Cutis

Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.¹ Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.² The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.³

Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.² Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.⁴ Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.⁵ We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.

Methods

We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.

Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.

Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.

Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.

Results

A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).

A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.

Comment

Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.^18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.²⁰ The advantages and limitations of TB staining of BCC are presented in Table 2.

Humphreys et al⁶ suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.⁶ The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.²¹ This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.⁶

The margin behavior of BCC stained with TB was further characterized by Goldberg et al,⁸ who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.⁸

The nasal surface has a predilection for BCC.²² The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.²² When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.¹⁰ None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.¹⁰

The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.⁹ Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.⁹

Bennett and Taher⁷ described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.⁷

Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues⁶ of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.⁶

Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.¹² All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.¹² The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.¹³ Drosou et al¹³ suggested that TB may enhance the diagnostic accuracy for perineural SCC.

Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.¹⁵

Although PCACC is rare, the recurrence rate is high.²³ Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.¹⁴

Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.¹⁷ In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.⁶

Conclusion

Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.

Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.¹ Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.² The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.³

Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.² Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.⁴ Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.⁵ We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.

Methods

We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.

Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.

Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.

Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.

Results

A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).

A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.

Comment

Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.^18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.²⁰ The advantages and limitations of TB staining of BCC are presented in Table 2.

Humphreys et al⁶ suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.⁶ The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.²¹ This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.⁶

The margin behavior of BCC stained with TB was further characterized by Goldberg et al,⁸ who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.⁸

The nasal surface has a predilection for BCC.²² The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.²² When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.¹⁰ None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.¹⁰

The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.⁹ Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.⁹

Bennett and Taher⁷ described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.⁷

Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues⁶ of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.⁶

Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.¹² All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.¹² The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.¹³ Drosou et al¹³ suggested that TB may enhance the diagnostic accuracy for perineural SCC.

Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.¹⁵

Although PCACC is rare, the recurrence rate is high.²³ Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.¹⁴

Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.¹⁷ In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.⁶

Conclusion

Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.

Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.¹ Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.² The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.³

Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.² Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.⁴ Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.⁵ We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.

Methods

We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.

Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.

Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.

Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.

Results

A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).

A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.

Comment

Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.^18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.²⁰ The advantages and limitations of TB staining of BCC are presented in Table 2.

Humphreys et al⁶ suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.⁶ The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.²¹ This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.⁶

The margin behavior of BCC stained with TB was further characterized by Goldberg et al,⁸ who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.⁸

The nasal surface has a predilection for BCC.²² The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.²² When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.¹⁰ None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.¹⁰

The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.⁹ Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.⁹

Bennett and Taher⁷ described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.⁷

Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues⁶ of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.⁶

Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.¹² All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.¹² The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.¹³ Drosou et al¹³ suggested that TB may enhance the diagnostic accuracy for perineural SCC.

Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.¹⁵

Although PCACC is rare, the recurrence rate is high.²³ Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.¹⁴

Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.¹⁷ In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.⁶

Conclusion

Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.

To the Editor:

Reactive angioendotheliomatosis (RAE) is a rare self-limited cutaneous vascular proliferation of endothelial cells within blood vessels that manifests clinically as infiltrated red-blue patches and plaques with purpura that can progress to occlude vascular lumina. The etiology of RAE is mostly idiopathic; however, the disorder typically occurs in association with a range of systemic diseases, including infection, cryoglobulinemia, leukemia, antiphospholipid syndrome, peripheral vascular disease, and arteriovenous fistula. Histopathologic examination of these lesions shows marked proliferation of endothelial cells, including occlusion of the lumen of blood vessels over wide areas.

After ruling out malignancy, treatment of RAE focuses on targeting the underlying cause or disease, if any is present; 75% of reported cases occur in association with systemic disease.¹ Onset can occur at any age without predilection for sex. Reactive angioendotheliomatosis commonly manifests on the extremities but may occur on the head and neck in rare instances.²

The rarity of the condition and its poorly defined clinical characteristics make it difficult to develop a treatment plan. There are no standardized treatment guidelines for the reactive form of angiomatosis. We report a case of RAE that developed 2 weeks after vaccination with the Ad26.COV2.S vaccine (Johnson & Johnson Innovative Medicine [formerly Janssen Pharmaceutical Companies of Johnson & Johnson]) that improved following 2 weeks of treatment with a topical corticosteroid and an oral antihistamine.

A 58-year-old man presented to an outpatient dermatology clinic with pruritus and occasional paresthesia associated with a rash over the left arm of 1 month’s duration. The patient suspected that the rash may have formed secondary to the bite of oak mites on the arms and chest while he was carrying milled wood. Further inquiry into the patient’s history revealed that he received the Ad26.COV2.S vaccine 2 weeks prior to the appearance of the rash. He denied mechanical trauma. His medical history included hypercholesterolemia and a mild COVID-19 infection 8 months prior to the appearance of the rash that did not require hospitalization. He denied fever or chills during the 2 weeks following vaccination. The pruritus was minimally relieved for short periods with over-the-counter calamine lotion. The patient’s medication regimen included daily pravastatin and loratadine at the time of the initial visit. He used acetaminophen as needed for knee pain.

Physical examination revealed palpable purpura in a dermatomal distribution with nonpitting edema over the left scapula (Figure 1A), left anterolateral shoulder, left lateral volar forearm, and thenar eminence of the left hand (Figure 1B). Notably, the entire right arm, conjunctivae, tongue, lips, and bilateral fingernails were clear. Three 4-mm punch biopsies were performed at the initial presentation: 1 perilesional biopsy for direct immunofluorescence testing and 2 lesional biopsies for routine histologic evaluation. An extensive serologic workup failed to reveal abnormalities. An activated partial thromboplastin time, dilute Russell viper venom time, serum protein electrophoresis, and levels of rheumatoid factor and angiotensin-converting enzyme were within reference range. Anticardiolipin antibodies IgA, IgM, and IgG were negative. A cryoglobulin test was negative.

Histopathology revealed a proliferation of irregularly shaped vascular spaces with plump endothelium in the papillary dermis (Figure 2). Scattered leukocyte common antigen-positive lymphocytes were noted within lesions. The epidermis appeared normal, without evidence of spongiosis or alteration of the stratum corneum. Immunohistochemical studies of the perilesional skin biopsy revealed positivity for CD31 and D2-40 (Figure 3). Specimens were negative for CD20 and human herpesvirus 8. Direct immunofluorescence of the perilesional biopsy was negative.

A diagnosis of RAE was made based on clinical and histologic findings. Treatment with triamcinolone ointment 0.1% twice daily and oral cetirizine 10 mg twice daily was initiated. Re-evaluation 2 weeks later revealed notable improvement in the affected areas, including decreased edema, improvement of the purpura, and absence of pruritus. The patient noted no further spread or blister formation while the active areas were being treated with the topical steroid. The treatment regimen was modified to triamcinolone ointment 0.1% once daily, and cetirizine was discontinued. At 3-month follow-up, active areas had completely resolved (Figure 4) and triamcinolone was discontinued. To date, the patient has not had recurrence of symptoms and remains healthy.

Gottron and Nikolowski³ reported the first case of RAE in an adult patient who presented with purpuric patches secondary to skin infarction. Current definitions use the umbrella term cutaneous reactive angiomatosis to cover 3 major subtypes: reactive angioendotheliomatosis, diffuse dermal angioendotheliomatosis, and acroangiodermatitis (pseudo-Kaposi sarcoma [KS]). The manifestation of these subgroups is clinically similar, and they must be differentiated through histologic evaluation.⁴

Reactive angioendotheliomatosis has an unknown pathogenesis and is poorly defined clinically. The exact pathophysiology is unknown but likely is linked to vaso-occlusion and hypoxia.¹ A PubMed search of articles indexed for MEDLINE, as well as a review of Science Direct, Google Scholar, and Cochrane Library, using the terms reactive angioendotheliomatosis, COVID, vaccine, Ad26.COV2.S, and RAE in any combination revealed no prior cases of RAE in association with Ad26.COV2.S vaccination.

By the late 1980s, systemic angioendotheliomatosis was segregated into 2 distinct entities: malignant and reactive.⁴ The differential diagnosis of malignant systemic angioendotheliomatosis includes KS and angiosarcoma; nonmalignant causes are the variants of cutaneous reactive angiomatosis. It is important to rule out KS because of its malignant and deceptive nature. It is unknown if KS originates in blood vessels or lymphatic endothelial cells; however, evidence is strongly in favor of blood vessel origin using CD31 and CD34 endothelial markers.⁵ CD34 positivity is more reliable than CD31 in diagnosing KS, but the absence of both markers does not offer enough evidence to rule out KS on its own.⁶

In our patient, histopathology revealed cells positive for CD31 and D2-40; the latter is a lymphatic endothelial cell marker that stains the endothelium of lymphatic channels but not blood vessels.⁷ Positive D2-40 can be indicative of KS and non-KS lesions, each with a distinct staining pattern. D2-40 staining on non-KS lesions is confined to lymphatic vessels, as it was in our patient; in contrast, spindle-shaped cells also will be stained in KS lesions.⁸

Another cell marker, CD20, is a B cell–specific protein that can be measured to help diagnose malignant diseases such as B-cell lymphoma and leukemia. Human herpesvirus 8 (also known as KS-associated herpesvirus) is the infectious cause of KS and traditionally has been detected using methods such as the polymerase chain reaction.^9,10

Most cases of RAE are idiopathic and occur in association with systemic disease, which was not the case in our patient. We speculated that his reaction was most likely triggered by vascular transfection of endothelial cells secondary to Ad26.COV2.S vaccination. Alternatively, vaccination may have caused vascular occlusion, though the lack of cyanosis, nail changes, and route of inoculant make this less likely.

All approved COVID-19 vaccines are designed solely for intramuscular injection. In comparison to other types of tissue, muscles have superior vascularity, allowing for enhanced mobilization of compounds, which results in faster systemic circulation.¹¹ Alternative methods of injection, including intravascular, subcutaneous, and intradermal, may lead to decreased efficacy or adverse events, or both.

Prior cases of RAE have been treated with laser therapy, topical or systemic corticosteroids, excisional removal, or topical β-blockers, such as timolol.¹² β-Blocking agents act on β-adrenergic receptors on endothelial cells to inhibit angiogenesis by reducing release of blood vessel growth-signaling molecules and triggering apoptosis. In this patient, topical steroids and oral antihistamines were sufficient treatment.

Vaccine-related adverse events have been reported but remain rare. The benefits of Ad26.COV2.S vaccination for protection against COVID-19 outweigh the extremely low risk for adverse events.¹³ For that reason, the Centers for Disease Control and Prevention recommends a booster for individuals who are eligible to maximize protection. Intramuscular injection of Ad26.COV2.S resulted in a lower incidence of moderate to severe COVID-19 cases in all age groups vs the placebo group. Hypersensitivity adverse events were reported in 0.4% of Ad26.COV2.S-vaccinated patients vs 0.4% of patients who received a placebo; the more common reactions were nonanaphylactic.¹³

There have been 12 reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, which sparked nationwide controversy over the safety of the Ad26.COV2.S vaccine.¹⁴ After further investigation into those reports, the US Food and Drug Administration and the Centers for Disease Control and Prevention concluded that the benefits of the Ad26.COV2.S vaccine outweigh the low risk for associated thrombosis.¹⁵

Although adverse reactions are rare, it is important that health care providers take proper safety measures before and while administering any COVID-19 vaccine. Patients should be screened for contraindications to the COVID-19 vaccine to mitigate adverse effects seen in the small percentage of patients who may need to take alternative precautions.

The broad tissue tropism and high transmissibility of SARS-CoV-2 are the main contributors to its infection having reached pandemic scale. The spike (S) protein on SARS-CoV-2 binds to ACE2, the most thoroughly studied SARS-CoV-2 receptor, which is found in a range of tissues, including arterial endothelial cells, leading to its transfection. Several studies have proposed that expression of the S protein causes endothelial dysfunction through cytokine release, activation of complement, and ultimately microvascular occlusion.¹⁶

Recent developments in the use of viral-like particles, such as vesicular stomatitis virus, may mitigate future cases of RAE that are associated with endothelial cell transfection. Vesicular stomatitis virus is a popular model virus for research applications due to its glycoprotein and matrix protein contributing to its broad tropism. Recent efforts to alter these proteins have successfully limited the broad tropism of vesicular stomatitis virus.¹⁷

The SARS-CoV-2 virus must be handled in a Biosafety Level 3 laboratory. Conversely, pseudoviruses can be handled in lower containment facilities due to their safe and efficacious nature, offering an avenue to expedite vaccine development against many viral outbreaks, including SARS-CoV-2.¹⁸

An increasing number of cutaneous manifestations have been associated with COVID-19 infection and vaccination. Eruptive pseudoangiomatosis, a rare self-limiting exanthem, has been reported in association with ­COVID-19 vaccination.¹⁹ Eruptive pseudoangiomatosis manifests as erythematous blanchable papules that resemble angiomas, typically in a widespread distribution. Eruptive pseudoangiomatosis has striking similarities to RAE histologically; both manifest as dilated dermal blood vessels with plump endothelial cells.

Our case is unique because of the vasculitic palpable nature of the lesions, which were localized to the left arm. Eruptive pseudoangiomatosis formation after COVID-19 infection or SARS-CoV-2 vaccination may suggest alteration of ACE2 by binding of S protein.²⁰ Such alteration of the ACE2 pathway would lead to inflammation of angiotensin II, causing proliferation of endothelial cells in the formation of angiomalike lesions. This hypothesis suggests a paraviral eruption secondary to an immunologic reaction, not a classical virtual eruption from direct contact of the virus on blood vessels. Although EPA and RAE are harmless and self-limiting, these reports will spread awareness of the increasing number of skin manifestations related to COVID-19 and SARS-CoV-2 virus vaccination.

Acknowledgment—Thoughtful insights and comments on this manuscript were provided by Christine J. Ko, MD (New Haven, Connecticut); Christine L. Egan, MD (Glen Mills, Pennsylvania); Howard A. Bueller, MD (Delray Beach, Florida); and Juan Pablo Robles, PhD (Juriquilla, Mexico).

To the Editor:

Reactive angioendotheliomatosis (RAE) is a rare self-limited cutaneous vascular proliferation of endothelial cells within blood vessels that manifests clinically as infiltrated red-blue patches and plaques with purpura that can progress to occlude vascular lumina. The etiology of RAE is mostly idiopathic; however, the disorder typically occurs in association with a range of systemic diseases, including infection, cryoglobulinemia, leukemia, antiphospholipid syndrome, peripheral vascular disease, and arteriovenous fistula. Histopathologic examination of these lesions shows marked proliferation of endothelial cells, including occlusion of the lumen of blood vessels over wide areas.

After ruling out malignancy, treatment of RAE focuses on targeting the underlying cause or disease, if any is present; 75% of reported cases occur in association with systemic disease.¹ Onset can occur at any age without predilection for sex. Reactive angioendotheliomatosis commonly manifests on the extremities but may occur on the head and neck in rare instances.²

The rarity of the condition and its poorly defined clinical characteristics make it difficult to develop a treatment plan. There are no standardized treatment guidelines for the reactive form of angiomatosis. We report a case of RAE that developed 2 weeks after vaccination with the Ad26.COV2.S vaccine (Johnson & Johnson Innovative Medicine [formerly Janssen Pharmaceutical Companies of Johnson & Johnson]) that improved following 2 weeks of treatment with a topical corticosteroid and an oral antihistamine.

A 58-year-old man presented to an outpatient dermatology clinic with pruritus and occasional paresthesia associated with a rash over the left arm of 1 month’s duration. The patient suspected that the rash may have formed secondary to the bite of oak mites on the arms and chest while he was carrying milled wood. Further inquiry into the patient’s history revealed that he received the Ad26.COV2.S vaccine 2 weeks prior to the appearance of the rash. He denied mechanical trauma. His medical history included hypercholesterolemia and a mild COVID-19 infection 8 months prior to the appearance of the rash that did not require hospitalization. He denied fever or chills during the 2 weeks following vaccination. The pruritus was minimally relieved for short periods with over-the-counter calamine lotion. The patient’s medication regimen included daily pravastatin and loratadine at the time of the initial visit. He used acetaminophen as needed for knee pain.

Physical examination revealed palpable purpura in a dermatomal distribution with nonpitting edema over the left scapula (Figure 1A), left anterolateral shoulder, left lateral volar forearm, and thenar eminence of the left hand (Figure 1B). Notably, the entire right arm, conjunctivae, tongue, lips, and bilateral fingernails were clear. Three 4-mm punch biopsies were performed at the initial presentation: 1 perilesional biopsy for direct immunofluorescence testing and 2 lesional biopsies for routine histologic evaluation. An extensive serologic workup failed to reveal abnormalities. An activated partial thromboplastin time, dilute Russell viper venom time, serum protein electrophoresis, and levels of rheumatoid factor and angiotensin-converting enzyme were within reference range. Anticardiolipin antibodies IgA, IgM, and IgG were negative. A cryoglobulin test was negative.

Histopathology revealed a proliferation of irregularly shaped vascular spaces with plump endothelium in the papillary dermis (Figure 2). Scattered leukocyte common antigen-positive lymphocytes were noted within lesions. The epidermis appeared normal, without evidence of spongiosis or alteration of the stratum corneum. Immunohistochemical studies of the perilesional skin biopsy revealed positivity for CD31 and D2-40 (Figure 3). Specimens were negative for CD20 and human herpesvirus 8. Direct immunofluorescence of the perilesional biopsy was negative.

A diagnosis of RAE was made based on clinical and histologic findings. Treatment with triamcinolone ointment 0.1% twice daily and oral cetirizine 10 mg twice daily was initiated. Re-evaluation 2 weeks later revealed notable improvement in the affected areas, including decreased edema, improvement of the purpura, and absence of pruritus. The patient noted no further spread or blister formation while the active areas were being treated with the topical steroid. The treatment regimen was modified to triamcinolone ointment 0.1% once daily, and cetirizine was discontinued. At 3-month follow-up, active areas had completely resolved (Figure 4) and triamcinolone was discontinued. To date, the patient has not had recurrence of symptoms and remains healthy.

Gottron and Nikolowski³ reported the first case of RAE in an adult patient who presented with purpuric patches secondary to skin infarction. Current definitions use the umbrella term cutaneous reactive angiomatosis to cover 3 major subtypes: reactive angioendotheliomatosis, diffuse dermal angioendotheliomatosis, and acroangiodermatitis (pseudo-Kaposi sarcoma [KS]). The manifestation of these subgroups is clinically similar, and they must be differentiated through histologic evaluation.⁴

Reactive angioendotheliomatosis has an unknown pathogenesis and is poorly defined clinically. The exact pathophysiology is unknown but likely is linked to vaso-occlusion and hypoxia.¹ A PubMed search of articles indexed for MEDLINE, as well as a review of Science Direct, Google Scholar, and Cochrane Library, using the terms reactive angioendotheliomatosis, COVID, vaccine, Ad26.COV2.S, and RAE in any combination revealed no prior cases of RAE in association with Ad26.COV2.S vaccination.

By the late 1980s, systemic angioendotheliomatosis was segregated into 2 distinct entities: malignant and reactive.⁴ The differential diagnosis of malignant systemic angioendotheliomatosis includes KS and angiosarcoma; nonmalignant causes are the variants of cutaneous reactive angiomatosis. It is important to rule out KS because of its malignant and deceptive nature. It is unknown if KS originates in blood vessels or lymphatic endothelial cells; however, evidence is strongly in favor of blood vessel origin using CD31 and CD34 endothelial markers.⁵ CD34 positivity is more reliable than CD31 in diagnosing KS, but the absence of both markers does not offer enough evidence to rule out KS on its own.⁶

In our patient, histopathology revealed cells positive for CD31 and D2-40; the latter is a lymphatic endothelial cell marker that stains the endothelium of lymphatic channels but not blood vessels.⁷ Positive D2-40 can be indicative of KS and non-KS lesions, each with a distinct staining pattern. D2-40 staining on non-KS lesions is confined to lymphatic vessels, as it was in our patient; in contrast, spindle-shaped cells also will be stained in KS lesions.⁸

Another cell marker, CD20, is a B cell–specific protein that can be measured to help diagnose malignant diseases such as B-cell lymphoma and leukemia. Human herpesvirus 8 (also known as KS-associated herpesvirus) is the infectious cause of KS and traditionally has been detected using methods such as the polymerase chain reaction.^9,10

Most cases of RAE are idiopathic and occur in association with systemic disease, which was not the case in our patient. We speculated that his reaction was most likely triggered by vascular transfection of endothelial cells secondary to Ad26.COV2.S vaccination. Alternatively, vaccination may have caused vascular occlusion, though the lack of cyanosis, nail changes, and route of inoculant make this less likely.

All approved COVID-19 vaccines are designed solely for intramuscular injection. In comparison to other types of tissue, muscles have superior vascularity, allowing for enhanced mobilization of compounds, which results in faster systemic circulation.¹¹ Alternative methods of injection, including intravascular, subcutaneous, and intradermal, may lead to decreased efficacy or adverse events, or both.

Prior cases of RAE have been treated with laser therapy, topical or systemic corticosteroids, excisional removal, or topical β-blockers, such as timolol.¹² β-Blocking agents act on β-adrenergic receptors on endothelial cells to inhibit angiogenesis by reducing release of blood vessel growth-signaling molecules and triggering apoptosis. In this patient, topical steroids and oral antihistamines were sufficient treatment.

