is an inflammatory variant of seborrheic keratosis, which often is challenging to identify clinically due to its similar features with SCC; however, SCC is more likely to demonstrate dotted or branched vessels, white structureless areas, white circles around follicles, irregular or peripheral vessel patterns, and central scales on dermoscopy. In contrast, irritated seborrheic keratosis is more likely to have hairpin vessels, regular vessel patterns, and white halos around vessels, which may aid in the differentiation between the two entities.⁶

Due to the higher sensitivity of dermoscopy for detecting pigmented BCC compared to nonpigmented BCC, it holds substantial diagnostic value in Asian populations, in whom pigmented BCC is the most common subtype.^6,8 However, the lack of pigmentation in the nodule in our case posed a diagnostic challenge, as the diagnosis of BCC had to rely on subtle vascular and shiny white structures rather than more obvious pigment clues. This absence of pigment, however, also helped rule out pigmented BCC as a diagnosis for the nodule. Short fine telangiectasias is the second most common vascular pattern in BCC, and bright white structures are highly suggestive of nonpigmented BCC.⁶ Therefore, dermoscopic findings of bright-white structures with fine telangiectasias should be alerted to the possibility of nonpigmented BCC.

Basosquamous carcinoma has clinical and dermoscopic features between SCC and BCC, and the presence of dermatoscopic features from both BCC and SCC should raise suspicion, but the diagnosis is particularly challenging because its presentation is nonspecific.⁹ We need to be vigilant about the possibility of coexistence of 2 types of skin cancer, and that regular physical examination and dermatoscopy are very important for early detection and diagnosis.

TOPLINE:

In a review of physician-related malpractice cases from 1930 to 2025, melanoma was the most frequently litigated skin cancer, and failure or delay in diagnosis was the most common allegation, with documented death in nearly one third of cases.

METHODOLOGY:

Researchers conducted a review of physician-related medicolegal cases involving skin cancer using the LexisNexis legal database and identified 188 unique cases from 1930 through May 2025.

Cases were included if physicians were named as defendants and the litigation centered on diagnosis or management of a cutaneous malignancy.

Study outcomes examined case characteristics including cancer type, practice setting, defendant specialty, primary allegations, clinical outcomes, and case verdicts across the US.

TAKEAWAY:

Melanoma accounted for 49.5% of litigated cases, followed by squamous cell carcinoma (21.6%), basal cell carcinoma (14.2%), unspecified skin cancer (11.6%), and other rare tumors (3.1%). Death was reported in 29.8% of cases and metastatic disease in 39.9%.

Failure or delay in diagnosis was the leading allegation (38.1%), followed by treatment or management errors (24.2%), misdiagnosis (11.4%), “deliberate indifference” (8.3%), inadequate informed consent (7.5%), and pathology-related errors (7.2%).

Family physicians were the most common defendants (27.5%), followed by dermatologists, including Mohs surgeons (20.1%), and pathologists or dermatopathologists (14.4%), followed by general or plastic surgeons (7.9%), and internists (4.4%). Most cases originated in private practices (59.7%), and New York (16.0%) and California (13.3%) were the states with the most cases.

Among 109 closed cases, 5.5% resulted in plaintiff verdicts, whereas defense verdicts predominated in 55.0%. Plaintiff awards ranged from $10,000 to $4.25 million.

IN PRACTICE:

“This comprehensive review demonstrates that melanoma is the most frequently litigated skin cancer, particularly in cases involving metastatic disease or death, and that family physicians are the most commonly named defendants overall,” the authors wrote. “By examining both allegations and outcomes,” they added, “this analysis provides a pragmatic assessment of real-world litigation exposure and the clinical scenarios that expose physicians to legal proceedings, financial cost, reputational harm, and psychological burden, regardless of case disposition.”

SOURCE:

The study was led by Ghassan Barnawi, MD, Division of Dermatology, McGill University in Montreal, Quebec, Canada, and was published online on February 20, 2026, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The study relied on published court decisions, which likely underestimated malpractice burden by excluding settlements and unreported claims.

DISCLOSURES:

The study did not receive any funding. The authors reported having no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

The study had no commercial funding. The authors had no relevant disclosures.