Vaccine-related adverse events have been reported but remain rare. The benefits of Ad26.COV2.S vaccination for protection against COVID-19 outweigh the extremely low risk for adverse events.¹³ For that reason, the Centers for Disease Control and Prevention recommends a booster for individuals who are eligible to maximize protection. Intramuscular injection of Ad26.COV2.S resulted in a lower incidence of moderate to severe COVID-19 cases in all age groups vs the placebo group. Hypersensitivity adverse events were reported in 0.4% of Ad26.COV2.S-vaccinated patients vs 0.4% of patients who received a placebo; the more common reactions were nonanaphylactic.¹³

There have been 12 reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, which sparked nationwide controversy over the safety of the Ad26.COV2.S vaccine.¹⁴ After further investigation into those reports, the US Food and Drug Administration and the Centers for Disease Control and Prevention concluded that the benefits of the Ad26.COV2.S vaccine outweigh the low risk for associated thrombosis.¹⁵

Although adverse reactions are rare, it is important that health care providers take proper safety measures before and while administering any COVID-19 vaccine. Patients should be screened for contraindications to the COVID-19 vaccine to mitigate adverse effects seen in the small percentage of patients who may need to take alternative precautions.

The broad tissue tropism and high transmissibility of SARS-CoV-2 are the main contributors to its infection having reached pandemic scale. The spike (S) protein on SARS-CoV-2 binds to ACE2, the most thoroughly studied SARS-CoV-2 receptor, which is found in a range of tissues, including arterial endothelial cells, leading to its transfection. Several studies have proposed that expression of the S protein causes endothelial dysfunction through cytokine release, activation of complement, and ultimately microvascular occlusion.¹⁶

Recent developments in the use of viral-like particles, such as vesicular stomatitis virus, may mitigate future cases of RAE that are associated with endothelial cell transfection. Vesicular stomatitis virus is a popular model virus for research applications due to its glycoprotein and matrix protein contributing to its broad tropism. Recent efforts to alter these proteins have successfully limited the broad tropism of vesicular stomatitis virus.¹⁷

The SARS-CoV-2 virus must be handled in a Biosafety Level 3 laboratory. Conversely, pseudoviruses can be handled in lower containment facilities due to their safe and efficacious nature, offering an avenue to expedite vaccine development against many viral outbreaks, including SARS-CoV-2.¹⁸

An increasing number of cutaneous manifestations have been associated with COVID-19 infection and vaccination. Eruptive pseudoangiomatosis, a rare self-limiting exanthem, has been reported in association with ­COVID-19 vaccination.¹⁹ Eruptive pseudoangiomatosis manifests as erythematous blanchable papules that resemble angiomas, typically in a widespread distribution. Eruptive pseudoangiomatosis has striking similarities to RAE histologically; both manifest as dilated dermal blood vessels with plump endothelial cells.

Our case is unique because of the vasculitic palpable nature of the lesions, which were localized to the left arm. Eruptive pseudoangiomatosis formation after COVID-19 infection or SARS-CoV-2 vaccination may suggest alteration of ACE2 by binding of S protein.²⁰ Such alteration of the ACE2 pathway would lead to inflammation of angiotensin II, causing proliferation of endothelial cells in the formation of angiomalike lesions. This hypothesis suggests a paraviral eruption secondary to an immunologic reaction, not a classical virtual eruption from direct contact of the virus on blood vessels. Although EPA and RAE are harmless and self-limiting, these reports will spread awareness of the increasing number of skin manifestations related to COVID-19 and SARS-CoV-2 virus vaccination.

Acknowledgment—Thoughtful insights and comments on this manuscript were provided by Christine J. Ko, MD (New Haven, Connecticut); Christine L. Egan, MD (Glen Mills, Pennsylvania); Howard A. Bueller, MD (Delray Beach, Florida); and Juan Pablo Robles, PhD (Juriquilla, Mexico).

To the Editor:

Reactive angioendotheliomatosis (RAE) is a rare self-limited cutaneous vascular proliferation of endothelial cells within blood vessels that manifests clinically as infiltrated red-blue patches and plaques with purpura that can progress to occlude vascular lumina. The etiology of RAE is mostly idiopathic; however, the disorder typically occurs in association with a range of systemic diseases, including infection, cryoglobulinemia, leukemia, antiphospholipid syndrome, peripheral vascular disease, and arteriovenous fistula. Histopathologic examination of these lesions shows marked proliferation of endothelial cells, including occlusion of the lumen of blood vessels over wide areas.

After ruling out malignancy, treatment of RAE focuses on targeting the underlying cause or disease, if any is present; 75% of reported cases occur in association with systemic disease.¹ Onset can occur at any age without predilection for sex. Reactive angioendotheliomatosis commonly manifests on the extremities but may occur on the head and neck in rare instances.²

The rarity of the condition and its poorly defined clinical characteristics make it difficult to develop a treatment plan. There are no standardized treatment guidelines for the reactive form of angiomatosis. We report a case of RAE that developed 2 weeks after vaccination with the Ad26.COV2.S vaccine (Johnson & Johnson Innovative Medicine [formerly Janssen Pharmaceutical Companies of Johnson & Johnson]) that improved following 2 weeks of treatment with a topical corticosteroid and an oral antihistamine.

A 58-year-old man presented to an outpatient dermatology clinic with pruritus and occasional paresthesia associated with a rash over the left arm of 1 month’s duration. The patient suspected that the rash may have formed secondary to the bite of oak mites on the arms and chest while he was carrying milled wood. Further inquiry into the patient’s history revealed that he received the Ad26.COV2.S vaccine 2 weeks prior to the appearance of the rash. He denied mechanical trauma. His medical history included hypercholesterolemia and a mild COVID-19 infection 8 months prior to the appearance of the rash that did not require hospitalization. He denied fever or chills during the 2 weeks following vaccination. The pruritus was minimally relieved for short periods with over-the-counter calamine lotion. The patient’s medication regimen included daily pravastatin and loratadine at the time of the initial visit. He used acetaminophen as needed for knee pain.

Physical examination revealed palpable purpura in a dermatomal distribution with nonpitting edema over the left scapula (Figure 1A), left anterolateral shoulder, left lateral volar forearm, and thenar eminence of the left hand (Figure 1B). Notably, the entire right arm, conjunctivae, tongue, lips, and bilateral fingernails were clear. Three 4-mm punch biopsies were performed at the initial presentation: 1 perilesional biopsy for direct immunofluorescence testing and 2 lesional biopsies for routine histologic evaluation. An extensive serologic workup failed to reveal abnormalities. An activated partial thromboplastin time, dilute Russell viper venom time, serum protein electrophoresis, and levels of rheumatoid factor and angiotensin-converting enzyme were within reference range. Anticardiolipin antibodies IgA, IgM, and IgG were negative. A cryoglobulin test was negative.

Histopathology revealed a proliferation of irregularly shaped vascular spaces with plump endothelium in the papillary dermis (Figure 2). Scattered leukocyte common antigen-positive lymphocytes were noted within lesions. The epidermis appeared normal, without evidence of spongiosis or alteration of the stratum corneum. Immunohistochemical studies of the perilesional skin biopsy revealed positivity for CD31 and D2-40 (Figure 3). Specimens were negative for CD20 and human herpesvirus 8. Direct immunofluorescence of the perilesional biopsy was negative.

A diagnosis of RAE was made based on clinical and histologic findings. Treatment with triamcinolone ointment 0.1% twice daily and oral cetirizine 10 mg twice daily was initiated. Re-evaluation 2 weeks later revealed notable improvement in the affected areas, including decreased edema, improvement of the purpura, and absence of pruritus. The patient noted no further spread or blister formation while the active areas were being treated with the topical steroid. The treatment regimen was modified to triamcinolone ointment 0.1% once daily, and cetirizine was discontinued. At 3-month follow-up, active areas had completely resolved (Figure 4) and triamcinolone was discontinued. To date, the patient has not had recurrence of symptoms and remains healthy.

Gottron and Nikolowski³ reported the first case of RAE in an adult patient who presented with purpuric patches secondary to skin infarction. Current definitions use the umbrella term cutaneous reactive angiomatosis to cover 3 major subtypes: reactive angioendotheliomatosis, diffuse dermal angioendotheliomatosis, and acroangiodermatitis (pseudo-Kaposi sarcoma [KS]). The manifestation of these subgroups is clinically similar, and they must be differentiated through histologic evaluation.⁴

Reactive angioendotheliomatosis has an unknown pathogenesis and is poorly defined clinically. The exact pathophysiology is unknown but likely is linked to vaso-occlusion and hypoxia.¹ A PubMed search of articles indexed for MEDLINE, as well as a review of Science Direct, Google Scholar, and Cochrane Library, using the terms reactive angioendotheliomatosis, COVID, vaccine, Ad26.COV2.S, and RAE in any combination revealed no prior cases of RAE in association with Ad26.COV2.S vaccination.

By the late 1980s, systemic angioendotheliomatosis was segregated into 2 distinct entities: malignant and reactive.⁴ The differential diagnosis of malignant systemic angioendotheliomatosis includes KS and angiosarcoma; nonmalignant causes are the variants of cutaneous reactive angiomatosis. It is important to rule out KS because of its malignant and deceptive nature. It is unknown if KS originates in blood vessels or lymphatic endothelial cells; however, evidence is strongly in favor of blood vessel origin using CD31 and CD34 endothelial markers.⁵ CD34 positivity is more reliable than CD31 in diagnosing KS, but the absence of both markers does not offer enough evidence to rule out KS on its own.⁶

In our patient, histopathology revealed cells positive for CD31 and D2-40; the latter is a lymphatic endothelial cell marker that stains the endothelium of lymphatic channels but not blood vessels.⁷ Positive D2-40 can be indicative of KS and non-KS lesions, each with a distinct staining pattern. D2-40 staining on non-KS lesions is confined to lymphatic vessels, as it was in our patient; in contrast, spindle-shaped cells also will be stained in KS lesions.⁸

Another cell marker, CD20, is a B cell–specific protein that can be measured to help diagnose malignant diseases such as B-cell lymphoma and leukemia. Human herpesvirus 8 (also known as KS-associated herpesvirus) is the infectious cause of KS and traditionally has been detected using methods such as the polymerase chain reaction.^9,10

Most cases of RAE are idiopathic and occur in association with systemic disease, which was not the case in our patient. We speculated that his reaction was most likely triggered by vascular transfection of endothelial cells secondary to Ad26.COV2.S vaccination. Alternatively, vaccination may have caused vascular occlusion, though the lack of cyanosis, nail changes, and route of inoculant make this less likely.

All approved COVID-19 vaccines are designed solely for intramuscular injection. In comparison to other types of tissue, muscles have superior vascularity, allowing for enhanced mobilization of compounds, which results in faster systemic circulation.¹¹ Alternative methods of injection, including intravascular, subcutaneous, and intradermal, may lead to decreased efficacy or adverse events, or both.

Prior cases of RAE have been treated with laser therapy, topical or systemic corticosteroids, excisional removal, or topical β-blockers, such as timolol.¹² β-Blocking agents act on β-adrenergic receptors on endothelial cells to inhibit angiogenesis by reducing release of blood vessel growth-signaling molecules and triggering apoptosis. In this patient, topical steroids and oral antihistamines were sufficient treatment.

Vaccine-related adverse events have been reported but remain rare. The benefits of Ad26.COV2.S vaccination for protection against COVID-19 outweigh the extremely low risk for adverse events.¹³ For that reason, the Centers for Disease Control and Prevention recommends a booster for individuals who are eligible to maximize protection. Intramuscular injection of Ad26.COV2.S resulted in a lower incidence of moderate to severe COVID-19 cases in all age groups vs the placebo group. Hypersensitivity adverse events were reported in 0.4% of Ad26.COV2.S-vaccinated patients vs 0.4% of patients who received a placebo; the more common reactions were nonanaphylactic.¹³

There have been 12 reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, which sparked nationwide controversy over the safety of the Ad26.COV2.S vaccine.¹⁴ After further investigation into those reports, the US Food and Drug Administration and the Centers for Disease Control and Prevention concluded that the benefits of the Ad26.COV2.S vaccine outweigh the low risk for associated thrombosis.¹⁵

Although adverse reactions are rare, it is important that health care providers take proper safety measures before and while administering any COVID-19 vaccine. Patients should be screened for contraindications to the COVID-19 vaccine to mitigate adverse effects seen in the small percentage of patients who may need to take alternative precautions.

The broad tissue tropism and high transmissibility of SARS-CoV-2 are the main contributors to its infection having reached pandemic scale. The spike (S) protein on SARS-CoV-2 binds to ACE2, the most thoroughly studied SARS-CoV-2 receptor, which is found in a range of tissues, including arterial endothelial cells, leading to its transfection. Several studies have proposed that expression of the S protein causes endothelial dysfunction through cytokine release, activation of complement, and ultimately microvascular occlusion.¹⁶

Recent developments in the use of viral-like particles, such as vesicular stomatitis virus, may mitigate future cases of RAE that are associated with endothelial cell transfection. Vesicular stomatitis virus is a popular model virus for research applications due to its glycoprotein and matrix protein contributing to its broad tropism. Recent efforts to alter these proteins have successfully limited the broad tropism of vesicular stomatitis virus.¹⁷

The SARS-CoV-2 virus must be handled in a Biosafety Level 3 laboratory. Conversely, pseudoviruses can be handled in lower containment facilities due to their safe and efficacious nature, offering an avenue to expedite vaccine development against many viral outbreaks, including SARS-CoV-2.¹⁸

An increasing number of cutaneous manifestations have been associated with COVID-19 infection and vaccination. Eruptive pseudoangiomatosis, a rare self-limiting exanthem, has been reported in association with ­COVID-19 vaccination.¹⁹ Eruptive pseudoangiomatosis manifests as erythematous blanchable papules that resemble angiomas, typically in a widespread distribution. Eruptive pseudoangiomatosis has striking similarities to RAE histologically; both manifest as dilated dermal blood vessels with plump endothelial cells.

Our case is unique because of the vasculitic palpable nature of the lesions, which were localized to the left arm. Eruptive pseudoangiomatosis formation after COVID-19 infection or SARS-CoV-2 vaccination may suggest alteration of ACE2 by binding of S protein.²⁰ Such alteration of the ACE2 pathway would lead to inflammation of angiotensin II, causing proliferation of endothelial cells in the formation of angiomalike lesions. This hypothesis suggests a paraviral eruption secondary to an immunologic reaction, not a classical virtual eruption from direct contact of the virus on blood vessels. Although EPA and RAE are harmless and self-limiting, these reports will spread awareness of the increasing number of skin manifestations related to COVID-19 and SARS-CoV-2 virus vaccination.

Acknowledgment—Thoughtful insights and comments on this manuscript were provided by Christine J. Ko, MD (New Haven, Connecticut); Christine L. Egan, MD (Glen Mills, Pennsylvania); Howard A. Bueller, MD (Delray Beach, Florida); and Juan Pablo Robles, PhD (Juriquilla, Mexico).

The Diagnosis: Lichen Sclerosus

Histopathology revealed a thin epidermis with homogenization of the upper dermal collagen. By contrast, the lower dermis was sclerotic with patchy chronic dermal infiltrate (Figure). Ultimately, the patient’s clinical presentation and histopathologic findings led to a diagnosis of lichen sclerosus (LS).

Lichen sclerosus is a rare chronic inflammatory skin condition that typically is characterized by porcelainwhite atrophic plaques on the skin, most often involving the external female genitalia including the vulva and perianal area.¹ It is thought to be underdiagnosed and underreported.² Extragenital manifestations may occur, though some cases are characterized by concomitant genital involvement.^3,4 Our patient presented with palmoplantar distribution of plaques without genitalia involvement. Approximately 6% to 10% of patients with extragenital LS do not have genital involvement at the time of diagnosis.^3,5 Furthermore, LS involving the palms and soles is exceedingly rare.² Although extragenital LS may be asymptomatic, patients can experience debilitating pruritus; bullae with hemorrhage and erosion; plaque thickening with repeated excoriations; and painful fissuring, especially if lesions are in areas that are susceptible to friction or tension.^3,6 New lesions on previously unaffected skin also may develop secondary to trauma through the Koebner phenomenon.^1,6

Histologically, LS is characterized by epidermal hyperkeratosis accompanied by follicular plugging, epidermal atrophy with flattened rete ridges, vacuolization of the basal epidermis, marked edema in the superficial dermis (in early lesions) or homogenized collagen in the upper dermis (in established lesions), and a lymphohistiocytic infiltrate beneath the homogenized collagen. Although the pathogenesis of LS is unclear, purported etiologic factors from studies in genital disease include immune dysfunction, genetic predisposition, infection, and trauma.⁶ Lichen sclerosus is associated strongly with autoimmune diseases including alopecia areata, vitiligo, autoimmune thyroiditis, diabetes mellitus, and pernicious anemia, indicating its potential multifactorial etiology and linkage to T-lymphocyte dysfunction.¹ Early LS lesions often appear as flat-topped and slightly scaly, hypopigmented, white or mildly erythematous, polygonal papules that coalesce to form larger plaques with peripheral erythema. With time, the inflammation subsides, and lesions become porcelain-white with varying degrees of palpable sclerosis, resembling thin paperlike wrinkles indicative of epidermal atrophy.⁶

The differential diagnosis of LS includes lichen planus (LP), morphea, discoid lupus erythematosus (DLE), and vitiligo.³ Lesions of LP commonly are described as flat-topped, polygonal, pink-purple papules localized mostly along the volar wrists, shins, presacral area, and hands.⁷ Lichen planus is considered to be more pruritic³ than LS and can be further distinguished by biopsy through identifying a well-formed granular layer and numerous cytoid bodies. Unlike LS, LP is not characterized by basement membrane thickening or epidermal atrophy.⁸

Skin lesions seen in morphea may resemble the classic atrophic white lesions of extragenital LS; however, it is unclear if the appearance of LS-like lesions with morphea is a simultaneous occurrence of 2 separate disorders or the development of clinical findings resembling LS in lesions of morphea.⁶ Furthermore, morphea involves deep inflammation and sclerosis of the dermis that may extend into subcutaneous fat without follicular plugging of the epidermis.^3,9 In contrast, LS primarily affects the epidermis and dermis with the presence of epidermal follicular plugging.⁶

Lesions seen in DLE are characterized as well-defined, annular, erythematous patches and plaques followed by follicular hyperkeratosis with adherent scaling. Upon removal of the scale, follicle-sized keratotic spikes (carpet tacks) are present.¹⁰ Scaling of lesions and the carpet tack sign were absent in our patient. In addition, DLE typically reveals surrounding pigmentation and scarring over plaques,3 which were not observed in our patient.

Vitiligo commonly is associated with extragenital LS. As with LS, vitiligo can be explained by mechanisms of immune checkpoint inhibitor–induced cytotoxicity as well as perforin and granzyme-B expression.¹¹ Although vitiligo resembles the late hypopigmented lesions of extragenital LS, there are no plaques or surface changes, and a larger, more generalized area of the skin typically is involved.³

The Diagnosis: Lichen Sclerosus

Histopathology revealed a thin epidermis with homogenization of the upper dermal collagen. By contrast, the lower dermis was sclerotic with patchy chronic dermal infiltrate (Figure). Ultimately, the patient’s clinical presentation and histopathologic findings led to a diagnosis of lichen sclerosus (LS).

Lichen sclerosus is a rare chronic inflammatory skin condition that typically is characterized by porcelainwhite atrophic plaques on the skin, most often involving the external female genitalia including the vulva and perianal area.¹ It is thought to be underdiagnosed and underreported.² Extragenital manifestations may occur, though some cases are characterized by concomitant genital involvement.^3,4 Our patient presented with palmoplantar distribution of plaques without genitalia involvement. Approximately 6% to 10% of patients with extragenital LS do not have genital involvement at the time of diagnosis.^3,5 Furthermore, LS involving the palms and soles is exceedingly rare.² Although extragenital LS may be asymptomatic, patients can experience debilitating pruritus; bullae with hemorrhage and erosion; plaque thickening with repeated excoriations; and painful fissuring, especially if lesions are in areas that are susceptible to friction or tension.^3,6 New lesions on previously unaffected skin also may develop secondary to trauma through the Koebner phenomenon.^1,6

Histologically, LS is characterized by epidermal hyperkeratosis accompanied by follicular plugging, epidermal atrophy with flattened rete ridges, vacuolization of the basal epidermis, marked edema in the superficial dermis (in early lesions) or homogenized collagen in the upper dermis (in established lesions), and a lymphohistiocytic infiltrate beneath the homogenized collagen. Although the pathogenesis of LS is unclear, purported etiologic factors from studies in genital disease include immune dysfunction, genetic predisposition, infection, and trauma.⁶ Lichen sclerosus is associated strongly with autoimmune diseases including alopecia areata, vitiligo, autoimmune thyroiditis, diabetes mellitus, and pernicious anemia, indicating its potential multifactorial etiology and linkage to T-lymphocyte dysfunction.¹ Early LS lesions often appear as flat-topped and slightly scaly, hypopigmented, white or mildly erythematous, polygonal papules that coalesce to form larger plaques with peripheral erythema. With time, the inflammation subsides, and lesions become porcelain-white with varying degrees of palpable sclerosis, resembling thin paperlike wrinkles indicative of epidermal atrophy.⁶

The differential diagnosis of LS includes lichen planus (LP), morphea, discoid lupus erythematosus (DLE), and vitiligo.³ Lesions of LP commonly are described as flat-topped, polygonal, pink-purple papules localized mostly along the volar wrists, shins, presacral area, and hands.⁷ Lichen planus is considered to be more pruritic³ than LS and can be further distinguished by biopsy through identifying a well-formed granular layer and numerous cytoid bodies. Unlike LS, LP is not characterized by basement membrane thickening or epidermal atrophy.⁸

Skin lesions seen in morphea may resemble the classic atrophic white lesions of extragenital LS; however, it is unclear if the appearance of LS-like lesions with morphea is a simultaneous occurrence of 2 separate disorders or the development of clinical findings resembling LS in lesions of morphea.⁶ Furthermore, morphea involves deep inflammation and sclerosis of the dermis that may extend into subcutaneous fat without follicular plugging of the epidermis.^3,9 In contrast, LS primarily affects the epidermis and dermis with the presence of epidermal follicular plugging.⁶

Lesions seen in DLE are characterized as well-defined, annular, erythematous patches and plaques followed by follicular hyperkeratosis with adherent scaling. Upon removal of the scale, follicle-sized keratotic spikes (carpet tacks) are present.¹⁰ Scaling of lesions and the carpet tack sign were absent in our patient. In addition, DLE typically reveals surrounding pigmentation and scarring over plaques,3 which were not observed in our patient.

Vitiligo commonly is associated with extragenital LS. As with LS, vitiligo can be explained by mechanisms of immune checkpoint inhibitor–induced cytotoxicity as well as perforin and granzyme-B expression.¹¹ Although vitiligo resembles the late hypopigmented lesions of extragenital LS, there are no plaques or surface changes, and a larger, more generalized area of the skin typically is involved.³

The Diagnosis: Lichen Sclerosus

Histopathology revealed a thin epidermis with homogenization of the upper dermal collagen. By contrast, the lower dermis was sclerotic with patchy chronic dermal infiltrate (Figure). Ultimately, the patient’s clinical presentation and histopathologic findings led to a diagnosis of lichen sclerosus (LS).

Lichen sclerosus is a rare chronic inflammatory skin condition that typically is characterized by porcelainwhite atrophic plaques on the skin, most often involving the external female genitalia including the vulva and perianal area.¹ It is thought to be underdiagnosed and underreported.² Extragenital manifestations may occur, though some cases are characterized by concomitant genital involvement.^3,4 Our patient presented with palmoplantar distribution of plaques without genitalia involvement. Approximately 6% to 10% of patients with extragenital LS do not have genital involvement at the time of diagnosis.^3,5 Furthermore, LS involving the palms and soles is exceedingly rare.² Although extragenital LS may be asymptomatic, patients can experience debilitating pruritus; bullae with hemorrhage and erosion; plaque thickening with repeated excoriations; and painful fissuring, especially if lesions are in areas that are susceptible to friction or tension.^3,6 New lesions on previously unaffected skin also may develop secondary to trauma through the Koebner phenomenon.^1,6

Histologically, LS is characterized by epidermal hyperkeratosis accompanied by follicular plugging, epidermal atrophy with flattened rete ridges, vacuolization of the basal epidermis, marked edema in the superficial dermis (in early lesions) or homogenized collagen in the upper dermis (in established lesions), and a lymphohistiocytic infiltrate beneath the homogenized collagen. Although the pathogenesis of LS is unclear, purported etiologic factors from studies in genital disease include immune dysfunction, genetic predisposition, infection, and trauma.⁶ Lichen sclerosus is associated strongly with autoimmune diseases including alopecia areata, vitiligo, autoimmune thyroiditis, diabetes mellitus, and pernicious anemia, indicating its potential multifactorial etiology and linkage to T-lymphocyte dysfunction.¹ Early LS lesions often appear as flat-topped and slightly scaly, hypopigmented, white or mildly erythematous, polygonal papules that coalesce to form larger plaques with peripheral erythema. With time, the inflammation subsides, and lesions become porcelain-white with varying degrees of palpable sclerosis, resembling thin paperlike wrinkles indicative of epidermal atrophy.⁶

The differential diagnosis of LS includes lichen planus (LP), morphea, discoid lupus erythematosus (DLE), and vitiligo.³ Lesions of LP commonly are described as flat-topped, polygonal, pink-purple papules localized mostly along the volar wrists, shins, presacral area, and hands.⁷ Lichen planus is considered to be more pruritic³ than LS and can be further distinguished by biopsy through identifying a well-formed granular layer and numerous cytoid bodies. Unlike LS, LP is not characterized by basement membrane thickening or epidermal atrophy.⁸

Skin lesions seen in morphea may resemble the classic atrophic white lesions of extragenital LS; however, it is unclear if the appearance of LS-like lesions with morphea is a simultaneous occurrence of 2 separate disorders or the development of clinical findings resembling LS in lesions of morphea.⁶ Furthermore, morphea involves deep inflammation and sclerosis of the dermis that may extend into subcutaneous fat without follicular plugging of the epidermis.^3,9 In contrast, LS primarily affects the epidermis and dermis with the presence of epidermal follicular plugging.⁶

Lesions seen in DLE are characterized as well-defined, annular, erythematous patches and plaques followed by follicular hyperkeratosis with adherent scaling. Upon removal of the scale, follicle-sized keratotic spikes (carpet tacks) are present.¹⁰ Scaling of lesions and the carpet tack sign were absent in our patient. In addition, DLE typically reveals surrounding pigmentation and scarring over plaques,3 which were not observed in our patient.

Vitiligo commonly is associated with extragenital LS. As with LS, vitiligo can be explained by mechanisms of immune checkpoint inhibitor–induced cytotoxicity as well as perforin and granzyme-B expression.¹¹ Although vitiligo resembles the late hypopigmented lesions of extragenital LS, there are no plaques or surface changes, and a larger, more generalized area of the skin typically is involved.³

To the Editor:

Capillary malformations (CMs), the most common vascular malformations that can affect the skin,¹ present clinically as macules and patches of various colors, shapes, and sizes. Congenital structural abnormalities are associated with conditions such as Klippel-Trenaunay syndrome (KTS), cutis marmorata telangiectatica congenita (CMTC), and megalencephaly–capillary malformation syndrome.² Diffuse CM with overgrowth (DCMO) of the soft tissue and bones is an established association of CMs; however, diffuse capillary malformation with undergrowth (DCMU) is a more recent term that describes the lesser-recognized counterpart to DCMO.³ Herein, we describe a case of CM with left-sided undergrowth.

An 11-year-old boy presented to our clinic with asymptomatic vascular patterning on the left side of the body that had been present since birth. He previously was diagnosed with congenital right hemihypertrophy. He reported that the areas gradually lightened over time, and he denied any history of ulceration or venous or lymphatic malformations. Additionally, he explained how the left arm and leg have been noticeably smaller than the right extremities throughout his life. Physical examination revealed superficial, violaceous, reticulated patches along the left upper back tracking down the arm, abdomen (Figure 1A), and anterior thigh (Figure 1B) without crossing the midline. A few dilated veins were noted in the same region as the patches. There was no evidence of scarring or depression found in the skin. The right arms and legs were visibly larger compared to the left side (Figure 2A), and there also was macrodactyly of the third digit of the left hand (Figure 2B). Radiography confirmed the limb length discrepancy and showed the right and left legs to measure 73.2 cm and 71.3 cm, respectively. Given the patient’s multifocal reticulated CMs and ipsilateral undergrowth, a diagnosis of DCMU was rendered. The superficial vascular pattern is likely to fade over time, which will partially be hidden by his darker complexion. He also was advised to continue to see an orthopedist to monitor the limb length incongruity. Surgical intervention was not recommended.

It ordinarily is thought that vascular anomalies of a limb may result in hypertrophy due to increased blood flow such as in KTS, but there are occasions where the affected limb(s) are inexplicably smaller.^2,4 Cubiró et al³ observed that in 6 patients with unilateral CMs, all had ipsilateral limb undergrowth. They proposed the term diffuse capillary malformation with undergrowth as a distinct counterpart to DCMO. Diffuse capillary malformation with undergrowth is most similar to CMTC, as both can present with patchy or reticulated capillary staining with ipsilateral limb hypotrophy, but girth more often is affected than length; CMTC also may be associated with dermal atrophy and ulceration.² The lesions of CMTC typically diminish within the first few years of life whereas those in DCMU tend to persist. Patients with KTS also can exhibit soft-tissue and bony undergrowth, which is termed inverse Klippel-Trenaunay syndrome³; however, the lack of the triad of capillary-lymphatic-venous malformation in our patient made this condition less likely. Additionally, it appears that our patient had left-sided undergrowth rather than the previously diagnosed right hemihypertrophy. The ipsilateral macrodactyly of the third digit of the left hand was an interesting observation and contrasted the undergrowth apparent in the rest of the left limb, which could be caused by increased blood flow specifically to the third digit resembling DCMO.⁴

Of note, genetic mutations have been implicated as a cause of vascular malformations and growth abnormalities. Specifically, mutations in the phosphoinositide-3-kinase–AKT pathway have been reported in these cases likely due its role in cell growth, proliferation, and angiogenesis.^3,4 Future studies should investigate genetic associations in patients with DCMU to determine if there is a robust genotypic-phenotypic link.

Although CMs are a common occurrence in pediatric dermatology, CMs with concurrent limb undergrowth are rare. Our patient’s unique features included involvement of both an arm and leg as well as the presence of macrodactyly. We agree with the terminology for DCMU to describe multifocal reticulated vascular patterning with ipsilateral undergrowth.³

To the Editor:

Capillary malformations (CMs), the most common vascular malformations that can affect the skin,¹ present clinically as macules and patches of various colors, shapes, and sizes. Congenital structural abnormalities are associated with conditions such as Klippel-Trenaunay syndrome (KTS), cutis marmorata telangiectatica congenita (CMTC), and megalencephaly–capillary malformation syndrome.² Diffuse CM with overgrowth (DCMO) of the soft tissue and bones is an established association of CMs; however, diffuse capillary malformation with undergrowth (DCMU) is a more recent term that describes the lesser-recognized counterpart to DCMO.³ Herein, we describe a case of CM with left-sided undergrowth.

An 11-year-old boy presented to our clinic with asymptomatic vascular patterning on the left side of the body that had been present since birth. He previously was diagnosed with congenital right hemihypertrophy. He reported that the areas gradually lightened over time, and he denied any history of ulceration or venous or lymphatic malformations. Additionally, he explained how the left arm and leg have been noticeably smaller than the right extremities throughout his life. Physical examination revealed superficial, violaceous, reticulated patches along the left upper back tracking down the arm, abdomen (Figure 1A), and anterior thigh (Figure 1B) without crossing the midline. A few dilated veins were noted in the same region as the patches. There was no evidence of scarring or depression found in the skin. The right arms and legs were visibly larger compared to the left side (Figure 2A), and there also was macrodactyly of the third digit of the left hand (Figure 2B). Radiography confirmed the limb length discrepancy and showed the right and left legs to measure 73.2 cm and 71.3 cm, respectively. Given the patient’s multifocal reticulated CMs and ipsilateral undergrowth, a diagnosis of DCMU was rendered. The superficial vascular pattern is likely to fade over time, which will partially be hidden by his darker complexion. He also was advised to continue to see an orthopedist to monitor the limb length incongruity. Surgical intervention was not recommended.

It ordinarily is thought that vascular anomalies of a limb may result in hypertrophy due to increased blood flow such as in KTS, but there are occasions where the affected limb(s) are inexplicably smaller.^2,4 Cubiró et al³ observed that in 6 patients with unilateral CMs, all had ipsilateral limb undergrowth. They proposed the term diffuse capillary malformation with undergrowth as a distinct counterpart to DCMO. Diffuse capillary malformation with undergrowth is most similar to CMTC, as both can present with patchy or reticulated capillary staining with ipsilateral limb hypotrophy, but girth more often is affected than length; CMTC also may be associated with dermal atrophy and ulceration.² The lesions of CMTC typically diminish within the first few years of life whereas those in DCMU tend to persist. Patients with KTS also can exhibit soft-tissue and bony undergrowth, which is termed inverse Klippel-Trenaunay syndrome³; however, the lack of the triad of capillary-lymphatic-venous malformation in our patient made this condition less likely. Additionally, it appears that our patient had left-sided undergrowth rather than the previously diagnosed right hemihypertrophy. The ipsilateral macrodactyly of the third digit of the left hand was an interesting observation and contrasted the undergrowth apparent in the rest of the left limb, which could be caused by increased blood flow specifically to the third digit resembling DCMO.⁴

Of note, genetic mutations have been implicated as a cause of vascular malformations and growth abnormalities. Specifically, mutations in the phosphoinositide-3-kinase–AKT pathway have been reported in these cases likely due its role in cell growth, proliferation, and angiogenesis.^3,4 Future studies should investigate genetic associations in patients with DCMU to determine if there is a robust genotypic-phenotypic link.

Although CMs are a common occurrence in pediatric dermatology, CMs with concurrent limb undergrowth are rare. Our patient’s unique features included involvement of both an arm and leg as well as the presence of macrodactyly. We agree with the terminology for DCMU to describe multifocal reticulated vascular patterning with ipsilateral undergrowth.³

To the Editor:

Capillary malformations (CMs), the most common vascular malformations that can affect the skin,¹ present clinically as macules and patches of various colors, shapes, and sizes. Congenital structural abnormalities are associated with conditions such as Klippel-Trenaunay syndrome (KTS), cutis marmorata telangiectatica congenita (CMTC), and megalencephaly–capillary malformation syndrome.² Diffuse CM with overgrowth (DCMO) of the soft tissue and bones is an established association of CMs; however, diffuse capillary malformation with undergrowth (DCMU) is a more recent term that describes the lesser-recognized counterpart to DCMO.³ Herein, we describe a case of CM with left-sided undergrowth.

An 11-year-old boy presented to our clinic with asymptomatic vascular patterning on the left side of the body that had been present since birth. He previously was diagnosed with congenital right hemihypertrophy. He reported that the areas gradually lightened over time, and he denied any history of ulceration or venous or lymphatic malformations. Additionally, he explained how the left arm and leg have been noticeably smaller than the right extremities throughout his life. Physical examination revealed superficial, violaceous, reticulated patches along the left upper back tracking down the arm, abdomen (Figure 1A), and anterior thigh (Figure 1B) without crossing the midline. A few dilated veins were noted in the same region as the patches. There was no evidence of scarring or depression found in the skin. The right arms and legs were visibly larger compared to the left side (Figure 2A), and there also was macrodactyly of the third digit of the left hand (Figure 2B). Radiography confirmed the limb length discrepancy and showed the right and left legs to measure 73.2 cm and 71.3 cm, respectively. Given the patient’s multifocal reticulated CMs and ipsilateral undergrowth, a diagnosis of DCMU was rendered. The superficial vascular pattern is likely to fade over time, which will partially be hidden by his darker complexion. He also was advised to continue to see an orthopedist to monitor the limb length incongruity. Surgical intervention was not recommended.

It ordinarily is thought that vascular anomalies of a limb may result in hypertrophy due to increased blood flow such as in KTS, but there are occasions where the affected limb(s) are inexplicably smaller.^2,4 Cubiró et al³ observed that in 6 patients with unilateral CMs, all had ipsilateral limb undergrowth. They proposed the term diffuse capillary malformation with undergrowth as a distinct counterpart to DCMO. Diffuse capillary malformation with undergrowth is most similar to CMTC, as both can present with patchy or reticulated capillary staining with ipsilateral limb hypotrophy, but girth more often is affected than length; CMTC also may be associated with dermal atrophy and ulceration.² The lesions of CMTC typically diminish within the first few years of life whereas those in DCMU tend to persist. Patients with KTS also can exhibit soft-tissue and bony undergrowth, which is termed inverse Klippel-Trenaunay syndrome³; however, the lack of the triad of capillary-lymphatic-venous malformation in our patient made this condition less likely. Additionally, it appears that our patient had left-sided undergrowth rather than the previously diagnosed right hemihypertrophy. The ipsilateral macrodactyly of the third digit of the left hand was an interesting observation and contrasted the undergrowth apparent in the rest of the left limb, which could be caused by increased blood flow specifically to the third digit resembling DCMO.⁴

Of note, genetic mutations have been implicated as a cause of vascular malformations and growth abnormalities. Specifically, mutations in the phosphoinositide-3-kinase–AKT pathway have been reported in these cases likely due its role in cell growth, proliferation, and angiogenesis.^3,4 Future studies should investigate genetic associations in patients with DCMU to determine if there is a robust genotypic-phenotypic link.

Although CMs are a common occurrence in pediatric dermatology, CMs with concurrent limb undergrowth are rare. Our patient’s unique features included involvement of both an arm and leg as well as the presence of macrodactyly. We agree with the terminology for DCMU to describe multifocal reticulated vascular patterning with ipsilateral undergrowth.³

Fleas (order Siphonaptera) are vectors for various diseases, such as plague (as carriers of Yersinia pestis) and rickettsial infections.^1-4 The sticktight flea (Echidnophaga gallinacea) commonly is seen on birds and mammals, including ground squirrels, dogs, cats, and rodents, and can attach to its host for days at a time by burrowing its head into the skin. Similar to other fleas, the sticktight flea needs a blood supply to reproduce.⁵ Therefore, it is important to study the sticktight flea, its habitat, and infection patterns to improve public health and prevent infestation.

Identification

Echidnophaga gallinacea is named for the female flea’s behavior—it “sticks tight” to the surface of the host by embedding its head into the skin for days at a time.⁵ The sticktight flea and the rat flea (Xenopsylla cheopis) can be differentiated by the sticktight’s reduced thorax and lack of a pleural rod (the vertical ridge that divides the mesosternum above the second pair of legs)(Figure, A and B). The sticktight flea can be differentiated from the dog flea (Ctenocephalides canis) and the cat flea (Ctenocephalides felis) by its lack of genal ctenidia (horizontal combs in the mustache area) and pronotal ctenidia (vertical combs behind the head)(Figure, B and C).^6,7 Other defining features of E gallinacea include 2 pairs of large postantennal setae (hairs) on its anteriorly flattened head; a C-shaped reproductive organ known as the spermatheca; and broad maxillary lacinia (Figure, C).⁸

Habitat, Seasonality, and Behavior

Echidnophaga gallinacea commonly infests the comb, wattles, and surrounding ears of chickens; the flea also has been found on dogs, cats, rodents, and other species of birds.⁹ The sticktight flea is more prevalent in summer and autumn, which may explain its predominance in warmer climates, including California, Florida, Mexico, Egypt, Africa, and Iran.^1,9-11

When a female sticktight flea begins to feed, it stays on the host for days at a time, waiting for a male.⁵ The female deposits its fertilized eggs in nests on the host or in lesions caused by infestation. Eventually, eggs hatch and fall into soil, where they lay dormant or grow to adulthood.⁵

Cutaneous Reaction to Infestation

Flea bites cause a hypersensitivity reaction, with pruritic pustules and erythematous papules that have a central punctum.¹² In a reported case in Los Angeles, California, a female sticktight flea buried itself into the cheek of a young boy for more than 12 hours. The lesion was not marked by surrounding erythema, tenderness, pruritus, or swelling; however, several days after the flea was removed, erythema developed at the site then spontaneously resolved.⁷ In a study of dogs that were infested with E gallinacea, the flea never disengaged to attach to a human; when the flea was deliberately placed on a human, it fed and left hastily.¹¹

Management

Because E gallinacea burrows its head into the skin, the best removal method is applying slow gentle traction under sterile conditions to ensure removal of mouthparts.⁷ An oral antihistamine can be administered or a topical antihistamine or corticosteroid can be applied to the affected area.¹² Flea infestation should be treated with an insecticide. Affected animals should be treated by a veterinarian using a pesticide, such as fipronil, selamectin, imidacloprid, metaflumizone, nitenpyram, lufenuron, methoprene, or pyriproxyfen.¹³

Fleas (order Siphonaptera) are vectors for various diseases, such as plague (as carriers of Yersinia pestis) and rickettsial infections.^1-4 The sticktight flea (Echidnophaga gallinacea) commonly is seen on birds and mammals, including ground squirrels, dogs, cats, and rodents, and can attach to its host for days at a time by burrowing its head into the skin. Similar to other fleas, the sticktight flea needs a blood supply to reproduce.⁵ Therefore, it is important to study the sticktight flea, its habitat, and infection patterns to improve public health and prevent infestation.

Identification

Echidnophaga gallinacea is named for the female flea’s behavior—it “sticks tight” to the surface of the host by embedding its head into the skin for days at a time.⁵ The sticktight flea and the rat flea (Xenopsylla cheopis) can be differentiated by the sticktight’s reduced thorax and lack of a pleural rod (the vertical ridge that divides the mesosternum above the second pair of legs)(Figure, A and B). The sticktight flea can be differentiated from the dog flea (Ctenocephalides canis) and the cat flea (Ctenocephalides felis) by its lack of genal ctenidia (horizontal combs in the mustache area) and pronotal ctenidia (vertical combs behind the head)(Figure, B and C).^6,7 Other defining features of E gallinacea include 2 pairs of large postantennal setae (hairs) on its anteriorly flattened head; a C-shaped reproductive organ known as the spermatheca; and broad maxillary lacinia (Figure, C).⁸

Habitat, Seasonality, and Behavior

Echidnophaga gallinacea commonly infests the comb, wattles, and surrounding ears of chickens; the flea also has been found on dogs, cats, rodents, and other species of birds.⁹ The sticktight flea is more prevalent in summer and autumn, which may explain its predominance in warmer climates, including California, Florida, Mexico, Egypt, Africa, and Iran.^1,9-11

When a female sticktight flea begins to feed, it stays on the host for days at a time, waiting for a male.⁵ The female deposits its fertilized eggs in nests on the host or in lesions caused by infestation. Eventually, eggs hatch and fall into soil, where they lay dormant or grow to adulthood.⁵

Cutaneous Reaction to Infestation

Flea bites cause a hypersensitivity reaction, with pruritic pustules and erythematous papules that have a central punctum.¹² In a reported case in Los Angeles, California, a female sticktight flea buried itself into the cheek of a young boy for more than 12 hours. The lesion was not marked by surrounding erythema, tenderness, pruritus, or swelling; however, several days after the flea was removed, erythema developed at the site then spontaneously resolved.⁷ In a study of dogs that were infested with E gallinacea, the flea never disengaged to attach to a human; when the flea was deliberately placed on a human, it fed and left hastily.¹¹

Management

Because E gallinacea burrows its head into the skin, the best removal method is applying slow gentle traction under sterile conditions to ensure removal of mouthparts.⁷ An oral antihistamine can be administered or a topical antihistamine or corticosteroid can be applied to the affected area.¹² Flea infestation should be treated with an insecticide. Affected animals should be treated by a veterinarian using a pesticide, such as fipronil, selamectin, imidacloprid, metaflumizone, nitenpyram, lufenuron, methoprene, or pyriproxyfen.¹³

Fleas (order Siphonaptera) are vectors for various diseases, such as plague (as carriers of Yersinia pestis) and rickettsial infections.^1-4 The sticktight flea (Echidnophaga gallinacea) commonly is seen on birds and mammals, including ground squirrels, dogs, cats, and rodents, and can attach to its host for days at a time by burrowing its head into the skin. Similar to other fleas, the sticktight flea needs a blood supply to reproduce.⁵ Therefore, it is important to study the sticktight flea, its habitat, and infection patterns to improve public health and prevent infestation.