A version of this article first appeared on Medscape.com

TOPLINE:

In a review of physician-related malpractice cases from 1930 to 2025, melanoma was the most frequently litigated skin cancer, and failure or delay in diagnosis was the most common allegation, with documented death in nearly one third of cases.

METHODOLOGY:

Researchers conducted a review of physician-related medicolegal cases involving skin cancer using the LexisNexis legal database and identified 188 unique cases from 1930 through May 2025.

Cases were included if physicians were named as defendants and the litigation centered on diagnosis or management of a cutaneous malignancy.

Study outcomes examined case characteristics including cancer type, practice setting, defendant specialty, primary allegations, clinical outcomes, and case verdicts across the US.

TAKEAWAY:

Melanoma accounted for 49.5% of litigated cases, followed by squamous cell carcinoma (21.6%), basal cell carcinoma (14.2%), unspecified skin cancer (11.6%), and other rare tumors (3.1%). Death was reported in 29.8% of cases and metastatic disease in 39.9%.

Failure or delay in diagnosis was the leading allegation (38.1%), followed by treatment or management errors (24.2%), misdiagnosis (11.4%), “deliberate indifference” (8.3%), inadequate informed consent (7.5%), and pathology-related errors (7.2%).

Family physicians were the most common defendants (27.5%), followed by dermatologists, including Mohs surgeons (20.1%), and pathologists or dermatopathologists (14.4%), followed by general or plastic surgeons (7.9%), and internists (4.4%). Most cases originated in private practices (59.7%), and New York (16.0%) and California (13.3%) were the states with the most cases.

Among 109 closed cases, 5.5% resulted in plaintiff verdicts, whereas defense verdicts predominated in 55.0%. Plaintiff awards ranged from $10,000 to $4.25 million.

IN PRACTICE:

“This comprehensive review demonstrates that melanoma is the most frequently litigated skin cancer, particularly in cases involving metastatic disease or death, and that family physicians are the most commonly named defendants overall,” the authors wrote. “By examining both allegations and outcomes,” they added, “this analysis provides a pragmatic assessment of real-world litigation exposure and the clinical scenarios that expose physicians to legal proceedings, financial cost, reputational harm, and psychological burden, regardless of case disposition.”

SOURCE:

The study was led by Ghassan Barnawi, MD, Division of Dermatology, McGill University in Montreal, Quebec, Canada, and was published online on February 20, 2026, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The study relied on published court decisions, which likely underestimated malpractice burden by excluding settlements and unreported claims.

DISCLOSURES:

The study did not receive any funding. The authors reported having no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

The study had no commercial funding. The authors had no relevant disclosures.

A version of this article first appeared on Medscape.com

TOPLINE:

In a review of physician-related malpractice cases from 1930 to 2025, melanoma was the most frequently litigated skin cancer, and failure or delay in diagnosis was the most common allegation, with documented death in nearly one third of cases.

METHODOLOGY:

Researchers conducted a review of physician-related medicolegal cases involving skin cancer using the LexisNexis legal database and identified 188 unique cases from 1930 through May 2025.

Cases were included if physicians were named as defendants and the litigation centered on diagnosis or management of a cutaneous malignancy.

Study outcomes examined case characteristics including cancer type, practice setting, defendant specialty, primary allegations, clinical outcomes, and case verdicts across the US.

TAKEAWAY:

Melanoma accounted for 49.5% of litigated cases, followed by squamous cell carcinoma (21.6%), basal cell carcinoma (14.2%), unspecified skin cancer (11.6%), and other rare tumors (3.1%). Death was reported in 29.8% of cases and metastatic disease in 39.9%.

Failure or delay in diagnosis was the leading allegation (38.1%), followed by treatment or management errors (24.2%), misdiagnosis (11.4%), “deliberate indifference” (8.3%), inadequate informed consent (7.5%), and pathology-related errors (7.2%).

Family physicians were the most common defendants (27.5%), followed by dermatologists, including Mohs surgeons (20.1%), and pathologists or dermatopathologists (14.4%), followed by general or plastic surgeons (7.9%), and internists (4.4%). Most cases originated in private practices (59.7%), and New York (16.0%) and California (13.3%) were the states with the most cases.