Identification

Echidnophaga gallinacea is named for the female flea’s behavior—it “sticks tight” to the surface of the host by embedding its head into the skin for days at a time.⁵ The sticktight flea and the rat flea (Xenopsylla cheopis) can be differentiated by the sticktight’s reduced thorax and lack of a pleural rod (the vertical ridge that divides the mesosternum above the second pair of legs)(Figure, A and B). The sticktight flea can be differentiated from the dog flea (Ctenocephalides canis) and the cat flea (Ctenocephalides felis) by its lack of genal ctenidia (horizontal combs in the mustache area) and pronotal ctenidia (vertical combs behind the head)(Figure, B and C).^6,7 Other defining features of E gallinacea include 2 pairs of large postantennal setae (hairs) on its anteriorly flattened head; a C-shaped reproductive organ known as the spermatheca; and broad maxillary lacinia (Figure, C).⁸

Habitat, Seasonality, and Behavior

Echidnophaga gallinacea commonly infests the comb, wattles, and surrounding ears of chickens; the flea also has been found on dogs, cats, rodents, and other species of birds.⁹ The sticktight flea is more prevalent in summer and autumn, which may explain its predominance in warmer climates, including California, Florida, Mexico, Egypt, Africa, and Iran.^1,9-11

When a female sticktight flea begins to feed, it stays on the host for days at a time, waiting for a male.⁵ The female deposits its fertilized eggs in nests on the host or in lesions caused by infestation. Eventually, eggs hatch and fall into soil, where they lay dormant or grow to adulthood.⁵

Cutaneous Reaction to Infestation

Flea bites cause a hypersensitivity reaction, with pruritic pustules and erythematous papules that have a central punctum.¹² In a reported case in Los Angeles, California, a female sticktight flea buried itself into the cheek of a young boy for more than 12 hours. The lesion was not marked by surrounding erythema, tenderness, pruritus, or swelling; however, several days after the flea was removed, erythema developed at the site then spontaneously resolved.⁷ In a study of dogs that were infested with E gallinacea, the flea never disengaged to attach to a human; when the flea was deliberately placed on a human, it fed and left hastily.¹¹

Management

Because E gallinacea burrows its head into the skin, the best removal method is applying slow gentle traction under sterile conditions to ensure removal of mouthparts.⁷ An oral antihistamine can be administered or a topical antihistamine or corticosteroid can be applied to the affected area.¹² Flea infestation should be treated with an insecticide. Affected animals should be treated by a veterinarian using a pesticide, such as fipronil, selamectin, imidacloprid, metaflumizone, nitenpyram, lufenuron, methoprene, or pyriproxyfen.¹³

The Diagnosis: Carcinoma en Cuirasse

Histopathology demonstrated a cellular infiltrate filling the dermis with sparing of the papillary and superficial reticular dermis (Figure 1A). The cells were arranged in strands and cords that infiltrated between sclerotic collagen bundles. Cytomorphologically, the cells ranged from epithelioid with large vesicular nuclei and prominent nucleoli to cuboidal with hyperchromatic nuclei with irregular contours and a high nuclear to cytoplasmic ratio (Figure 1B). Occasional mitotic figures were identified, and cells demonstrated diffuse nuclear positivity for GATA-3 (Figure 1C); 55% of the cells demonstrated estrogen receptor positivity, and immunohistochemistry of progesterone receptors was negative. These findings confirmed our patient’s diagnosis of breast carcinoma en cuirasse (CeC) as the primary manifestation of metastatic invasive ductal carcinoma. Our patient was treated with intravenous chemotherapy and tamoxifen.

Histopathologic findings of morphea include thickened hyalinized collagen bundles and loss of adventitial fat.¹ A diagnosis of chronic radiation dermatitis was inconsistent with our patient’s medical history and biopsy results, as pathology should reveal hyalinized collagen or stellate radiation fibroblasts.^2,3 Nests of squamous epithelial cells with abundant eosinophilic cytoplasm and large vesicular nuclei were not seen, excluding squamous cell carcinoma as a possible diagnosis.⁴ Although sclerosing sweat duct carcinoma is characterized by infiltrating cords in sclerotic dermis, the cells were not arranged in ductlike structures 1– to 2–cell layers thick, excluding this diagnosis.⁵

Carcinoma en cuirasse—named for skin involvement that appears similar to the metal breastplate of a cuirassier—is a rare form of cutaneous metastasis that typically presents with extensive infiltrative plaques resulting in fibrosis of the skin and subcutaneous tissue.^6,7 Carcinoma en cuirasse most commonly metastasizes from the breast but also may represent metastases from the lungs, gastrointestinal tract, or genitourinary systems.⁸ In the setting of a primary breast malignancy, metastatic plaques of CeC tend to represent tumor recurrence following a mastectomy procedure; however, in rare cases CeC can present as the primary manifestation of breast cancer or as a result of untreated malignancy.^6,9 In our patient, CeC was the primary manifestation of metastatic invasive ductal carcinoma with additional paraneoplastic ichthyosis (Figure 2).

Carcinoma en cuirasse comprises 3% to 6% of cutaneous metastases originating from the breast.^10,11 Breast cancer is the most common primary neoplasm displaying extracutaneous metastasis, comprising 70% of all cutaneous metastases in females.¹¹ Cutaneous metastasis often indicates late stage of disease, portending a poor prognosis. In our patient, the cutaneous nodules were present for approximately 3 years prior to the diagnosis of stage IV invasive ductal cell carcinoma with metastasis to the skin and lungs. Prior to admission, she had not been diagnosed with breast cancer, thus no treatments had been administered. It is uncommon for CeC to present as the initial finding and without prior treatment of the underlying malignancy. The median length of survival after diagnosis of cutaneous metastasis from breast cancer is 13.8 months, with a 10-year survival rate of 3.1%.¹²

In addition to cutaneous metastasis, breast cancer also may present with paraneoplastic dermatoses such as ichthyosis.¹³ Ichthyosis is characterized by extreme dryness, flaking, thickening, and mild pruritus.¹⁴ It most commonly is an inherited condition, but it may be acquired due to malignancy. Acquired ichthyosis may manifest in systemic diseases including systemic lupus erythematosus, sarcoidosis, and hypothyroidism.15 Although acquired ichthyosis is rare, it has been reported in cases of internal malignancy, most commonly lymphoproliferative malignancies and less frequently carcinoma of the breasts, cervix, and lungs. Patients who acquire ichthyosis in association with malignancy usually present with late-stage disease.¹⁵ Our patient acquired ichthyosis 3 months prior to admission and had never experienced it previously. Although the exact mechanism for acquiring ichthyosis remains unknown, it is uncertain if ichthyosis associated with malignancy is paraneoplastic or a result of chemotherapy.^14,16 In this case, the patient had not yet started chemotherapy at the time of the ichthyosis diagnosis, suggesting a paraneoplastic etiology.

Carcinoma en cuirasse and paraneoplastic ichthyosis individually are extremely rare manifestations of breast cancer. Thus, it is even rarer for these conditions to present concurrently. Treatment options for CeC include chemotherapy, radiotherapy, hormonal antagonists, and snake venom.¹¹ Systemic chemotherapy targeting the histopathologic type of the primary tumor is the treatment of choice. Other treatment methods usually are chosen for late stages of disease progression.10 Paraneoplastic ichthyosis has been reported to show improvement with treatment of the underlying primary malignancy by surgical removal or chemotherapy.^14,17 Tamoxifen less commonly is used for systemic treatment of CeC, but one case in the literature reported favorable outcomes.¹⁸

We describe 2 rare cutaneous manifestations of breast cancer occurring concomitantly: CeC and paraneoplastic ichthyosis. The combination of clinical and pathologic findings presented in this case solidified the diagnosis of metastatic invasive ductal carcinoma. We aim to improve recognition of paraneoplastic skin findings to accelerate the process of effective and efficient treatment.

The Diagnosis: Carcinoma en Cuirasse

Histopathology demonstrated a cellular infiltrate filling the dermis with sparing of the papillary and superficial reticular dermis (Figure 1A). The cells were arranged in strands and cords that infiltrated between sclerotic collagen bundles. Cytomorphologically, the cells ranged from epithelioid with large vesicular nuclei and prominent nucleoli to cuboidal with hyperchromatic nuclei with irregular contours and a high nuclear to cytoplasmic ratio (Figure 1B). Occasional mitotic figures were identified, and cells demonstrated diffuse nuclear positivity for GATA-3 (Figure 1C); 55% of the cells demonstrated estrogen receptor positivity, and immunohistochemistry of progesterone receptors was negative. These findings confirmed our patient’s diagnosis of breast carcinoma en cuirasse (CeC) as the primary manifestation of metastatic invasive ductal carcinoma. Our patient was treated with intravenous chemotherapy and tamoxifen.

Histopathologic findings of morphea include thickened hyalinized collagen bundles and loss of adventitial fat.¹ A diagnosis of chronic radiation dermatitis was inconsistent with our patient’s medical history and biopsy results, as pathology should reveal hyalinized collagen or stellate radiation fibroblasts.^2,3 Nests of squamous epithelial cells with abundant eosinophilic cytoplasm and large vesicular nuclei were not seen, excluding squamous cell carcinoma as a possible diagnosis.⁴ Although sclerosing sweat duct carcinoma is characterized by infiltrating cords in sclerotic dermis, the cells were not arranged in ductlike structures 1– to 2–cell layers thick, excluding this diagnosis.⁵

Carcinoma en cuirasse—named for skin involvement that appears similar to the metal breastplate of a cuirassier—is a rare form of cutaneous metastasis that typically presents with extensive infiltrative plaques resulting in fibrosis of the skin and subcutaneous tissue.^6,7 Carcinoma en cuirasse most commonly metastasizes from the breast but also may represent metastases from the lungs, gastrointestinal tract, or genitourinary systems.⁸ In the setting of a primary breast malignancy, metastatic plaques of CeC tend to represent tumor recurrence following a mastectomy procedure; however, in rare cases CeC can present as the primary manifestation of breast cancer or as a result of untreated malignancy.^6,9 In our patient, CeC was the primary manifestation of metastatic invasive ductal carcinoma with additional paraneoplastic ichthyosis (Figure 2).

Carcinoma en cuirasse comprises 3% to 6% of cutaneous metastases originating from the breast.^10,11 Breast cancer is the most common primary neoplasm displaying extracutaneous metastasis, comprising 70% of all cutaneous metastases in females.¹¹ Cutaneous metastasis often indicates late stage of disease, portending a poor prognosis. In our patient, the cutaneous nodules were present for approximately 3 years prior to the diagnosis of stage IV invasive ductal cell carcinoma with metastasis to the skin and lungs. Prior to admission, she had not been diagnosed with breast cancer, thus no treatments had been administered. It is uncommon for CeC to present as the initial finding and without prior treatment of the underlying malignancy. The median length of survival after diagnosis of cutaneous metastasis from breast cancer is 13.8 months, with a 10-year survival rate of 3.1%.¹²

In addition to cutaneous metastasis, breast cancer also may present with paraneoplastic dermatoses such as ichthyosis.¹³ Ichthyosis is characterized by extreme dryness, flaking, thickening, and mild pruritus.¹⁴ It most commonly is an inherited condition, but it may be acquired due to malignancy. Acquired ichthyosis may manifest in systemic diseases including systemic lupus erythematosus, sarcoidosis, and hypothyroidism.15 Although acquired ichthyosis is rare, it has been reported in cases of internal malignancy, most commonly lymphoproliferative malignancies and less frequently carcinoma of the breasts, cervix, and lungs. Patients who acquire ichthyosis in association with malignancy usually present with late-stage disease.¹⁵ Our patient acquired ichthyosis 3 months prior to admission and had never experienced it previously. Although the exact mechanism for acquiring ichthyosis remains unknown, it is uncertain if ichthyosis associated with malignancy is paraneoplastic or a result of chemotherapy.^14,16 In this case, the patient had not yet started chemotherapy at the time of the ichthyosis diagnosis, suggesting a paraneoplastic etiology.

Carcinoma en cuirasse and paraneoplastic ichthyosis individually are extremely rare manifestations of breast cancer. Thus, it is even rarer for these conditions to present concurrently. Treatment options for CeC include chemotherapy, radiotherapy, hormonal antagonists, and snake venom.¹¹ Systemic chemotherapy targeting the histopathologic type of the primary tumor is the treatment of choice. Other treatment methods usually are chosen for late stages of disease progression.10 Paraneoplastic ichthyosis has been reported to show improvement with treatment of the underlying primary malignancy by surgical removal or chemotherapy.^14,17 Tamoxifen less commonly is used for systemic treatment of CeC, but one case in the literature reported favorable outcomes.¹⁸

We describe 2 rare cutaneous manifestations of breast cancer occurring concomitantly: CeC and paraneoplastic ichthyosis. The combination of clinical and pathologic findings presented in this case solidified the diagnosis of metastatic invasive ductal carcinoma. We aim to improve recognition of paraneoplastic skin findings to accelerate the process of effective and efficient treatment.

The Diagnosis: Carcinoma en Cuirasse

Histopathology demonstrated a cellular infiltrate filling the dermis with sparing of the papillary and superficial reticular dermis (Figure 1A). The cells were arranged in strands and cords that infiltrated between sclerotic collagen bundles. Cytomorphologically, the cells ranged from epithelioid with large vesicular nuclei and prominent nucleoli to cuboidal with hyperchromatic nuclei with irregular contours and a high nuclear to cytoplasmic ratio (Figure 1B). Occasional mitotic figures were identified, and cells demonstrated diffuse nuclear positivity for GATA-3 (Figure 1C); 55% of the cells demonstrated estrogen receptor positivity, and immunohistochemistry of progesterone receptors was negative. These findings confirmed our patient’s diagnosis of breast carcinoma en cuirasse (CeC) as the primary manifestation of metastatic invasive ductal carcinoma. Our patient was treated with intravenous chemotherapy and tamoxifen.

Histopathologic findings of morphea include thickened hyalinized collagen bundles and loss of adventitial fat.¹ A diagnosis of chronic radiation dermatitis was inconsistent with our patient’s medical history and biopsy results, as pathology should reveal hyalinized collagen or stellate radiation fibroblasts.^2,3 Nests of squamous epithelial cells with abundant eosinophilic cytoplasm and large vesicular nuclei were not seen, excluding squamous cell carcinoma as a possible diagnosis.⁴ Although sclerosing sweat duct carcinoma is characterized by infiltrating cords in sclerotic dermis, the cells were not arranged in ductlike structures 1– to 2–cell layers thick, excluding this diagnosis.⁵

Carcinoma en cuirasse—named for skin involvement that appears similar to the metal breastplate of a cuirassier—is a rare form of cutaneous metastasis that typically presents with extensive infiltrative plaques resulting in fibrosis of the skin and subcutaneous tissue.^6,7 Carcinoma en cuirasse most commonly metastasizes from the breast but also may represent metastases from the lungs, gastrointestinal tract, or genitourinary systems.⁸ In the setting of a primary breast malignancy, metastatic plaques of CeC tend to represent tumor recurrence following a mastectomy procedure; however, in rare cases CeC can present as the primary manifestation of breast cancer or as a result of untreated malignancy.^6,9 In our patient, CeC was the primary manifestation of metastatic invasive ductal carcinoma with additional paraneoplastic ichthyosis (Figure 2).

Carcinoma en cuirasse comprises 3% to 6% of cutaneous metastases originating from the breast.^10,11 Breast cancer is the most common primary neoplasm displaying extracutaneous metastasis, comprising 70% of all cutaneous metastases in females.¹¹ Cutaneous metastasis often indicates late stage of disease, portending a poor prognosis. In our patient, the cutaneous nodules were present for approximately 3 years prior to the diagnosis of stage IV invasive ductal cell carcinoma with metastasis to the skin and lungs. Prior to admission, she had not been diagnosed with breast cancer, thus no treatments had been administered. It is uncommon for CeC to present as the initial finding and without prior treatment of the underlying malignancy. The median length of survival after diagnosis of cutaneous metastasis from breast cancer is 13.8 months, with a 10-year survival rate of 3.1%.¹²

In addition to cutaneous metastasis, breast cancer also may present with paraneoplastic dermatoses such as ichthyosis.¹³ Ichthyosis is characterized by extreme dryness, flaking, thickening, and mild pruritus.¹⁴ It most commonly is an inherited condition, but it may be acquired due to malignancy. Acquired ichthyosis may manifest in systemic diseases including systemic lupus erythematosus, sarcoidosis, and hypothyroidism.15 Although acquired ichthyosis is rare, it has been reported in cases of internal malignancy, most commonly lymphoproliferative malignancies and less frequently carcinoma of the breasts, cervix, and lungs. Patients who acquire ichthyosis in association with malignancy usually present with late-stage disease.¹⁵ Our patient acquired ichthyosis 3 months prior to admission and had never experienced it previously. Although the exact mechanism for acquiring ichthyosis remains unknown, it is uncertain if ichthyosis associated with malignancy is paraneoplastic or a result of chemotherapy.^14,16 In this case, the patient had not yet started chemotherapy at the time of the ichthyosis diagnosis, suggesting a paraneoplastic etiology.

Carcinoma en cuirasse and paraneoplastic ichthyosis individually are extremely rare manifestations of breast cancer. Thus, it is even rarer for these conditions to present concurrently. Treatment options for CeC include chemotherapy, radiotherapy, hormonal antagonists, and snake venom.¹¹ Systemic chemotherapy targeting the histopathologic type of the primary tumor is the treatment of choice. Other treatment methods usually are chosen for late stages of disease progression.10 Paraneoplastic ichthyosis has been reported to show improvement with treatment of the underlying primary malignancy by surgical removal or chemotherapy.^14,17 Tamoxifen less commonly is used for systemic treatment of CeC, but one case in the literature reported favorable outcomes.¹⁸

We describe 2 rare cutaneous manifestations of breast cancer occurring concomitantly: CeC and paraneoplastic ichthyosis. The combination of clinical and pathologic findings presented in this case solidified the diagnosis of metastatic invasive ductal carcinoma. We aim to improve recognition of paraneoplastic skin findings to accelerate the process of effective and efficient treatment.

Complex medical dermatology has become an emerging field in dermatology. Although a rather protean and broad term, complex medical dermatology encompasses patients with autoimmune conditions, bullous disease, connective tissue disease, vasculitis, severe dermatoses requiring immunomodulation, and inpatient consultations. Importantly, dermatology inpatient consultations aid in lowering health care costs due to accurate diagnoses, correct treatment, and decreased hospital stays.¹ A fellowship is not required for holding an inpatient role in the hospital system as a dermatologist but can be beneficial. There are combined internal medicine–dermatology programs available for medical students applying to dermatology residency, but a complex medical dermatology fellowship is an option after residency for those who are interested. I believe that a focused complex medical dermatology fellowship differs from the training offered in combined internal medicine–dermatology residency. My fellow colleagues in combined internal medicine–dermatology programs are exposed to systemic manifestations of cutaneous disease and are experts in the interplay between the skin and other organ systems. However, the focus of their programs is with the intention of becoming double boarded in internal medicine and dermatology with comprehensive exposure to both fields. In my fellowship, I am able to tailor my schedule to focus on any dermatologic disease such as connective tissue disease, pruritus, graft vs host disease, and Merkel cell carcinoma. I ultimately can determine a niche in dermatology and hone my skills for a year under supervision.

Available Fellowships

Fellowship Locations—Importantly, the complex medical dermatology fellowship is not accredited by the Accreditation Council for Graduate Medical Education, which can make it difficult to identify and apply to programs. The complex medical dermatology fellowship is different than a rheumatology-dermatology fellowship, cutaneous oncology fellowship, pediatric dermatology fellowship, or other subspecialty fellowships such as those in itch or autoimmune blistering diseases. The fellowship often encompasses gaining clinical expertise in many of these conditions. I performed a thorough search online and spoke with complex medical dermatologists to compile a list of programs that offer a complex medical dermatology fellowship: Brigham and Women’s Hospital (Boston, Massachusetts); University of California San Francisco (San Francisco, California); University of Pennsylvania (Philadelphia, Pennsylvania); Cleveland Clinic (Cleveland, Ohio); and New York University (New York, New York)(Table). Only 1 spot is offered at each of these programs.

Reason to Pursue the Fellowship—There are many reasons to pursue a fellowship in complex medical dermatology such as a desire to enhance exposure to the field, to practice in an academic center and develop a niche within dermatology, to practice dermatology in an inpatient setting, to improve delivery of health care to medically challenging populations in a community setting, and to become an expert on cutaneous manifestations of internal and systemic disease.

Application—There is no standardized application or deadline for this fellowship; however, there is a concerted attempt from some of the programs to offer interviews and decisions at a similar time. Deadlines and contact information are listed on the program websites, along with more details (Table).