Among 109 closed cases, 5.5% resulted in plaintiff verdicts, whereas defense verdicts predominated in 55.0%. Plaintiff awards ranged from $10,000 to $4.25 million.

IN PRACTICE:

“This comprehensive review demonstrates that melanoma is the most frequently litigated skin cancer, particularly in cases involving metastatic disease or death, and that family physicians are the most commonly named defendants overall,” the authors wrote. “By examining both allegations and outcomes,” they added, “this analysis provides a pragmatic assessment of real-world litigation exposure and the clinical scenarios that expose physicians to legal proceedings, financial cost, reputational harm, and psychological burden, regardless of case disposition.”

SOURCE:

The study was led by Ghassan Barnawi, MD, Division of Dermatology, McGill University in Montreal, Quebec, Canada, and was published online on February 20, 2026, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The study relied on published court decisions, which likely underestimated malpractice burden by excluding settlements and unreported claims.

DISCLOSURES:

The study did not receive any funding. The authors reported having no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

The study had no commercial funding. The authors had no relevant disclosures.

A version of this article first appeared on Medscape.com

To the Editor:

Primary cutaneous B-cell lymphomas (pcBCLs) can clinically mimic basal cell carcinomas (BCCs); however, histopathologic examination typically demonstrates features of lymphoma without evidence of an epithelial tumor. We present the case of a patient who demonstrated histologic features of both pcBCL and BCC in the same lesion, which was discovered during Mohs micrographic surgery.

An 84-year-old man presented for Mohs surgery for a biopsy-proven nodular and infiltrative BCC on the right superior helix of the ear of 1 year’s duration. Physical examination of the ear revealed a 1.0×1.3–cm ulcerated indurated plaque with rolled borders and a central hyperkeratotic crust (Figure 1). Frozen sections from the first Mohs stage demonstrated residual superficial, infiltrative, and basosquamous BCC (Figure 2). In addition, there was a brisk inflammatory infiltrate throughout the deep margins. The second stage showed no residual BCC, but there still was a brisk atypical lymphocytic infiltrate, with some areas showing lymphocytes in a linear cordlike distribution (Figure 3). Permanent sections demonstrated infiltration of small to medium lymphoid cells. Immunohistochemistry stains were positive for CD20 and BCL2 and negative for CD5, CD10, BCL6, and CD43; a low Ki-67 proliferation fraction also was observed. B-cell clonality studies and polymerase chain reaction demonstrated rearrangements of the IgH and IgK genes, consistent with primary cutaneous marginal zone lymphoma (pcMZL). Positron emission tomography showed no spread of malignancy; therefore, medical oncology recommended observation and close monitoring.

Primary cutaneous B-cell lymphoma accounts for approximately 25% of all cutaneous lymphomas.¹ Three main cutaneous subtypes exist: pcMZL; primary cutaneous follicular center lymphoma; and primary cutaneous diffuse large B-cell lymphoma, leg type. The second most common type of cutaneous lymphoma, pcMZL, accounts for 25% of cases of pcBCL.¹ Primary cutaneous follicular center lymphoma makes up 60% of cutaneous lymphomas, and the remainder are primary cutaneous diffuse large B-cell lymphoma, leg type. All share a notable male predominance and onset most commonly in the sixth through eighth decades of life, although they also can occur in younger patients.¹

Histologically, pcMZL has 2 distinct subtypes: one resembling mucosal-associated lymphoid tissue lymphomas and a more clinically aggressive subtype with heavy chain class switching, although intermediate forms also exist. Both are characterized by diffuse and/or nodular infiltrates in the subcutis and dermis with sparing of the epidermis. Often, these infiltrates are more prominent in the deeper sections examined, and occasionally they may be accompanied by germinal center follicles. Immunohistochemical stains are key in determining the pcBCL subtype. Primary cutaneous marginal zone lymphoma will most commonly show a BCL2+, BCL6–, CD20+, and CD10– immunophenotype, as in our case. If a majority of cells have undergone plasmacytoid differentiation, loss of CD20 can occur, but retention of other B-cell markers, such as CD79a and CD19, will be seen. Proliferation fraction via Ki-67 commonly is low, reflecting the indolence of this subtype of lymphoma.¹