Recommendations—I would recommend reaching out at the beginning of postgraduate year (PGY) 4 to these programs and voicing your interest in the fellowship. It is possible to set up an away rotation at some of the programs, and if your program offers elective time, pursuing an away rotation during PGY-3 or early in PGY-4 can prove to be advantageous. Furthermore, during my application cycle I toured the University of California San Francisco, University of Pennsylvania, and Brigham and Women’s Hospital to gain further insight into each program.

Brigham and Women’s Complex Medical Dermatology Fellowship

I am currently the complex medical dermatology fellow at Brigham and Women’s Hospital, and it has been an outstanding experience thus far. The program offers numerous subspecialty clinics focusing solely on cutaneous-oncodermatology, psoriasis, rheumatology-dermatology, skin of color, mole mapping backed by artificial intelligence, cosmetics, high-risk skin cancer, neutrophilic dermatoses, patch testing, phototherapy, psychodermatology, and transplant dermatology. In addition to a wide variety of subspecialty clinics, fellows have the opportunity to participate in inpatient dermatology rounds and act as a junior attending. I appreciate the flexibility of this program combined with the ability to work alongside worldwide experts. There are numerous teaching opportunities, and all of the faculty are amiable and intelligent and emphasize wellness, education, and autonomy. Overall, my experience and decision to pursue a complex medical dermatology fellowship has been extremely rewarding and invaluable. I am gaining additional skills to aid medically challenging patients while pursuing my true passion in dermatology.

Complex medical dermatology has become an emerging field in dermatology. Although a rather protean and broad term, complex medical dermatology encompasses patients with autoimmune conditions, bullous disease, connective tissue disease, vasculitis, severe dermatoses requiring immunomodulation, and inpatient consultations. Importantly, dermatology inpatient consultations aid in lowering health care costs due to accurate diagnoses, correct treatment, and decreased hospital stays.¹ A fellowship is not required for holding an inpatient role in the hospital system as a dermatologist but can be beneficial. There are combined internal medicine–dermatology programs available for medical students applying to dermatology residency, but a complex medical dermatology fellowship is an option after residency for those who are interested. I believe that a focused complex medical dermatology fellowship differs from the training offered in combined internal medicine–dermatology residency. My fellow colleagues in combined internal medicine–dermatology programs are exposed to systemic manifestations of cutaneous disease and are experts in the interplay between the skin and other organ systems. However, the focus of their programs is with the intention of becoming double boarded in internal medicine and dermatology with comprehensive exposure to both fields. In my fellowship, I am able to tailor my schedule to focus on any dermatologic disease such as connective tissue disease, pruritus, graft vs host disease, and Merkel cell carcinoma. I ultimately can determine a niche in dermatology and hone my skills for a year under supervision.

Available Fellowships

Fellowship Locations—Importantly, the complex medical dermatology fellowship is not accredited by the Accreditation Council for Graduate Medical Education, which can make it difficult to identify and apply to programs. The complex medical dermatology fellowship is different than a rheumatology-dermatology fellowship, cutaneous oncology fellowship, pediatric dermatology fellowship, or other subspecialty fellowships such as those in itch or autoimmune blistering diseases. The fellowship often encompasses gaining clinical expertise in many of these conditions. I performed a thorough search online and spoke with complex medical dermatologists to compile a list of programs that offer a complex medical dermatology fellowship: Brigham and Women’s Hospital (Boston, Massachusetts); University of California San Francisco (San Francisco, California); University of Pennsylvania (Philadelphia, Pennsylvania); Cleveland Clinic (Cleveland, Ohio); and New York University (New York, New York)(Table). Only 1 spot is offered at each of these programs.

Reason to Pursue the Fellowship—There are many reasons to pursue a fellowship in complex medical dermatology such as a desire to enhance exposure to the field, to practice in an academic center and develop a niche within dermatology, to practice dermatology in an inpatient setting, to improve delivery of health care to medically challenging populations in a community setting, and to become an expert on cutaneous manifestations of internal and systemic disease.

Application—There is no standardized application or deadline for this fellowship; however, there is a concerted attempt from some of the programs to offer interviews and decisions at a similar time. Deadlines and contact information are listed on the program websites, along with more details (Table).

Recommendations—I would recommend reaching out at the beginning of postgraduate year (PGY) 4 to these programs and voicing your interest in the fellowship. It is possible to set up an away rotation at some of the programs, and if your program offers elective time, pursuing an away rotation during PGY-3 or early in PGY-4 can prove to be advantageous. Furthermore, during my application cycle I toured the University of California San Francisco, University of Pennsylvania, and Brigham and Women’s Hospital to gain further insight into each program.

Brigham and Women’s Complex Medical Dermatology Fellowship

I am currently the complex medical dermatology fellow at Brigham and Women’s Hospital, and it has been an outstanding experience thus far. The program offers numerous subspecialty clinics focusing solely on cutaneous-oncodermatology, psoriasis, rheumatology-dermatology, skin of color, mole mapping backed by artificial intelligence, cosmetics, high-risk skin cancer, neutrophilic dermatoses, patch testing, phototherapy, psychodermatology, and transplant dermatology. In addition to a wide variety of subspecialty clinics, fellows have the opportunity to participate in inpatient dermatology rounds and act as a junior attending. I appreciate the flexibility of this program combined with the ability to work alongside worldwide experts. There are numerous teaching opportunities, and all of the faculty are amiable and intelligent and emphasize wellness, education, and autonomy. Overall, my experience and decision to pursue a complex medical dermatology fellowship has been extremely rewarding and invaluable. I am gaining additional skills to aid medically challenging patients while pursuing my true passion in dermatology.

Complex medical dermatology has become an emerging field in dermatology. Although a rather protean and broad term, complex medical dermatology encompasses patients with autoimmune conditions, bullous disease, connective tissue disease, vasculitis, severe dermatoses requiring immunomodulation, and inpatient consultations. Importantly, dermatology inpatient consultations aid in lowering health care costs due to accurate diagnoses, correct treatment, and decreased hospital stays.¹ A fellowship is not required for holding an inpatient role in the hospital system as a dermatologist but can be beneficial. There are combined internal medicine–dermatology programs available for medical students applying to dermatology residency, but a complex medical dermatology fellowship is an option after residency for those who are interested. I believe that a focused complex medical dermatology fellowship differs from the training offered in combined internal medicine–dermatology residency. My fellow colleagues in combined internal medicine–dermatology programs are exposed to systemic manifestations of cutaneous disease and are experts in the interplay between the skin and other organ systems. However, the focus of their programs is with the intention of becoming double boarded in internal medicine and dermatology with comprehensive exposure to both fields. In my fellowship, I am able to tailor my schedule to focus on any dermatologic disease such as connective tissue disease, pruritus, graft vs host disease, and Merkel cell carcinoma. I ultimately can determine a niche in dermatology and hone my skills for a year under supervision.

Available Fellowships

Fellowship Locations—Importantly, the complex medical dermatology fellowship is not accredited by the Accreditation Council for Graduate Medical Education, which can make it difficult to identify and apply to programs. The complex medical dermatology fellowship is different than a rheumatology-dermatology fellowship, cutaneous oncology fellowship, pediatric dermatology fellowship, or other subspecialty fellowships such as those in itch or autoimmune blistering diseases. The fellowship often encompasses gaining clinical expertise in many of these conditions. I performed a thorough search online and spoke with complex medical dermatologists to compile a list of programs that offer a complex medical dermatology fellowship: Brigham and Women’s Hospital (Boston, Massachusetts); University of California San Francisco (San Francisco, California); University of Pennsylvania (Philadelphia, Pennsylvania); Cleveland Clinic (Cleveland, Ohio); and New York University (New York, New York)(Table). Only 1 spot is offered at each of these programs.

Reason to Pursue the Fellowship—There are many reasons to pursue a fellowship in complex medical dermatology such as a desire to enhance exposure to the field, to practice in an academic center and develop a niche within dermatology, to practice dermatology in an inpatient setting, to improve delivery of health care to medically challenging populations in a community setting, and to become an expert on cutaneous manifestations of internal and systemic disease.

Application—There is no standardized application or deadline for this fellowship; however, there is a concerted attempt from some of the programs to offer interviews and decisions at a similar time. Deadlines and contact information are listed on the program websites, along with more details (Table).

Recommendations—I would recommend reaching out at the beginning of postgraduate year (PGY) 4 to these programs and voicing your interest in the fellowship. It is possible to set up an away rotation at some of the programs, and if your program offers elective time, pursuing an away rotation during PGY-3 or early in PGY-4 can prove to be advantageous. Furthermore, during my application cycle I toured the University of California San Francisco, University of Pennsylvania, and Brigham and Women’s Hospital to gain further insight into each program.

Brigham and Women’s Complex Medical Dermatology Fellowship

I am currently the complex medical dermatology fellow at Brigham and Women’s Hospital, and it has been an outstanding experience thus far. The program offers numerous subspecialty clinics focusing solely on cutaneous-oncodermatology, psoriasis, rheumatology-dermatology, skin of color, mole mapping backed by artificial intelligence, cosmetics, high-risk skin cancer, neutrophilic dermatoses, patch testing, phototherapy, psychodermatology, and transplant dermatology. In addition to a wide variety of subspecialty clinics, fellows have the opportunity to participate in inpatient dermatology rounds and act as a junior attending. I appreciate the flexibility of this program combined with the ability to work alongside worldwide experts. There are numerous teaching opportunities, and all of the faculty are amiable and intelligent and emphasize wellness, education, and autonomy. Overall, my experience and decision to pursue a complex medical dermatology fellowship has been extremely rewarding and invaluable. I am gaining additional skills to aid medically challenging patients while pursuing my true passion in dermatology.

The Diagnosis: Merkel Cell Carcinoma

Multiple diagnoses should be considered for a small, round, blue cell neoplasm of the skin, including both primary and metastatic entities. In our patient, histopathology revealed sheets and nests of infiltrative neoplastic cells with dispersed chromatin, minimal cytoplasm, and multiple mitoses (quiz image 1).¹ The lesional cells were in the dermis and superficial subcutaneous tissue but did not appear to be arising from the epidermis. Lymphovascular invasion also was evident on additional sections. Metastatic disease was identified in 3 sentinel lymph nodes from the right inguinal and right iliac regions. These features were compatible with a diagnosis of Merkel cell carcinoma (MCC).

Merkel cell carcinoma is a rare malignant neuroendocrine cutaneous tumor with a worldwide incidence of 0.1 to 1.6 cases per 100,000 individuals annually.² The typical patient is older than 75 years with fair skin and a history of extensive sun exposure. Immunocompromised individuals are predisposed and more susceptible to infection with the Merkel cell polyomavirus, which promotes oncogenesis in the majority of MCCs. Our patient’s history of combined variable immunodeficiency likely explains her presentation at a younger age.

The prognosis in patients with MCC is poor, with 5-year survival rates of 51% for local disease, 35% for nodal disease, and 14% for systemic metastases. Survival also is reduced in cases with head/ neck primary tumors and polyomavirus-negative tumors, as well as in immunocompromised patients.² Treatment of resectable MCC consists of Mohs micrographic surgery or wide local excision depending on the patient’s cosmetic concerns. Radiation therapy is recommended for cases with increased risk for recurrence or positive surgical margins, as well as when additional resection is impossible. A study investigating immunotherapy with nivolumab demonstrated complete pathologic response and radiographic tumor regression in nearly half of patients when given 4 weeks prior to surgery.³

Immunohistochemistry is essential in discerning MCC from other small blue cell tumors. Most MCC cases show positive expression of neuroendocrine markers such as synaptophysin, chromogranin, and insulinomaassociated protein 1. Perinuclear dotlike staining with cytokeratin (CK) 20 (quiz image 2) commonly is seen, but up to 15% of cases may be CK20 negative. Many of these CK20-negative cases also express CK7. This tumor also may stain with paired box 5 (PAX-5), CD99, terminal deoxynucleotidyl transferase, Ber-EP4, and CD117^1,4; melanoma stains (ie, human melanoma black [HMB] 45, SRYrelated HMB-box 10 [SOX-10], S-100, melanoma antigen recognized by T-cells 1 [MART-1]) should be negative. However, PAX-5 expression may be a potential pitfall given that B-cell lymphomas also would express that marker and could mimic MCC histologically. Therefore, other universal lymphoid markers such as CD45 should be ordered to rule out this entity. Even with one or a few aberrant stains, a diagnosis of MCC still can be rendered using the histomorphology and the overall staining profile.⁴ Of prognostic significance, p63 expression is associated with more aggressive tumors, while Bcl-2 expression is favorable, as it offers an additional targeted treatment option.^5,6

Basal cell carcinoma (BCC) is linked to excessive sun exposure and is the most common skin cancer. Similar to MCC, it typically is mitotically active and hyperchromatic; however, lymphovascular invasion or metastasis almost never is observed in BCC, whereas approximately one-third of MCC cases have metastasized by the time of diagnosis. Additionally, BCC lacks the perinuclear dotlike staining seen with CK20.^2,7 Features present in BCC that are unusual for MCC include peripheral nuclear palisading, mucin, and retraction artifact on paraffin-embedded sections (Figure 1).⁷

Leukemia cutis (or cutaneous infiltrates of leukemia) commonly displays a perivascular and periadnexal pattern in the dermis and subcutis. These infiltrates of neoplastic leukocytes can congregate into sheets, sometimes with an overlying Grenz zone, or form single-file infiltrates (Figure 2).^1,4 The neoplastic cells can be monomorphic or atypical and commonly are susceptible to crush artifact.⁴ Although the immunohistochemical profile varies depending on the etiology of the underlying leukemia, broad hematologic markers such as CD43 and CD45 are helpful to discern these malignancies from MCC.⁴

Being neuroendocrine in origin, metastatic small cell carcinoma (Figure 3) strongly mimics MCC histologically and usually stains with synaptophysin, chromogranin, and insulinoma-associated protein 1. Both tumor cells typically exhibit nuclear molding and high mitotic rates. Although small cell carcinoma is more likely to stain with high-molecular-weight cytokeratins (ie, CK7), it is not uncommon for these tumors to express lowmolecular- weight cytokeratins such as CK20. Because most cases originate from the lungs, these lesions should be positive for thyroid transcription factor 1 and negative for PAX-5, whereas MCC would show the reverse for those stains.¹ Ultimately, however, clinical correlation with imaging results is the single best methodology for differentiation.

Small cell melanoma, a variant of nevoid melanoma, can strongly resemble an MCC or a lymphoma. Usually located on the scalp or arising from a congenital nevus, small cell melanomas are aggressive and confer an unfavorable prognosis. Histologically, they consist of nests to sheets of atypical cells within the epidermis and dermis. These cells typically exhibit hyperchromatic nuclei, minimal cytoplasm, and frequent mitoses (Figure 4). Furthermore, the cells do not display maturation based on depth.⁸ These tumors usually are positive for HMB45, S-100, MART-1, SOX-10, and tyrosinase, all of which are extremely unlikely to stain an MCC.¹

The Diagnosis: Merkel Cell Carcinoma

Multiple diagnoses should be considered for a small, round, blue cell neoplasm of the skin, including both primary and metastatic entities. In our patient, histopathology revealed sheets and nests of infiltrative neoplastic cells with dispersed chromatin, minimal cytoplasm, and multiple mitoses (quiz image 1).¹ The lesional cells were in the dermis and superficial subcutaneous tissue but did not appear to be arising from the epidermis. Lymphovascular invasion also was evident on additional sections. Metastatic disease was identified in 3 sentinel lymph nodes from the right inguinal and right iliac regions. These features were compatible with a diagnosis of Merkel cell carcinoma (MCC).

Merkel cell carcinoma is a rare malignant neuroendocrine cutaneous tumor with a worldwide incidence of 0.1 to 1.6 cases per 100,000 individuals annually.² The typical patient is older than 75 years with fair skin and a history of extensive sun exposure. Immunocompromised individuals are predisposed and more susceptible to infection with the Merkel cell polyomavirus, which promotes oncogenesis in the majority of MCCs. Our patient’s history of combined variable immunodeficiency likely explains her presentation at a younger age.

The prognosis in patients with MCC is poor, with 5-year survival rates of 51% for local disease, 35% for nodal disease, and 14% for systemic metastases. Survival also is reduced in cases with head/ neck primary tumors and polyomavirus-negative tumors, as well as in immunocompromised patients.² Treatment of resectable MCC consists of Mohs micrographic surgery or wide local excision depending on the patient’s cosmetic concerns. Radiation therapy is recommended for cases with increased risk for recurrence or positive surgical margins, as well as when additional resection is impossible. A study investigating immunotherapy with nivolumab demonstrated complete pathologic response and radiographic tumor regression in nearly half of patients when given 4 weeks prior to surgery.³

Immunohistochemistry is essential in discerning MCC from other small blue cell tumors. Most MCC cases show positive expression of neuroendocrine markers such as synaptophysin, chromogranin, and insulinomaassociated protein 1. Perinuclear dotlike staining with cytokeratin (CK) 20 (quiz image 2) commonly is seen, but up to 15% of cases may be CK20 negative. Many of these CK20-negative cases also express CK7. This tumor also may stain with paired box 5 (PAX-5), CD99, terminal deoxynucleotidyl transferase, Ber-EP4, and CD117^1,4; melanoma stains (ie, human melanoma black [HMB] 45, SRYrelated HMB-box 10 [SOX-10], S-100, melanoma antigen recognized by T-cells 1 [MART-1]) should be negative. However, PAX-5 expression may be a potential pitfall given that B-cell lymphomas also would express that marker and could mimic MCC histologically. Therefore, other universal lymphoid markers such as CD45 should be ordered to rule out this entity. Even with one or a few aberrant stains, a diagnosis of MCC still can be rendered using the histomorphology and the overall staining profile.⁴ Of prognostic significance, p63 expression is associated with more aggressive tumors, while Bcl-2 expression is favorable, as it offers an additional targeted treatment option.^5,6

Basal cell carcinoma (BCC) is linked to excessive sun exposure and is the most common skin cancer. Similar to MCC, it typically is mitotically active and hyperchromatic; however, lymphovascular invasion or metastasis almost never is observed in BCC, whereas approximately one-third of MCC cases have metastasized by the time of diagnosis. Additionally, BCC lacks the perinuclear dotlike staining seen with CK20.^2,7 Features present in BCC that are unusual for MCC include peripheral nuclear palisading, mucin, and retraction artifact on paraffin-embedded sections (Figure 1).⁷

Leukemia cutis (or cutaneous infiltrates of leukemia) commonly displays a perivascular and periadnexal pattern in the dermis and subcutis. These infiltrates of neoplastic leukocytes can congregate into sheets, sometimes with an overlying Grenz zone, or form single-file infiltrates (Figure 2).^1,4 The neoplastic cells can be monomorphic or atypical and commonly are susceptible to crush artifact.⁴ Although the immunohistochemical profile varies depending on the etiology of the underlying leukemia, broad hematologic markers such as CD43 and CD45 are helpful to discern these malignancies from MCC.⁴

Being neuroendocrine in origin, metastatic small cell carcinoma (Figure 3) strongly mimics MCC histologically and usually stains with synaptophysin, chromogranin, and insulinoma-associated protein 1. Both tumor cells typically exhibit nuclear molding and high mitotic rates. Although small cell carcinoma is more likely to stain with high-molecular-weight cytokeratins (ie, CK7), it is not uncommon for these tumors to express lowmolecular- weight cytokeratins such as CK20. Because most cases originate from the lungs, these lesions should be positive for thyroid transcription factor 1 and negative for PAX-5, whereas MCC would show the reverse for those stains.¹ Ultimately, however, clinical correlation with imaging results is the single best methodology for differentiation.

Small cell melanoma, a variant of nevoid melanoma, can strongly resemble an MCC or a lymphoma. Usually located on the scalp or arising from a congenital nevus, small cell melanomas are aggressive and confer an unfavorable prognosis. Histologically, they consist of nests to sheets of atypical cells within the epidermis and dermis. These cells typically exhibit hyperchromatic nuclei, minimal cytoplasm, and frequent mitoses (Figure 4). Furthermore, the cells do not display maturation based on depth.⁸ These tumors usually are positive for HMB45, S-100, MART-1, SOX-10, and tyrosinase, all of which are extremely unlikely to stain an MCC.¹

The Diagnosis: Merkel Cell Carcinoma

Multiple diagnoses should be considered for a small, round, blue cell neoplasm of the skin, including both primary and metastatic entities. In our patient, histopathology revealed sheets and nests of infiltrative neoplastic cells with dispersed chromatin, minimal cytoplasm, and multiple mitoses (quiz image 1).¹ The lesional cells were in the dermis and superficial subcutaneous tissue but did not appear to be arising from the epidermis. Lymphovascular invasion also was evident on additional sections. Metastatic disease was identified in 3 sentinel lymph nodes from the right inguinal and right iliac regions. These features were compatible with a diagnosis of Merkel cell carcinoma (MCC).

Merkel cell carcinoma is a rare malignant neuroendocrine cutaneous tumor with a worldwide incidence of 0.1 to 1.6 cases per 100,000 individuals annually.² The typical patient is older than 75 years with fair skin and a history of extensive sun exposure. Immunocompromised individuals are predisposed and more susceptible to infection with the Merkel cell polyomavirus, which promotes oncogenesis in the majority of MCCs. Our patient’s history of combined variable immunodeficiency likely explains her presentation at a younger age.