Monoclonal rearrangement of immunoglobulins also can occur, with IgH rearrangements detected in 60% to 80% of cases of pcMZL. Translocations are not a reliable method of diagnosis for pcMZL but can be present in a variable manner, with t(14;18), t(3;14), and t(11;18) reported in a subset of cases.² Leukemic infiltrates encountered on frozen sections should prompt the Mohs surgeon to consider the possibility of a concomitant leukemia or lymphoma. In one study, 36% (20/55) of patients with chronic lymphocytic leukemia (CLL) were found to have predominantly leukemic B-cell infiltrates on frozen sections.³ Numerous reports also exist of asymptomatic patients being diagnosed with CLL due to leukemic infiltrates identified during Mohs surgery.^4,5 Patients with systemic hematologic malignancies, including CLL and non-Hodgkin lymphoma, also are known to be at an increased risk for skin cancers, including keratinocyte cancers, melanoma, and Merkel cell carcinoma. This can be attributed partially to immunosuppression, a well-known risk factor for development of cutaneous malignancies.⁵ Padgett et al⁵ speculated that local immune suppression due to underlying pcBCL and reaction of lymphocytes to tumor antigens could have played a role in the development of BCC at this site. If a leukemic infiltrate is demonstrated, the surgeon should consider sending tissue for permanent section and immunostaining. This can be helpful to determine if it is a reactive or neoplastic process and aid in characterizing the leukemic infiltrate if it is suspected to be neoplastic in nature.

There are numerous reports of pcBCL imitating the cutaneous findings of BCC clinically, but this is quite uncommon on histopathology. As in our case, findings of sheets of dense, monomorphic lymphocytes; inability to clear inflammation on deeper Mohs sections; presence of primordial follicles; and atypical cytology, including predominance of blastic forms, plasmacytoid cells, or cleaved lymphocytes, should give the clinician pause to consider further evaluation through permanent sections as well as genetic and immunoglobulin studies by a dermatopathologist. This case highlights the importance of further evaluation when an atypical finding is encountered during Mohs surgery.

To the Editor:

Primary cutaneous B-cell lymphomas (pcBCLs) can clinically mimic basal cell carcinomas (BCCs); however, histopathologic examination typically demonstrates features of lymphoma without evidence of an epithelial tumor. We present the case of a patient who demonstrated histologic features of both pcBCL and BCC in the same lesion, which was discovered during Mohs micrographic surgery.

An 84-year-old man presented for Mohs surgery for a biopsy-proven nodular and infiltrative BCC on the right superior helix of the ear of 1 year’s duration. Physical examination of the ear revealed a 1.0×1.3–cm ulcerated indurated plaque with rolled borders and a central hyperkeratotic crust (Figure 1). Frozen sections from the first Mohs stage demonstrated residual superficial, infiltrative, and basosquamous BCC (Figure 2). In addition, there was a brisk inflammatory infiltrate throughout the deep margins. The second stage showed no residual BCC, but there still was a brisk atypical lymphocytic infiltrate, with some areas showing lymphocytes in a linear cordlike distribution (Figure 3). Permanent sections demonstrated infiltration of small to medium lymphoid cells. Immunohistochemistry stains were positive for CD20 and BCL2 and negative for CD5, CD10, BCL6, and CD43; a low Ki-67 proliferation fraction also was observed. B-cell clonality studies and polymerase chain reaction demonstrated rearrangements of the IgH and IgK genes, consistent with primary cutaneous marginal zone lymphoma (pcMZL). Positron emission tomography showed no spread of malignancy; therefore, medical oncology recommended observation and close monitoring.