The prognosis in patients with MCC is poor, with 5-year survival rates of 51% for local disease, 35% for nodal disease, and 14% for systemic metastases. Survival also is reduced in cases with head/ neck primary tumors and polyomavirus-negative tumors, as well as in immunocompromised patients.² Treatment of resectable MCC consists of Mohs micrographic surgery or wide local excision depending on the patient’s cosmetic concerns. Radiation therapy is recommended for cases with increased risk for recurrence or positive surgical margins, as well as when additional resection is impossible. A study investigating immunotherapy with nivolumab demonstrated complete pathologic response and radiographic tumor regression in nearly half of patients when given 4 weeks prior to surgery.³

Immunohistochemistry is essential in discerning MCC from other small blue cell tumors. Most MCC cases show positive expression of neuroendocrine markers such as synaptophysin, chromogranin, and insulinomaassociated protein 1. Perinuclear dotlike staining with cytokeratin (CK) 20 (quiz image 2) commonly is seen, but up to 15% of cases may be CK20 negative. Many of these CK20-negative cases also express CK7. This tumor also may stain with paired box 5 (PAX-5), CD99, terminal deoxynucleotidyl transferase, Ber-EP4, and CD117^1,4; melanoma stains (ie, human melanoma black [HMB] 45, SRYrelated HMB-box 10 [SOX-10], S-100, melanoma antigen recognized by T-cells 1 [MART-1]) should be negative. However, PAX-5 expression may be a potential pitfall given that B-cell lymphomas also would express that marker and could mimic MCC histologically. Therefore, other universal lymphoid markers such as CD45 should be ordered to rule out this entity. Even with one or a few aberrant stains, a diagnosis of MCC still can be rendered using the histomorphology and the overall staining profile.⁴ Of prognostic significance, p63 expression is associated with more aggressive tumors, while Bcl-2 expression is favorable, as it offers an additional targeted treatment option.^5,6

Basal cell carcinoma (BCC) is linked to excessive sun exposure and is the most common skin cancer. Similar to MCC, it typically is mitotically active and hyperchromatic; however, lymphovascular invasion or metastasis almost never is observed in BCC, whereas approximately one-third of MCC cases have metastasized by the time of diagnosis. Additionally, BCC lacks the perinuclear dotlike staining seen with CK20.^2,7 Features present in BCC that are unusual for MCC include peripheral nuclear palisading, mucin, and retraction artifact on paraffin-embedded sections (Figure 1).⁷

Leukemia cutis (or cutaneous infiltrates of leukemia) commonly displays a perivascular and periadnexal pattern in the dermis and subcutis. These infiltrates of neoplastic leukocytes can congregate into sheets, sometimes with an overlying Grenz zone, or form single-file infiltrates (Figure 2).^1,4 The neoplastic cells can be monomorphic or atypical and commonly are susceptible to crush artifact.⁴ Although the immunohistochemical profile varies depending on the etiology of the underlying leukemia, broad hematologic markers such as CD43 and CD45 are helpful to discern these malignancies from MCC.⁴

Being neuroendocrine in origin, metastatic small cell carcinoma (Figure 3) strongly mimics MCC histologically and usually stains with synaptophysin, chromogranin, and insulinoma-associated protein 1. Both tumor cells typically exhibit nuclear molding and high mitotic rates. Although small cell carcinoma is more likely to stain with high-molecular-weight cytokeratins (ie, CK7), it is not uncommon for these tumors to express lowmolecular- weight cytokeratins such as CK20. Because most cases originate from the lungs, these lesions should be positive for thyroid transcription factor 1 and negative for PAX-5, whereas MCC would show the reverse for those stains.¹ Ultimately, however, clinical correlation with imaging results is the single best methodology for differentiation.

Small cell melanoma, a variant of nevoid melanoma, can strongly resemble an MCC or a lymphoma. Usually located on the scalp or arising from a congenital nevus, small cell melanomas are aggressive and confer an unfavorable prognosis. Histologically, they consist of nests to sheets of atypical cells within the epidermis and dermis. These cells typically exhibit hyperchromatic nuclei, minimal cytoplasm, and frequent mitoses (Figure 4). Furthermore, the cells do not display maturation based on depth.⁸ These tumors usually are positive for HMB45, S-100, MART-1, SOX-10, and tyrosinase, all of which are extremely unlikely to stain an MCC.¹

Pseudofolliculitis barbae (PFB)(also referred to as razor bumps) is a skin disease of the face and neck caused by shaving and remains prevalent in the US Military. As the sharpened ends of curly hair strands penetrate back into the epidermis, they can trigger inflammatory reactions, leading to papules and pustules as well as hyperpigmentation and scarring.¹ Although anyone with thick curly hair can develop PFB, Black individuals are disproportionately affected, with 45% to 83% reporting PFB symptoms compared with 18% of White individuals.² In this article, we review the treatments and current policies on PFB in the military.

Treatment Options

Shaving Guidelines—Daily shaving remains the grooming standard for US service members who are encouraged to follow prescribed grooming techniques to prevent mild cases of PFB, defined as having “few, scattered papules with scant hair growth of the beard area,” according to the technical bulletin of the US Army, which provides the most detailed guidelines among the branches.³ The bulletin recommends hydrating the face with warm water, followed by a preshave lotion and shaving with a single pass superiorly to inferiorly. Following shaving, postrazor hydration lotion is recommended. Single-bladed razors are preferred, as there is less trauma to existing PFB and less potential for hair retraction under the epidermis, though multibladed razors can be used with adequate preshave and postrazor hydration.⁴ Shaving can be undertaken in the evening to ensure adequate time for preshave preparation and postshave hydration. Waterless shaving uses waterless soaps or lotions containing α-hydroxy acid just prior to shaving in lieu of preshaving and postshaving procedures.⁴

Topical Medications—For PFB cases that are recalcitrant to management by changes in shaving, topical retinoids are commonly prescribed, as they reduce follicular hyperkeratosis that may lead to PFB.⁵ The Army medical bulletin recommends a pea-sized amount of tretinoin cream or gel 0.025%, 0.05%, or 0.1% for moderate cases, defined as “heavier beard growth, more scattered papules, no evidence of pustules or denudation.”³ Adapalene cream 0.1% may be used instead of tretinoin for sensitive skin. Oral doxycycline or topical benzoyl peroxide–clindamycin may be added for secondary bacterial skin infections. Clinical trials have demonstrated that combination benzoyl peroxide–clindamycin significantly reduces papules and pustules in up to 63% of patients with PFB (P<.029).⁶ Azelaic acid can be prescribed for prominent postinflammatory hyperpigmentation. The bulletin also suggests depilatories such as barium sulfide to obtund the hair ends and make them less likely to re-enter the skin surface, though it notes low compliance rates due to strong sulfur odor, messy application, and irritation and reactions to ingredients in the preparations.⁴

Shaving Waivers and Laser Hair Removal—The definitive treatment of PFB is to not shave, and a shaving waiver or laser hair removal (LHR) are the best options for severe PFB or PFB refractory to other treatments. A shaving waiver (or shaving profile) allows for growth of up to 0.25 inches of facial hair with maintenance of the length using clippers. The shaving profile typically is issued by the referring primary care manager (PCM) but also can be recommended by a dermatologist. Each military branch implements different regulations on shaving profiles, which complicates care delivery at joint-service military treatment facilities (MTFs). The Table provides guidelines that govern the management of PFB by the US Army, Air Force, Navy, and Marine Corps. The issuance and duration of shaving waivers vary by service.

Laser hair removal therapy uses high-wavelength lasers that largely bypass the melanocyte-containing basal layer and selectively target hair follicles located deeper in the skin, which results in precise hair reduction with relative sparing of the epidermis.¹⁶ Clinical trials at military clinics have demonstrated that treatments with the 1064-nm long-pulse Nd:YAG laser generally are safe and effective in impeding hair growth in Fitzpatrick skin types IV, V, and VI.¹⁷ This laser, along with the Alexandrite 755-nm long-pulse laser for Fitzpatrick skin types I to III, is widely available and used for LHR at MTFs that house dermatologists. Eflornithine cream 13.9%, which is approved by the US Food and Drug Administration to treat hirsutism, can be used as monotherapy for treatment of PFB and has a synergistic depilatory effect in PFB patients when used in conjunction with LHR.^18,19 Laser hair removal treatments can induce a permanent change in facial hair density and pattern of growth. Side effects and complications of LHR include discomfort during treatment and, in rare instances, blistering and dyspigmentation of the skin as well as paradoxical hair growth.¹⁷

TRICARE, the uniformed health care program, covers LHR in the civilian sector if the following criteria are met: candidates must work in an environment that may require breathing protection, and they must have failed conservative therapy; an MTF dermatologist must evaluate each case and attempt LHR at an MTF to limit outside referrals; and the MTF dermatologist must process each outside referral claim to completion and ensure that the LHR is rendered by a civilian dermatologist and is consistent with branch-specific policies.²⁰

Service Policies on PFB

Army—The Army technical bulletin breaks down the treatment of PFB based on mild, moderate, and severe conditions.³ For mild conditions, a trial of shaving every 2 or 3 days until resolution is recommended. For moderate PFB, topical tretinoin as well as shaving every 2 to 3 days is recommended. For severe conditions, temporary beard growth with issuance of a temporary shaving profile up to 90 days is authorized.³

The technical bulletin also allows a permanent shaving profile for soldiers who demonstrate a severe adverse reaction to treatment or progression of the disease despite a trial of all these methods.³ The regulation stipulates that 0.125 to 0.25 inches of beard growth usually is sufficient to prevent PFB. Patients on profiles must be re-evaluated by a PCM or a dermatologist at least once a year.³

Air Force—Air Force Instruction 44-102 delegates PFB treatment and management strategies to each individual MTF, which allows for decentralized management of PFB, resulting in treatment protocols that can differ from one MTF to another.⁷ Since 2020, waivers have been valid for 5 years regardless of deployment or permanent change of station location. Previously, shaving profiles required annual renewals.⁷ Special duties, such as Honor Guard, Thunderbirds, Special Warfare Mission Support, recruiters, and the Air Force Band, often follow the professional appearance standards more strictly. Until recently, the Honor Guard used to reassign those with long-term medical shaving waivers but now allows airmen with shaving profiles to serve with exceptions (eg, shaving before ceremonies).²¹

Navy—BUPERS (Bureau of Naval Personnel) Instruction 1000.22C divides PFB severity into 2 categories.⁸ For mild to moderate PFB cases, topical tretinoin and adapalene are recommended, along with improved shaving hygiene practices. As an alternative to topical steroids, topical eflornithine monotherapy can be used twice daily for 60 days. For moderate to severe PFB cases, continued grooming modifications and LHR at military clinics with dermatologic services are expected.⁸

Naval administrative memorandum NAVADMIN 064/22 (released in 2022) no longer requires sailors with a shaving “chit,” or shaving waiver, to fully grow out their beards.⁹ Sailors may now outline or edge their beards as long as doing so does not trigger a skin irritation or outbreak. Furthermore, sailors are no longer required to carry a physical copy of their shaving chit at all times. Laser hair removal for sailors with PFB is now considered optional, whereas sailors with severe PFB were previously expected to receive LHR.⁹

Marine Corps—The Marine Corps endorses a 4-phase treatment algorithm (Table). As of January 2022, permanent shaving chits are authorized. Marines no longer need to carry physical copies of their chits at all times and cannot be separated from service because of PFB.¹⁰ New updates explicitly state that medical officers, not the commanding officers, now have final authority for granting shaving chits.¹¹

Final Thoughts

The Army provides the most detailed bulletin, which defines the clinical features and treatments expected for each stage of PFB. All 4 service branches permit temporary profiles, albeit for different lengths of time. However, only the Army and the Marine Corps currently authorize permanent shaving waivers if all treatments mentioned in their respective bulletins have failed.

The Air Force has adopted the most decentralized approach, in which each MTF is responsible for implementing its own treatment protocols and definitions. Air Force regulations now authorize a 5-year shaving profile for medical reasons, including PFB. The Air Force also has spearheaded efforts to create more inclusive policies. A study of 10,000 active-duty male Air Force members conducted by Air Force physicians found that shaving waivers were associated with longer times to promotion. Although self-identified race was not independently linked to longer promotion times, more Black service members were affected because of a higher prevalence of PFB and shaving profiles.²²

The Navy has outlined the most specific timeline for therapy for PFB. The regulations allow a 60-day temporary shaving chit that expires on the day of the appointment with the dermatologist or PCM. Although sailors were previously mandated to fully grow out their beards without modifications during the 60-day shaving chit period, Navy leadership recently overturned these requirements. However, permanent shaving chits are still not authorized in the Navy.

Service members are trying to destigmatize shaving profiles and facial hair in our military. A Facebook group called DoD Beard Action Initiative has more than 17,000 members and was created in 2021 to compile testimonies and data regarding the effects of PFB on airmen.²³ Soldiers also have petitioned for growing beards in the garrison environment with more than 100,000 signatures, citing that North Atlantic Treaty Organization allied nations permit beard growth in their respective ranks.²⁴ A Sikh marine captain recently won a lawsuit against the US Department of the Navy to maintain a beard with a turban in uniform on religious grounds.²⁵

The clean-shaven look remains standard across the military, not only for uniformity of appearance but also for safety concerns. The Naval Safety Center’s ALSAFE report concluded that any facial hair impedes a tight fit of gas masks, which can be lethal in chemical warfare. However, the report did not explore how different hair lengths would affect the seal of gas masks.²⁶ It remains unknown how 0.25 inch of facial hair, the maximum hair length authorized for most PFB patients, affects the seal. Department of Defense occupational health researchers currently are assessing how each specific facial hair length diminishes the effectiveness of gas masks.²⁷

Furthermore, the COVID-19 pandemic has led to frequent N95 respirator wear in the military. It is likely that growing a long beard disrupts the fitting of N95 respirators and could endanger service members, especially in clinical settings. However, one study confirmed that 0.125 inch of facial hair still results in 98% effectiveness in filtering particles for the respirator wearers.²⁸ Although unverified, it is surmisable that 0.25 inch of facial hair will likely not render all respirators useless. However, current Occupational Safety and Health Administration guidelines require fit tests to be conducted only on clean-shaven faces.²⁹ Effectively, service members with facial hair cannot be fit-tested for N95 respirators.

More research is needed to optimize treatment protocols and regulations for PFB in our military. As long as the current grooming standards remain in place, treatment of PFB will be a controversial topic. Guidelines will need to be continuously updated to balance the needs of our service members and to minimize risk to unit safety and mission success. Department of Defense Instruction 6130.03, Volume 1, revised in late 2022, now no longer designates PFB as a condition that disqualifies a candidate from entering service in any military branch.³⁰ The Department of Defense is demonstrating active research and adoption of policies regarding PFB that will benefit our service members.

Pseudofolliculitis barbae (PFB)(also referred to as razor bumps) is a skin disease of the face and neck caused by shaving and remains prevalent in the US Military. As the sharpened ends of curly hair strands penetrate back into the epidermis, they can trigger inflammatory reactions, leading to papules and pustules as well as hyperpigmentation and scarring.¹ Although anyone with thick curly hair can develop PFB, Black individuals are disproportionately affected, with 45% to 83% reporting PFB symptoms compared with 18% of White individuals.² In this article, we review the treatments and current policies on PFB in the military.

Treatment Options

Shaving Guidelines—Daily shaving remains the grooming standard for US service members who are encouraged to follow prescribed grooming techniques to prevent mild cases of PFB, defined as having “few, scattered papules with scant hair growth of the beard area,” according to the technical bulletin of the US Army, which provides the most detailed guidelines among the branches.³ The bulletin recommends hydrating the face with warm water, followed by a preshave lotion and shaving with a single pass superiorly to inferiorly. Following shaving, postrazor hydration lotion is recommended. Single-bladed razors are preferred, as there is less trauma to existing PFB and less potential for hair retraction under the epidermis, though multibladed razors can be used with adequate preshave and postrazor hydration.⁴ Shaving can be undertaken in the evening to ensure adequate time for preshave preparation and postshave hydration. Waterless shaving uses waterless soaps or lotions containing α-hydroxy acid just prior to shaving in lieu of preshaving and postshaving procedures.⁴

Topical Medications—For PFB cases that are recalcitrant to management by changes in shaving, topical retinoids are commonly prescribed, as they reduce follicular hyperkeratosis that may lead to PFB.⁵ The Army medical bulletin recommends a pea-sized amount of tretinoin cream or gel 0.025%, 0.05%, or 0.1% for moderate cases, defined as “heavier beard growth, more scattered papules, no evidence of pustules or denudation.”³ Adapalene cream 0.1% may be used instead of tretinoin for sensitive skin. Oral doxycycline or topical benzoyl peroxide–clindamycin may be added for secondary bacterial skin infections. Clinical trials have demonstrated that combination benzoyl peroxide–clindamycin significantly reduces papules and pustules in up to 63% of patients with PFB (P<.029).⁶ Azelaic acid can be prescribed for prominent postinflammatory hyperpigmentation. The bulletin also suggests depilatories such as barium sulfide to obtund the hair ends and make them less likely to re-enter the skin surface, though it notes low compliance rates due to strong sulfur odor, messy application, and irritation and reactions to ingredients in the preparations.⁴

Shaving Waivers and Laser Hair Removal—The definitive treatment of PFB is to not shave, and a shaving waiver or laser hair removal (LHR) are the best options for severe PFB or PFB refractory to other treatments. A shaving waiver (or shaving profile) allows for growth of up to 0.25 inches of facial hair with maintenance of the length using clippers. The shaving profile typically is issued by the referring primary care manager (PCM) but also can be recommended by a dermatologist. Each military branch implements different regulations on shaving profiles, which complicates care delivery at joint-service military treatment facilities (MTFs). The Table provides guidelines that govern the management of PFB by the US Army, Air Force, Navy, and Marine Corps. The issuance and duration of shaving waivers vary by service.

Laser hair removal therapy uses high-wavelength lasers that largely bypass the melanocyte-containing basal layer and selectively target hair follicles located deeper in the skin, which results in precise hair reduction with relative sparing of the epidermis.¹⁶ Clinical trials at military clinics have demonstrated that treatments with the 1064-nm long-pulse Nd:YAG laser generally are safe and effective in impeding hair growth in Fitzpatrick skin types IV, V, and VI.¹⁷ This laser, along with the Alexandrite 755-nm long-pulse laser for Fitzpatrick skin types I to III, is widely available and used for LHR at MTFs that house dermatologists. Eflornithine cream 13.9%, which is approved by the US Food and Drug Administration to treat hirsutism, can be used as monotherapy for treatment of PFB and has a synergistic depilatory effect in PFB patients when used in conjunction with LHR.^18,19 Laser hair removal treatments can induce a permanent change in facial hair density and pattern of growth. Side effects and complications of LHR include discomfort during treatment and, in rare instances, blistering and dyspigmentation of the skin as well as paradoxical hair growth.¹⁷

TRICARE, the uniformed health care program, covers LHR in the civilian sector if the following criteria are met: candidates must work in an environment that may require breathing protection, and they must have failed conservative therapy; an MTF dermatologist must evaluate each case and attempt LHR at an MTF to limit outside referrals; and the MTF dermatologist must process each outside referral claim to completion and ensure that the LHR is rendered by a civilian dermatologist and is consistent with branch-specific policies.²⁰

Service Policies on PFB

Army—The Army technical bulletin breaks down the treatment of PFB based on mild, moderate, and severe conditions.³ For mild conditions, a trial of shaving every 2 or 3 days until resolution is recommended. For moderate PFB, topical tretinoin as well as shaving every 2 to 3 days is recommended. For severe conditions, temporary beard growth with issuance of a temporary shaving profile up to 90 days is authorized.³

The technical bulletin also allows a permanent shaving profile for soldiers who demonstrate a severe adverse reaction to treatment or progression of the disease despite a trial of all these methods.³ The regulation stipulates that 0.125 to 0.25 inches of beard growth usually is sufficient to prevent PFB. Patients on profiles must be re-evaluated by a PCM or a dermatologist at least once a year.³

Air Force—Air Force Instruction 44-102 delegates PFB treatment and management strategies to each individual MTF, which allows for decentralized management of PFB, resulting in treatment protocols that can differ from one MTF to another.⁷ Since 2020, waivers have been valid for 5 years regardless of deployment or permanent change of station location. Previously, shaving profiles required annual renewals.⁷ Special duties, such as Honor Guard, Thunderbirds, Special Warfare Mission Support, recruiters, and the Air Force Band, often follow the professional appearance standards more strictly. Until recently, the Honor Guard used to reassign those with long-term medical shaving waivers but now allows airmen with shaving profiles to serve with exceptions (eg, shaving before ceremonies).²¹

Navy—BUPERS (Bureau of Naval Personnel) Instruction 1000.22C divides PFB severity into 2 categories.⁸ For mild to moderate PFB cases, topical tretinoin and adapalene are recommended, along with improved shaving hygiene practices. As an alternative to topical steroids, topical eflornithine monotherapy can be used twice daily for 60 days. For moderate to severe PFB cases, continued grooming modifications and LHR at military clinics with dermatologic services are expected.⁸

Naval administrative memorandum NAVADMIN 064/22 (released in 2022) no longer requires sailors with a shaving “chit,” or shaving waiver, to fully grow out their beards.⁹ Sailors may now outline or edge their beards as long as doing so does not trigger a skin irritation or outbreak. Furthermore, sailors are no longer required to carry a physical copy of their shaving chit at all times. Laser hair removal for sailors with PFB is now considered optional, whereas sailors with severe PFB were previously expected to receive LHR.⁹

Marine Corps—The Marine Corps endorses a 4-phase treatment algorithm (Table). As of January 2022, permanent shaving chits are authorized. Marines no longer need to carry physical copies of their chits at all times and cannot be separated from service because of PFB.¹⁰ New updates explicitly state that medical officers, not the commanding officers, now have final authority for granting shaving chits.¹¹

Final Thoughts

The Army provides the most detailed bulletin, which defines the clinical features and treatments expected for each stage of PFB. All 4 service branches permit temporary profiles, albeit for different lengths of time. However, only the Army and the Marine Corps currently authorize permanent shaving waivers if all treatments mentioned in their respective bulletins have failed.

The Air Force has adopted the most decentralized approach, in which each MTF is responsible for implementing its own treatment protocols and definitions. Air Force regulations now authorize a 5-year shaving profile for medical reasons, including PFB. The Air Force also has spearheaded efforts to create more inclusive policies. A study of 10,000 active-duty male Air Force members conducted by Air Force physicians found that shaving waivers were associated with longer times to promotion. Although self-identified race was not independently linked to longer promotion times, more Black service members were affected because of a higher prevalence of PFB and shaving profiles.²²

The Navy has outlined the most specific timeline for therapy for PFB. The regulations allow a 60-day temporary shaving chit that expires on the day of the appointment with the dermatologist or PCM. Although sailors were previously mandated to fully grow out their beards without modifications during the 60-day shaving chit period, Navy leadership recently overturned these requirements. However, permanent shaving chits are still not authorized in the Navy.

Service members are trying to destigmatize shaving profiles and facial hair in our military. A Facebook group called DoD Beard Action Initiative has more than 17,000 members and was created in 2021 to compile testimonies and data regarding the effects of PFB on airmen.²³ Soldiers also have petitioned for growing beards in the garrison environment with more than 100,000 signatures, citing that North Atlantic Treaty Organization allied nations permit beard growth in their respective ranks.²⁴ A Sikh marine captain recently won a lawsuit against the US Department of the Navy to maintain a beard with a turban in uniform on religious grounds.²⁵

The clean-shaven look remains standard across the military, not only for uniformity of appearance but also for safety concerns. The Naval Safety Center’s ALSAFE report concluded that any facial hair impedes a tight fit of gas masks, which can be lethal in chemical warfare. However, the report did not explore how different hair lengths would affect the seal of gas masks.²⁶ It remains unknown how 0.25 inch of facial hair, the maximum hair length authorized for most PFB patients, affects the seal. Department of Defense occupational health researchers currently are assessing how each specific facial hair length diminishes the effectiveness of gas masks.²⁷

Furthermore, the COVID-19 pandemic has led to frequent N95 respirator wear in the military. It is likely that growing a long beard disrupts the fitting of N95 respirators and could endanger service members, especially in clinical settings. However, one study confirmed that 0.125 inch of facial hair still results in 98% effectiveness in filtering particles for the respirator wearers.²⁸ Although unverified, it is surmisable that 0.25 inch of facial hair will likely not render all respirators useless. However, current Occupational Safety and Health Administration guidelines require fit tests to be conducted only on clean-shaven faces.²⁹ Effectively, service members with facial hair cannot be fit-tested for N95 respirators.

More research is needed to optimize treatment protocols and regulations for PFB in our military. As long as the current grooming standards remain in place, treatment of PFB will be a controversial topic. Guidelines will need to be continuously updated to balance the needs of our service members and to minimize risk to unit safety and mission success. Department of Defense Instruction 6130.03, Volume 1, revised in late 2022, now no longer designates PFB as a condition that disqualifies a candidate from entering service in any military branch.³⁰ The Department of Defense is demonstrating active research and adoption of policies regarding PFB that will benefit our service members.

Pseudofolliculitis barbae (PFB)(also referred to as razor bumps) is a skin disease of the face and neck caused by shaving and remains prevalent in the US Military. As the sharpened ends of curly hair strands penetrate back into the epidermis, they can trigger inflammatory reactions, leading to papules and pustules as well as hyperpigmentation and scarring.¹ Although anyone with thick curly hair can develop PFB, Black individuals are disproportionately affected, with 45% to 83% reporting PFB symptoms compared with 18% of White individuals.² In this article, we review the treatments and current policies on PFB in the military.

Treatment Options

Shaving Guidelines—Daily shaving remains the grooming standard for US service members who are encouraged to follow prescribed grooming techniques to prevent mild cases of PFB, defined as having “few, scattered papules with scant hair growth of the beard area,” according to the technical bulletin of the US Army, which provides the most detailed guidelines among the branches.³ The bulletin recommends hydrating the face with warm water, followed by a preshave lotion and shaving with a single pass superiorly to inferiorly. Following shaving, postrazor hydration lotion is recommended. Single-bladed razors are preferred, as there is less trauma to existing PFB and less potential for hair retraction under the epidermis, though multibladed razors can be used with adequate preshave and postrazor hydration.⁴ Shaving can be undertaken in the evening to ensure adequate time for preshave preparation and postshave hydration. Waterless shaving uses waterless soaps or lotions containing α-hydroxy acid just prior to shaving in lieu of preshaving and postshaving procedures.⁴

Topical Medications—For PFB cases that are recalcitrant to management by changes in shaving, topical retinoids are commonly prescribed, as they reduce follicular hyperkeratosis that may lead to PFB.⁵ The Army medical bulletin recommends a pea-sized amount of tretinoin cream or gel 0.025%, 0.05%, or 0.1% for moderate cases, defined as “heavier beard growth, more scattered papules, no evidence of pustules or denudation.”³ Adapalene cream 0.1% may be used instead of tretinoin for sensitive skin. Oral doxycycline or topical benzoyl peroxide–clindamycin may be added for secondary bacterial skin infections. Clinical trials have demonstrated that combination benzoyl peroxide–clindamycin significantly reduces papules and pustules in up to 63% of patients with PFB (P<.029).⁶ Azelaic acid can be prescribed for prominent postinflammatory hyperpigmentation. The bulletin also suggests depilatories such as barium sulfide to obtund the hair ends and make them less likely to re-enter the skin surface, though it notes low compliance rates due to strong sulfur odor, messy application, and irritation and reactions to ingredients in the preparations.⁴

Shaving Waivers and Laser Hair Removal—The definitive treatment of PFB is to not shave, and a shaving waiver or laser hair removal (LHR) are the best options for severe PFB or PFB refractory to other treatments. A shaving waiver (or shaving profile) allows for growth of up to 0.25 inches of facial hair with maintenance of the length using clippers. The shaving profile typically is issued by the referring primary care manager (PCM) but also can be recommended by a dermatologist. Each military branch implements different regulations on shaving profiles, which complicates care delivery at joint-service military treatment facilities (MTFs). The Table provides guidelines that govern the management of PFB by the US Army, Air Force, Navy, and Marine Corps. The issuance and duration of shaving waivers vary by service.

Laser hair removal therapy uses high-wavelength lasers that largely bypass the melanocyte-containing basal layer and selectively target hair follicles located deeper in the skin, which results in precise hair reduction with relative sparing of the epidermis.¹⁶ Clinical trials at military clinics have demonstrated that treatments with the 1064-nm long-pulse Nd:YAG laser generally are safe and effective in impeding hair growth in Fitzpatrick skin types IV, V, and VI.¹⁷ This laser, along with the Alexandrite 755-nm long-pulse laser for Fitzpatrick skin types I to III, is widely available and used for LHR at MTFs that house dermatologists. Eflornithine cream 13.9%, which is approved by the US Food and Drug Administration to treat hirsutism, can be used as monotherapy for treatment of PFB and has a synergistic depilatory effect in PFB patients when used in conjunction with LHR.^18,19 Laser hair removal treatments can induce a permanent change in facial hair density and pattern of growth. Side effects and complications of LHR include discomfort during treatment and, in rare instances, blistering and dyspigmentation of the skin as well as paradoxical hair growth.¹⁷

TRICARE, the uniformed health care program, covers LHR in the civilian sector if the following criteria are met: candidates must work in an environment that may require breathing protection, and they must have failed conservative therapy; an MTF dermatologist must evaluate each case and attempt LHR at an MTF to limit outside referrals; and the MTF dermatologist must process each outside referral claim to completion and ensure that the LHR is rendered by a civilian dermatologist and is consistent with branch-specific policies.²⁰

Service Policies on PFB

Army—The Army technical bulletin breaks down the treatment of PFB based on mild, moderate, and severe conditions.³ For mild conditions, a trial of shaving every 2 or 3 days until resolution is recommended. For moderate PFB, topical tretinoin as well as shaving every 2 to 3 days is recommended. For severe conditions, temporary beard growth with issuance of a temporary shaving profile up to 90 days is authorized.³

The technical bulletin also allows a permanent shaving profile for soldiers who demonstrate a severe adverse reaction to treatment or progression of the disease despite a trial of all these methods.³ The regulation stipulates that 0.125 to 0.25 inches of beard growth usually is sufficient to prevent PFB. Patients on profiles must be re-evaluated by a PCM or a dermatologist at least once a year.³

Air Force—Air Force Instruction 44-102 delegates PFB treatment and management strategies to each individual MTF, which allows for decentralized management of PFB, resulting in treatment protocols that can differ from one MTF to another.⁷ Since 2020, waivers have been valid for 5 years regardless of deployment or permanent change of station location. Previously, shaving profiles required annual renewals.⁷ Special duties, such as Honor Guard, Thunderbirds, Special Warfare Mission Support, recruiters, and the Air Force Band, often follow the professional appearance standards more strictly. Until recently, the Honor Guard used to reassign those with long-term medical shaving waivers but now allows airmen with shaving profiles to serve with exceptions (eg, shaving before ceremonies).²¹

Navy—BUPERS (Bureau of Naval Personnel) Instruction 1000.22C divides PFB severity into 2 categories.⁸ For mild to moderate PFB cases, topical tretinoin and adapalene are recommended, along with improved shaving hygiene practices. As an alternative to topical steroids, topical eflornithine monotherapy can be used twice daily for 60 days. For moderate to severe PFB cases, continued grooming modifications and LHR at military clinics with dermatologic services are expected.⁸

Naval administrative memorandum NAVADMIN 064/22 (released in 2022) no longer requires sailors with a shaving “chit,” or shaving waiver, to fully grow out their beards.⁹ Sailors may now outline or edge their beards as long as doing so does not trigger a skin irritation or outbreak. Furthermore, sailors are no longer required to carry a physical copy of their shaving chit at all times. Laser hair removal for sailors with PFB is now considered optional, whereas sailors with severe PFB were previously expected to receive LHR.⁹

Marine Corps—The Marine Corps endorses a 4-phase treatment algorithm (Table). As of January 2022, permanent shaving chits are authorized. Marines no longer need to carry physical copies of their chits at all times and cannot be separated from service because of PFB.¹⁰ New updates explicitly state that medical officers, not the commanding officers, now have final authority for granting shaving chits.¹¹

Final Thoughts

The Army provides the most detailed bulletin, which defines the clinical features and treatments expected for each stage of PFB. All 4 service branches permit temporary profiles, albeit for different lengths of time. However, only the Army and the Marine Corps currently authorize permanent shaving waivers if all treatments mentioned in their respective bulletins have failed.

The Air Force has adopted the most decentralized approach, in which each MTF is responsible for implementing its own treatment protocols and definitions. Air Force regulations now authorize a 5-year shaving profile for medical reasons, including PFB. The Air Force also has spearheaded efforts to create more inclusive policies. A study of 10,000 active-duty male Air Force members conducted by Air Force physicians found that shaving waivers were associated with longer times to promotion. Although self-identified race was not independently linked to longer promotion times, more Black service members were affected because of a higher prevalence of PFB and shaving profiles.²²

The Navy has outlined the most specific timeline for therapy for PFB. The regulations allow a 60-day temporary shaving chit that expires on the day of the appointment with the dermatologist or PCM. Although sailors were previously mandated to fully grow out their beards without modifications during the 60-day shaving chit period, Navy leadership recently overturned these requirements. However, permanent shaving chits are still not authorized in the Navy.

Service members are trying to destigmatize shaving profiles and facial hair in our military. A Facebook group called DoD Beard Action Initiative has more than 17,000 members and was created in 2021 to compile testimonies and data regarding the effects of PFB on airmen.²³ Soldiers also have petitioned for growing beards in the garrison environment with more than 100,000 signatures, citing that North Atlantic Treaty Organization allied nations permit beard growth in their respective ranks.²⁴ A Sikh marine captain recently won a lawsuit against the US Department of the Navy to maintain a beard with a turban in uniform on religious grounds.²⁵

The clean-shaven look remains standard across the military, not only for uniformity of appearance but also for safety concerns. The Naval Safety Center’s ALSAFE report concluded that any facial hair impedes a tight fit of gas masks, which can be lethal in chemical warfare. However, the report did not explore how different hair lengths would affect the seal of gas masks.²⁶ It remains unknown how 0.25 inch of facial hair, the maximum hair length authorized for most PFB patients, affects the seal. Department of Defense occupational health researchers currently are assessing how each specific facial hair length diminishes the effectiveness of gas masks.²⁷

Furthermore, the COVID-19 pandemic has led to frequent N95 respirator wear in the military. It is likely that growing a long beard disrupts the fitting of N95 respirators and could endanger service members, especially in clinical settings. However, one study confirmed that 0.125 inch of facial hair still results in 98% effectiveness in filtering particles for the respirator wearers.²⁸ Although unverified, it is surmisable that 0.25 inch of facial hair will likely not render all respirators useless. However, current Occupational Safety and Health Administration guidelines require fit tests to be conducted only on clean-shaven faces.²⁹ Effectively, service members with facial hair cannot be fit-tested for N95 respirators.

More research is needed to optimize treatment protocols and regulations for PFB in our military. As long as the current grooming standards remain in place, treatment of PFB will be a controversial topic. Guidelines will need to be continuously updated to balance the needs of our service members and to minimize risk to unit safety and mission success. Department of Defense Instruction 6130.03, Volume 1, revised in late 2022, now no longer designates PFB as a condition that disqualifies a candidate from entering service in any military branch.³⁰ The Department of Defense is demonstrating active research and adoption of policies regarding PFB that will benefit our service members.

Acrylates are a ubiquitous family of synthetic thermoplastic resins that are employed in a wide array of products. Since the discovery of acrylic acid in 1843 and its industrialization in the early 20th century, acrylates have been used by many different sectors of industry.¹ Today, acrylates can be found in diverse sources such as adhesives, coatings, electronics, nail cosmetics, dental materials, and medical devices. Although these versatile compounds have revolutionized numerous sectors, their potential to trigger allergic contact dermatitis (ACD) has garnered considerable attention in recent years. In 2012, acrylates as a group were named Allergen of the Year by the American Contact Dermatitis Society,² and one member—isobornyl acrylate—also was given the infamous award in 2020.³ In this article, we highlight the chemistry of acrylates, the growing prevalence of acrylate contact allergy, common sources of exposure, patch testing considerations, and management/prevention strategies.

Chemistry and Uses of Acrylates

Acrylates are widely used due to their pliable and resilient properties.⁴ They begin as liquid monomers of (meth)acrylic acid or cyanoacrylic acid that are molded to the desired application before being cured or hardened by one of several means: spontaneously, using chemical catalysts, or with heat, UV light, or a light-emitting diode. Once cured, the final polymers (ie, [meth]acrylates, cyanoacrylates) serve a myriad of different purposes. Table 1 includes some of the more clinically relevant sources of acrylate exposure. Although this list is not comprehensive, it offers a glimpse into the vast array of uses for acrylates.

Acrylate Contact Allergy

Acrylic monomers are potent contact allergens, but the polymerized final products are not considered allergenic, assuming they are completely cured; however, ACD can occur with incomplete curing.⁶ It is of clinical importance that once an individual becomes sensitized to one type of acrylate, they may develop cross-reactions to others contained in different products. Notably, cyanoacrylates generally do not cross-react with (meth)acrylates; this has important implications for choosing safe alternative products in sensitized patients, though independent sensitization to cyanoacrylates is possible.^7,8

Epidemiology and Risk Factors

The prevalence of acrylate allergy in the general population is unknown; however, there is a trend of increased patch test positivity in studies of patients referred for patch testing. A 2018 study by the European Environmental Contact Dermatitis Research Group reported positive patch tests to acrylates in 1.1% of 18,228 patients tested from 2013 to 2015.⁹ More recently, a multicenter European study (2019-2020) reported a 2.3% patch test positivity to 2-hydroxyethyl methacrylate (HEMA) among 7675 tested individuals,¹⁰ and even higher HEMA positivity was reported in Spain (3.7% of 1884 patients in 2019-2020).¹¹ In addition, the North American Contact Dermatitis Group (NACDG) reported positive patch test reactions to HEMA in 3.2% of 4111 patients tested from 2019 to 2020, a statistically significant increase compared with those tested in 2009 to 2018 (odds ratio, 1.25 [95% CI, 1.03-1.51]; P=.02).¹²

Historically, acrylate sensitization primarily stemmed from occupational exposure. A retrospective analysis of occupational dermatitis performed by the NACDG (2001-2016) showed that HEMA was among the top 10 most common occupational allergens (3.4% positivity [83/2461]) and had the fifth highest percentage of occupationally relevant reactions (73.5% [83/113]).¹³ High-risk occupations include dental providers and nail technicians. Dentistry utilizes many materials containing acrylates, including uncured plastic resins used in dental prostheses, dentin bonding materials, and glass ionomers.¹⁴ A retrospective analysis of 585 dental personnel who were patch tested by the NACDG (2001-2018) found that more than 20% of occupational ACD cases were related to acrylates.¹⁵ Nail technicians are another group routinely exposed to acrylates through a variety of modern nail cosmetics. In a 7-year study from Portugal evaluating acrylate ACD, 68% (25/37) of cases were attributed to occupation, 80% (20/25) of which were in nail technicians.¹⁶ Likewise, among 28 nail technicians in Sweden who were referred for patch testing, 57% (16/28) tested positive for at least 1 acrylate.¹⁷

Modern Sources of Acrylate Exposure

Once thought to be a predominantly occupational exposure, acrylates have rapidly made their way into everyday consumer products. Clinicians should be aware of several sources of clinically relevant acrylate exposure, including nail cosmetics, consumer electronics, and medical/surgical adhesives.

A 2016 study found a shift to nail cosmetics as the most common source of acrylate sensitization.¹⁸ Nail cosmetics that contain acrylates include traditional acrylic, gel (shellac), dipped, and press-on (false) nails.¹⁹ The NACDG found that the most common allergen in patients experiencing ACD associated with nail products (2001-2016) was HEMA (56.6% [273/482]), far ahead of the traditional nail polish allergen tosylamide (36.2% [273/755]). Over the study period, the frequency of positive patch tests statistically increased for HEMA (P=.0069) and decreased for tosylamide (P<.0001).²⁰ There is concern that the use of home gel nail kits, which can be purchased online at the click of a button, may be associated with a risk for acrylate sensitization.^21,22 A recent study surveyed a Facebook support group for individuals with self-reported reactions to nail cosmetics, finding that 78% of the 199 individuals had used at-home gel nail kits, and more than 80% of them first developed skin reactions after starting to use at-home kits.²³ The risks for sensitization are thought to be greater when self-applying nail acrylates compared to having them done professionally because individuals are more likely to spill allergenic monomers onto the skin at home; it also is possible that home techniques could lead to incomplete curing. Table 2 reviews the different types of acrylic nail cosmetics.

Medical adhesives and equipment are other important areas where acrylates can be encountered in abundance. A review by Spencer et al¹⁸ cautioned wound dressings as an up-and-coming source of sensitization, and this has been demonstrated in the literature as coming to fruition.²⁶ Another study identified acrylates in 15 of 16 (94%) tested medical adhesives; among 7 medical adhesives labeled as hypoallergenic, 100% still contained acrylates and/or abietic acid.²⁷ Multiple case reports have described ACD to adhesives of electrocardiogram electrodes containing acrylates.^28-31 Physicians providing care to patients with diabetes mellitus also must be aware of acrylates in glucose monitors and insulin pumps, either found in the adhesives or leaching from the inside of the device to reach the skin.³² Isobornyl acrylate in particular has made quite the name for itself in this sector, being crowned the 2020 Allergen of the Year owing to its key role in cases of ACD to diabetes devices.³

Cyanoacrylate-based tissue adhesives (eg, 2‐octyl cyanoacrylate) are now well documented to cause postoperative ACD.^33,34 Although robust prospective data are limited, studies suggest that 2% to 14% of patients develop postoperative skin reactions following 2-octyl cyanoacrylate application.^35-37 It has been shown that sensitization to tissue adhesives often occurs after the first application, followed by an eruption of ACD as long as a month later, which can create confusion about the nature of the rash for patients and health care providers alike, who may for instance attribute it to infection rather than allergy.³⁸ In the orthopedic literature, a woman with a known history of acrylic nail ACD had knee arthroplasty failure attributed to acrylic bone cement with resolution of the joint symptoms after changing to a cementless device.³⁹

Awareness of the common use of acrylates is important to identify the cause of reactions from products that would otherwise seem nonallergenic. A case of occupational ACD to isobornyl acrylate in UV-cured phone screen protectors has been reported⁴⁰; several cases of ACD to acrylates in headphones^41,42 as well as one related to a wearable fitness device also have been reported.⁴³ Given all these possible sources of exposure, ACD to acrylates should be on your radar.

When to Consider Acrylate ACD

When working up a patient with dermatitis, it is essential to ask about occupational history and hobbies to get a sense of potential contact allergen exposures. The typical presentation of occupational acrylate-associated ACD is hand eczema, specifically involving the fingertips.^5,24,25,44 Acrylate ACD should be considered in patients with nail dystrophy and a history of wearing acrylic nails.⁴⁵ There can even be involvement of the face and eyelids secondary to airborne contact or ectopic spread from the hands.²⁴ Spreading vesicular eruptions associated with adhesives also should raise concern. The Figure depicts several possible presentations of ACD to acrylates. In a time of abundant access to products containing acrylates, dermatologists should consider this allergy in their differential diagnosis and consider patch testing.

Photographs courtesy of Brandon L. Adler, MD.

Patch Testing to Acrylates

The gold standard for ACD diagnosis is patch testing. It should be noted that no acrylates are included in the thin-layer rapid use epicutaneous (T.R.U.E.) test series. Several acrylates are tested in expanded patch test series including the American Contact Dermatitis Society Core Allergen series and North American 80 Comprehensive Series. 2-Hydroxyethyl methacrylate is thought to be the most important screening allergen to test. Ramos et al¹⁶ reported a positive patch test to HEMA in 81% (30/37) of patients who had any type of acrylate allergy.