Primary cutaneous B-cell lymphoma accounts for approximately 25% of all cutaneous lymphomas.¹ Three main cutaneous subtypes exist: pcMZL; primary cutaneous follicular center lymphoma; and primary cutaneous diffuse large B-cell lymphoma, leg type. The second most common type of cutaneous lymphoma, pcMZL, accounts for 25% of cases of pcBCL.¹ Primary cutaneous follicular center lymphoma makes up 60% of cutaneous lymphomas, and the remainder are primary cutaneous diffuse large B-cell lymphoma, leg type. All share a notable male predominance and onset most commonly in the sixth through eighth decades of life, although they also can occur in younger patients.¹

Histologically, pcMZL has 2 distinct subtypes: one resembling mucosal-associated lymphoid tissue lymphomas and a more clinically aggressive subtype with heavy chain class switching, although intermediate forms also exist. Both are characterized by diffuse and/or nodular infiltrates in the subcutis and dermis with sparing of the epidermis. Often, these infiltrates are more prominent in the deeper sections examined, and occasionally they may be accompanied by germinal center follicles. Immunohistochemical stains are key in determining the pcBCL subtype. Primary cutaneous marginal zone lymphoma will most commonly show a BCL2+, BCL6–, CD20+, and CD10– immunophenotype, as in our case. If a majority of cells have undergone plasmacytoid differentiation, loss of CD20 can occur, but retention of other B-cell markers, such as CD79a and CD19, will be seen. Proliferation fraction via Ki-67 commonly is low, reflecting the indolence of this subtype of lymphoma.¹

Monoclonal rearrangement of immunoglobulins also can occur, with IgH rearrangements detected in 60% to 80% of cases of pcMZL. Translocations are not a reliable method of diagnosis for pcMZL but can be present in a variable manner, with t(14;18), t(3;14), and t(11;18) reported in a subset of cases.² Leukemic infiltrates encountered on frozen sections should prompt the Mohs surgeon to consider the possibility of a concomitant leukemia or lymphoma. In one study, 36% (20/55) of patients with chronic lymphocytic leukemia (CLL) were found to have predominantly leukemic B-cell infiltrates on frozen sections.³ Numerous reports also exist of asymptomatic patients being diagnosed with CLL due to leukemic infiltrates identified during Mohs surgery.^4,5 Patients with systemic hematologic malignancies, including CLL and non-Hodgkin lymphoma, also are known to be at an increased risk for skin cancers, including keratinocyte cancers, melanoma, and Merkel cell carcinoma. This can be attributed partially to immunosuppression, a well-known risk factor for development of cutaneous malignancies.⁵ Padgett et al⁵ speculated that local immune suppression due to underlying pcBCL and reaction of lymphocytes to tumor antigens could have played a role in the development of BCC at this site. If a leukemic infiltrate is demonstrated, the surgeon should consider sending tissue for permanent section and immunostaining. This can be helpful to determine if it is a reactive or neoplastic process and aid in characterizing the leukemic infiltrate if it is suspected to be neoplastic in nature.

There are numerous reports of pcBCL imitating the cutaneous findings of BCC clinically, but this is quite uncommon on histopathology. As in our case, findings of sheets of dense, monomorphic lymphocytes; inability to clear inflammation on deeper Mohs sections; presence of primordial follicles; and atypical cytology, including predominance of blastic forms, plasmacytoid cells, or cleaved lymphocytes, should give the clinician pause to consider further evaluation through permanent sections as well as genetic and immunoglobulin studies by a dermatopathologist. This case highlights the importance of further evaluation when an atypical finding is encountered during Mohs surgery.

To the Editor:

Primary cutaneous B-cell lymphomas (pcBCLs) can clinically mimic basal cell carcinomas (BCCs); however, histopathologic examination typically demonstrates features of lymphoma without evidence of an epithelial tumor. We present the case of a patient who demonstrated histologic features of both pcBCL and BCC in the same lesion, which was discovered during Mohs micrographic surgery.

An 84-year-old man presented for Mohs surgery for a biopsy-proven nodular and infiltrative BCC on the right superior helix of the ear of 1 year’s duration. Physical examination of the ear revealed a 1.0×1.3–cm ulcerated indurated plaque with rolled borders and a central hyperkeratotic crust (Figure 1). Frozen sections from the first Mohs stage demonstrated residual superficial, infiltrative, and basosquamous BCC (Figure 2). In addition, there was a brisk inflammatory infiltrate throughout the deep margins. The second stage showed no residual BCC, but there still was a brisk atypical lymphocytic infiltrate, with some areas showing lymphocytes in a linear cordlike distribution (Figure 3). Permanent sections demonstrated infiltration of small to medium lymphoid cells. Immunohistochemistry stains were positive for CD20 and BCL2 and negative for CD5, CD10, BCL6, and CD43; a low Ki-67 proliferation fraction also was observed. B-cell clonality studies and polymerase chain reaction demonstrated rearrangements of the IgH and IgK genes, consistent with primary cutaneous marginal zone lymphoma (pcMZL). Positron emission tomography showed no spread of malignancy; therefore, medical oncology recommended observation and close monitoring.

Primary cutaneous B-cell lymphoma accounts for approximately 25% of all cutaneous lymphomas.¹ Three main cutaneous subtypes exist: pcMZL; primary cutaneous follicular center lymphoma; and primary cutaneous diffuse large B-cell lymphoma, leg type. The second most common type of cutaneous lymphoma, pcMZL, accounts for 25% of cases of pcBCL.¹ Primary cutaneous follicular center lymphoma makes up 60% of cutaneous lymphomas, and the remainder are primary cutaneous diffuse large B-cell lymphoma, leg type. All share a notable male predominance and onset most commonly in the sixth through eighth decades of life, although they also can occur in younger patients.¹

Histologically, pcMZL has 2 distinct subtypes: one resembling mucosal-associated lymphoid tissue lymphomas and a more clinically aggressive subtype with heavy chain class switching, although intermediate forms also exist. Both are characterized by diffuse and/or nodular infiltrates in the subcutis and dermis with sparing of the epidermis. Often, these infiltrates are more prominent in the deeper sections examined, and occasionally they may be accompanied by germinal center follicles. Immunohistochemical stains are key in determining the pcBCL subtype. Primary cutaneous marginal zone lymphoma will most commonly show a BCL2+, BCL6–, CD20+, and CD10– immunophenotype, as in our case. If a majority of cells have undergone plasmacytoid differentiation, loss of CD20 can occur, but retention of other B-cell markers, such as CD79a and CD19, will be seen. Proliferation fraction via Ki-67 commonly is low, reflecting the indolence of this subtype of lymphoma.¹

Monoclonal rearrangement of immunoglobulins also can occur, with IgH rearrangements detected in 60% to 80% of cases of pcMZL. Translocations are not a reliable method of diagnosis for pcMZL but can be present in a variable manner, with t(14;18), t(3;14), and t(11;18) reported in a subset of cases.² Leukemic infiltrates encountered on frozen sections should prompt the Mohs surgeon to consider the possibility of a concomitant leukemia or lymphoma. In one study, 36% (20/55) of patients with chronic lymphocytic leukemia (CLL) were found to have predominantly leukemic B-cell infiltrates on frozen sections.³ Numerous reports also exist of asymptomatic patients being diagnosed with CLL due to leukemic infiltrates identified during Mohs surgery.^4,5 Patients with systemic hematologic malignancies, including CLL and non-Hodgkin lymphoma, also are known to be at an increased risk for skin cancers, including keratinocyte cancers, melanoma, and Merkel cell carcinoma. This can be attributed partially to immunosuppression, a well-known risk factor for development of cutaneous malignancies.⁵ Padgett et al⁵ speculated that local immune suppression due to underlying pcBCL and reaction of lymphocytes to tumor antigens could have played a role in the development of BCC at this site. If a leukemic infiltrate is demonstrated, the surgeon should consider sending tissue for permanent section and immunostaining. This can be helpful to determine if it is a reactive or neoplastic process and aid in characterizing the leukemic infiltrate if it is suspected to be neoplastic in nature.

There are numerous reports of pcBCL imitating the cutaneous findings of BCC clinically, but this is quite uncommon on histopathology. As in our case, findings of sheets of dense, monomorphic lymphocytes; inability to clear inflammation on deeper Mohs sections; presence of primordial follicles; and atypical cytology, including predominance of blastic forms, plasmacytoid cells, or cleaved lymphocytes, should give the clinician pause to consider further evaluation through permanent sections as well as genetic and immunoglobulin studies by a dermatopathologist. This case highlights the importance of further evaluation when an atypical finding is encountered during Mohs surgery.