If initial testing to a limited number of acrylates is negative but clinical suspicion remains high, expanded acrylates/plastics and glue series also are available from commercial patch test suppliers. Testing to an expanded panel of acrylates is especially pertinent to consider in suspected occupational cases given the risk of workplace absenteeism and even disability that come with continued exposure to the allergen. Of note, isobornyl acrylate is not included in the baseline patch test series and must be tested separately, particularly because it usually does not cross-react with other acrylates, and therefore allergy could be missed if not tested on its own.

Acrylates are volatile substances that have been shown to degrade at room temperature and to a lesser degree when refrigerated. Ideally, they should be stored in a freezer and not used beyond their expiration date. Furthermore, it is advised that acrylate patch tests be prepared immediately prior to placement on the patient and to discard the initial extrusion from the syringe, as the concentration at the tip may be decreased.^46,47

With regard to tissue adhesives, the actual product should be tested as-is because these are not commercially available patch test substances.⁴⁸ Occasionally, patients who are sensitized to the tissue adhesive will not react when patch tested on intact skin. If clinical suspicion remains high, scratch patch testing may confirm contact allergy in cases of negative testing on intact skin.⁴⁹

Management and Prevention

Once a diagnosis of ACD secondary to acrylates has been established, counseling patients on allergen avoidance strategies is essential. For (meth)acrylate-allergic patients who want to continue using modern nail products, cyanoacrylate-based options (eg, dipped, press-on nails) can be considered as an alternative, as they do not cross-react, though independent sensitization is still possible. However, traditional nail polish is the safest option to recommend.

The concern with acrylate sensitization extends beyond the immediate issue that brought the patient into your clinic. Dermatologists must counsel patients who are sensitized to acrylates on the possible sequelae of acrylate-containing dental or orthopedic procedures. Oral lichenoid lesions, denture stomatitis, burning mouth syndrome, or even acute facial swelling have been reported following dental work in patients with acrylate allergy.^50-53 Dentists of patients with acrylate ACD should be informed of the diagnosis so acrylates can be avoided during dental work; if unavoidable, all possible steps should be taken to ensure complete curing of the monomers. In the surgical setting, patients sensitized to cyanoacrylate-based tissue adhesives should be offered wound closure alternatives such as sutures or staples.³⁴

In patients with diabetes mellitus who develop ACD to their glucose monitor or insulin pump, ideally they should be switched to a device that does not contain acrylates. Problematically, these devices are constantly being reformulated, and manufacturers do not always divulge their components, which can make it challenging to determine safe alternative options.^32,54 Various barrier products may help on a case-by-case basis.⁵⁵Preventative measures should be implemented in workplaces that utilize acrylates, including dental practices and nail salons. Acrylic monomers have been shown to penetrate most gloves within minutes of exposure.^56,57 Double gloving with nitrile gloves affords some protection for no longer than 60 minutes.⁶ 4H gloves have been shown to provide true protection but result in a loss of dexterity.⁵⁸ The fingerstall technique involves removing the fingers from a 4H glove, inserting them on the fingers, and applying a more flexible glove on top to hold them in place; this offers a hybrid between protection and finger dexterity.⁵⁹

Final Interpretation

In a world characterized by technological advancements and increasing accessibility to acrylate-containing products, we hope this brief review serves as a resource and reminder to dermatologists to consider acrylates as a potential cause of ACD with diverse presentations and important future implications for affected individuals. The rising trend of acrylate allergy necessitates comprehensive assessment and shared decision-making between physicians and patients. As we navigate the ever-changing landscape of materials and technologies, clinicians must remain vigilant to avoid some potentially sticky situations for patients.

Acrylates are a ubiquitous family of synthetic thermoplastic resins that are employed in a wide array of products. Since the discovery of acrylic acid in 1843 and its industrialization in the early 20th century, acrylates have been used by many different sectors of industry.¹ Today, acrylates can be found in diverse sources such as adhesives, coatings, electronics, nail cosmetics, dental materials, and medical devices. Although these versatile compounds have revolutionized numerous sectors, their potential to trigger allergic contact dermatitis (ACD) has garnered considerable attention in recent years. In 2012, acrylates as a group were named Allergen of the Year by the American Contact Dermatitis Society,² and one member—isobornyl acrylate—also was given the infamous award in 2020.³ In this article, we highlight the chemistry of acrylates, the growing prevalence of acrylate contact allergy, common sources of exposure, patch testing considerations, and management/prevention strategies.

Chemistry and Uses of Acrylates

Acrylates are widely used due to their pliable and resilient properties.⁴ They begin as liquid monomers of (meth)acrylic acid or cyanoacrylic acid that are molded to the desired application before being cured or hardened by one of several means: spontaneously, using chemical catalysts, or with heat, UV light, or a light-emitting diode. Once cured, the final polymers (ie, [meth]acrylates, cyanoacrylates) serve a myriad of different purposes. Table 1 includes some of the more clinically relevant sources of acrylate exposure. Although this list is not comprehensive, it offers a glimpse into the vast array of uses for acrylates.

Acrylate Contact Allergy

Acrylic monomers are potent contact allergens, but the polymerized final products are not considered allergenic, assuming they are completely cured; however, ACD can occur with incomplete curing.⁶ It is of clinical importance that once an individual becomes sensitized to one type of acrylate, they may develop cross-reactions to others contained in different products. Notably, cyanoacrylates generally do not cross-react with (meth)acrylates; this has important implications for choosing safe alternative products in sensitized patients, though independent sensitization to cyanoacrylates is possible.^7,8

Epidemiology and Risk Factors

The prevalence of acrylate allergy in the general population is unknown; however, there is a trend of increased patch test positivity in studies of patients referred for patch testing. A 2018 study by the European Environmental Contact Dermatitis Research Group reported positive patch tests to acrylates in 1.1% of 18,228 patients tested from 2013 to 2015.⁹ More recently, a multicenter European study (2019-2020) reported a 2.3% patch test positivity to 2-hydroxyethyl methacrylate (HEMA) among 7675 tested individuals,¹⁰ and even higher HEMA positivity was reported in Spain (3.7% of 1884 patients in 2019-2020).¹¹ In addition, the North American Contact Dermatitis Group (NACDG) reported positive patch test reactions to HEMA in 3.2% of 4111 patients tested from 2019 to 2020, a statistically significant increase compared with those tested in 2009 to 2018 (odds ratio, 1.25 [95% CI, 1.03-1.51]; P=.02).¹²

Historically, acrylate sensitization primarily stemmed from occupational exposure. A retrospective analysis of occupational dermatitis performed by the NACDG (2001-2016) showed that HEMA was among the top 10 most common occupational allergens (3.4% positivity [83/2461]) and had the fifth highest percentage of occupationally relevant reactions (73.5% [83/113]).¹³ High-risk occupations include dental providers and nail technicians. Dentistry utilizes many materials containing acrylates, including uncured plastic resins used in dental prostheses, dentin bonding materials, and glass ionomers.¹⁴ A retrospective analysis of 585 dental personnel who were patch tested by the NACDG (2001-2018) found that more than 20% of occupational ACD cases were related to acrylates.¹⁵ Nail technicians are another group routinely exposed to acrylates through a variety of modern nail cosmetics. In a 7-year study from Portugal evaluating acrylate ACD, 68% (25/37) of cases were attributed to occupation, 80% (20/25) of which were in nail technicians.¹⁶ Likewise, among 28 nail technicians in Sweden who were referred for patch testing, 57% (16/28) tested positive for at least 1 acrylate.¹⁷

Modern Sources of Acrylate Exposure

Once thought to be a predominantly occupational exposure, acrylates have rapidly made their way into everyday consumer products. Clinicians should be aware of several sources of clinically relevant acrylate exposure, including nail cosmetics, consumer electronics, and medical/surgical adhesives.

A 2016 study found a shift to nail cosmetics as the most common source of acrylate sensitization.¹⁸ Nail cosmetics that contain acrylates include traditional acrylic, gel (shellac), dipped, and press-on (false) nails.¹⁹ The NACDG found that the most common allergen in patients experiencing ACD associated with nail products (2001-2016) was HEMA (56.6% [273/482]), far ahead of the traditional nail polish allergen tosylamide (36.2% [273/755]). Over the study period, the frequency of positive patch tests statistically increased for HEMA (P=.0069) and decreased for tosylamide (P<.0001).²⁰ There is concern that the use of home gel nail kits, which can be purchased online at the click of a button, may be associated with a risk for acrylate sensitization.^21,22 A recent study surveyed a Facebook support group for individuals with self-reported reactions to nail cosmetics, finding that 78% of the 199 individuals had used at-home gel nail kits, and more than 80% of them first developed skin reactions after starting to use at-home kits.²³ The risks for sensitization are thought to be greater when self-applying nail acrylates compared to having them done professionally because individuals are more likely to spill allergenic monomers onto the skin at home; it also is possible that home techniques could lead to incomplete curing. Table 2 reviews the different types of acrylic nail cosmetics.

Medical adhesives and equipment are other important areas where acrylates can be encountered in abundance. A review by Spencer et al¹⁸ cautioned wound dressings as an up-and-coming source of sensitization, and this has been demonstrated in the literature as coming to fruition.²⁶ Another study identified acrylates in 15 of 16 (94%) tested medical adhesives; among 7 medical adhesives labeled as hypoallergenic, 100% still contained acrylates and/or abietic acid.²⁷ Multiple case reports have described ACD to adhesives of electrocardiogram electrodes containing acrylates.^28-31 Physicians providing care to patients with diabetes mellitus also must be aware of acrylates in glucose monitors and insulin pumps, either found in the adhesives or leaching from the inside of the device to reach the skin.³² Isobornyl acrylate in particular has made quite the name for itself in this sector, being crowned the 2020 Allergen of the Year owing to its key role in cases of ACD to diabetes devices.³

Cyanoacrylate-based tissue adhesives (eg, 2‐octyl cyanoacrylate) are now well documented to cause postoperative ACD.^33,34 Although robust prospective data are limited, studies suggest that 2% to 14% of patients develop postoperative skin reactions following 2-octyl cyanoacrylate application.^35-37 It has been shown that sensitization to tissue adhesives often occurs after the first application, followed by an eruption of ACD as long as a month later, which can create confusion about the nature of the rash for patients and health care providers alike, who may for instance attribute it to infection rather than allergy.³⁸ In the orthopedic literature, a woman with a known history of acrylic nail ACD had knee arthroplasty failure attributed to acrylic bone cement with resolution of the joint symptoms after changing to a cementless device.³⁹

Awareness of the common use of acrylates is important to identify the cause of reactions from products that would otherwise seem nonallergenic. A case of occupational ACD to isobornyl acrylate in UV-cured phone screen protectors has been reported⁴⁰; several cases of ACD to acrylates in headphones^41,42 as well as one related to a wearable fitness device also have been reported.⁴³ Given all these possible sources of exposure, ACD to acrylates should be on your radar.

When to Consider Acrylate ACD

When working up a patient with dermatitis, it is essential to ask about occupational history and hobbies to get a sense of potential contact allergen exposures. The typical presentation of occupational acrylate-associated ACD is hand eczema, specifically involving the fingertips.^5,24,25,44 Acrylate ACD should be considered in patients with nail dystrophy and a history of wearing acrylic nails.⁴⁵ There can even be involvement of the face and eyelids secondary to airborne contact or ectopic spread from the hands.²⁴ Spreading vesicular eruptions associated with adhesives also should raise concern. The Figure depicts several possible presentations of ACD to acrylates. In a time of abundant access to products containing acrylates, dermatologists should consider this allergy in their differential diagnosis and consider patch testing.

Photographs courtesy of Brandon L. Adler, MD.

Patch Testing to Acrylates

The gold standard for ACD diagnosis is patch testing. It should be noted that no acrylates are included in the thin-layer rapid use epicutaneous (T.R.U.E.) test series. Several acrylates are tested in expanded patch test series including the American Contact Dermatitis Society Core Allergen series and North American 80 Comprehensive Series. 2-Hydroxyethyl methacrylate is thought to be the most important screening allergen to test. Ramos et al¹⁶ reported a positive patch test to HEMA in 81% (30/37) of patients who had any type of acrylate allergy.

If initial testing to a limited number of acrylates is negative but clinical suspicion remains high, expanded acrylates/plastics and glue series also are available from commercial patch test suppliers. Testing to an expanded panel of acrylates is especially pertinent to consider in suspected occupational cases given the risk of workplace absenteeism and even disability that come with continued exposure to the allergen. Of note, isobornyl acrylate is not included in the baseline patch test series and must be tested separately, particularly because it usually does not cross-react with other acrylates, and therefore allergy could be missed if not tested on its own.

Acrylates are volatile substances that have been shown to degrade at room temperature and to a lesser degree when refrigerated. Ideally, they should be stored in a freezer and not used beyond their expiration date. Furthermore, it is advised that acrylate patch tests be prepared immediately prior to placement on the patient and to discard the initial extrusion from the syringe, as the concentration at the tip may be decreased.^46,47

With regard to tissue adhesives, the actual product should be tested as-is because these are not commercially available patch test substances.⁴⁸ Occasionally, patients who are sensitized to the tissue adhesive will not react when patch tested on intact skin. If clinical suspicion remains high, scratch patch testing may confirm contact allergy in cases of negative testing on intact skin.⁴⁹

Management and Prevention

Once a diagnosis of ACD secondary to acrylates has been established, counseling patients on allergen avoidance strategies is essential. For (meth)acrylate-allergic patients who want to continue using modern nail products, cyanoacrylate-based options (eg, dipped, press-on nails) can be considered as an alternative, as they do not cross-react, though independent sensitization is still possible. However, traditional nail polish is the safest option to recommend.

The concern with acrylate sensitization extends beyond the immediate issue that brought the patient into your clinic. Dermatologists must counsel patients who are sensitized to acrylates on the possible sequelae of acrylate-containing dental or orthopedic procedures. Oral lichenoid lesions, denture stomatitis, burning mouth syndrome, or even acute facial swelling have been reported following dental work in patients with acrylate allergy.^50-53 Dentists of patients with acrylate ACD should be informed of the diagnosis so acrylates can be avoided during dental work; if unavoidable, all possible steps should be taken to ensure complete curing of the monomers. In the surgical setting, patients sensitized to cyanoacrylate-based tissue adhesives should be offered wound closure alternatives such as sutures or staples.³⁴

In patients with diabetes mellitus who develop ACD to their glucose monitor or insulin pump, ideally they should be switched to a device that does not contain acrylates. Problematically, these devices are constantly being reformulated, and manufacturers do not always divulge their components, which can make it challenging to determine safe alternative options.^32,54 Various barrier products may help on a case-by-case basis.⁵⁵Preventative measures should be implemented in workplaces that utilize acrylates, including dental practices and nail salons. Acrylic monomers have been shown to penetrate most gloves within minutes of exposure.^56,57 Double gloving with nitrile gloves affords some protection for no longer than 60 minutes.⁶ 4H gloves have been shown to provide true protection but result in a loss of dexterity.⁵⁸ The fingerstall technique involves removing the fingers from a 4H glove, inserting them on the fingers, and applying a more flexible glove on top to hold them in place; this offers a hybrid between protection and finger dexterity.⁵⁹

Final Interpretation

In a world characterized by technological advancements and increasing accessibility to acrylate-containing products, we hope this brief review serves as a resource and reminder to dermatologists to consider acrylates as a potential cause of ACD with diverse presentations and important future implications for affected individuals. The rising trend of acrylate allergy necessitates comprehensive assessment and shared decision-making between physicians and patients. As we navigate the ever-changing landscape of materials and technologies, clinicians must remain vigilant to avoid some potentially sticky situations for patients.

Acrylates are a ubiquitous family of synthetic thermoplastic resins that are employed in a wide array of products. Since the discovery of acrylic acid in 1843 and its industrialization in the early 20th century, acrylates have been used by many different sectors of industry.¹ Today, acrylates can be found in diverse sources such as adhesives, coatings, electronics, nail cosmetics, dental materials, and medical devices. Although these versatile compounds have revolutionized numerous sectors, their potential to trigger allergic contact dermatitis (ACD) has garnered considerable attention in recent years. In 2012, acrylates as a group were named Allergen of the Year by the American Contact Dermatitis Society,² and one member—isobornyl acrylate—also was given the infamous award in 2020.³ In this article, we highlight the chemistry of acrylates, the growing prevalence of acrylate contact allergy, common sources of exposure, patch testing considerations, and management/prevention strategies.

Chemistry and Uses of Acrylates

Acrylates are widely used due to their pliable and resilient properties.⁴ They begin as liquid monomers of (meth)acrylic acid or cyanoacrylic acid that are molded to the desired application before being cured or hardened by one of several means: spontaneously, using chemical catalysts, or with heat, UV light, or a light-emitting diode. Once cured, the final polymers (ie, [meth]acrylates, cyanoacrylates) serve a myriad of different purposes. Table 1 includes some of the more clinically relevant sources of acrylate exposure. Although this list is not comprehensive, it offers a glimpse into the vast array of uses for acrylates.

Acrylate Contact Allergy

Acrylic monomers are potent contact allergens, but the polymerized final products are not considered allergenic, assuming they are completely cured; however, ACD can occur with incomplete curing.⁶ It is of clinical importance that once an individual becomes sensitized to one type of acrylate, they may develop cross-reactions to others contained in different products. Notably, cyanoacrylates generally do not cross-react with (meth)acrylates; this has important implications for choosing safe alternative products in sensitized patients, though independent sensitization to cyanoacrylates is possible.^7,8

Epidemiology and Risk Factors

The prevalence of acrylate allergy in the general population is unknown; however, there is a trend of increased patch test positivity in studies of patients referred for patch testing. A 2018 study by the European Environmental Contact Dermatitis Research Group reported positive patch tests to acrylates in 1.1% of 18,228 patients tested from 2013 to 2015.⁹ More recently, a multicenter European study (2019-2020) reported a 2.3% patch test positivity to 2-hydroxyethyl methacrylate (HEMA) among 7675 tested individuals,¹⁰ and even higher HEMA positivity was reported in Spain (3.7% of 1884 patients in 2019-2020).¹¹ In addition, the North American Contact Dermatitis Group (NACDG) reported positive patch test reactions to HEMA in 3.2% of 4111 patients tested from 2019 to 2020, a statistically significant increase compared with those tested in 2009 to 2018 (odds ratio, 1.25 [95% CI, 1.03-1.51]; P=.02).¹²

Historically, acrylate sensitization primarily stemmed from occupational exposure. A retrospective analysis of occupational dermatitis performed by the NACDG (2001-2016) showed that HEMA was among the top 10 most common occupational allergens (3.4% positivity [83/2461]) and had the fifth highest percentage of occupationally relevant reactions (73.5% [83/113]).¹³ High-risk occupations include dental providers and nail technicians. Dentistry utilizes many materials containing acrylates, including uncured plastic resins used in dental prostheses, dentin bonding materials, and glass ionomers.¹⁴ A retrospective analysis of 585 dental personnel who were patch tested by the NACDG (2001-2018) found that more than 20% of occupational ACD cases were related to acrylates.¹⁵ Nail technicians are another group routinely exposed to acrylates through a variety of modern nail cosmetics. In a 7-year study from Portugal evaluating acrylate ACD, 68% (25/37) of cases were attributed to occupation, 80% (20/25) of which were in nail technicians.¹⁶ Likewise, among 28 nail technicians in Sweden who were referred for patch testing, 57% (16/28) tested positive for at least 1 acrylate.¹⁷

Modern Sources of Acrylate Exposure

Once thought to be a predominantly occupational exposure, acrylates have rapidly made their way into everyday consumer products. Clinicians should be aware of several sources of clinically relevant acrylate exposure, including nail cosmetics, consumer electronics, and medical/surgical adhesives.

A 2016 study found a shift to nail cosmetics as the most common source of acrylate sensitization.¹⁸ Nail cosmetics that contain acrylates include traditional acrylic, gel (shellac), dipped, and press-on (false) nails.¹⁹ The NACDG found that the most common allergen in patients experiencing ACD associated with nail products (2001-2016) was HEMA (56.6% [273/482]), far ahead of the traditional nail polish allergen tosylamide (36.2% [273/755]). Over the study period, the frequency of positive patch tests statistically increased for HEMA (P=.0069) and decreased for tosylamide (P<.0001).²⁰ There is concern that the use of home gel nail kits, which can be purchased online at the click of a button, may be associated with a risk for acrylate sensitization.^21,22 A recent study surveyed a Facebook support group for individuals with self-reported reactions to nail cosmetics, finding that 78% of the 199 individuals had used at-home gel nail kits, and more than 80% of them first developed skin reactions after starting to use at-home kits.²³ The risks for sensitization are thought to be greater when self-applying nail acrylates compared to having them done professionally because individuals are more likely to spill allergenic monomers onto the skin at home; it also is possible that home techniques could lead to incomplete curing. Table 2 reviews the different types of acrylic nail cosmetics.

Medical adhesives and equipment are other important areas where acrylates can be encountered in abundance. A review by Spencer et al¹⁸ cautioned wound dressings as an up-and-coming source of sensitization, and this has been demonstrated in the literature as coming to fruition.²⁶ Another study identified acrylates in 15 of 16 (94%) tested medical adhesives; among 7 medical adhesives labeled as hypoallergenic, 100% still contained acrylates and/or abietic acid.²⁷ Multiple case reports have described ACD to adhesives of electrocardiogram electrodes containing acrylates.^28-31 Physicians providing care to patients with diabetes mellitus also must be aware of acrylates in glucose monitors and insulin pumps, either found in the adhesives or leaching from the inside of the device to reach the skin.³² Isobornyl acrylate in particular has made quite the name for itself in this sector, being crowned the 2020 Allergen of the Year owing to its key role in cases of ACD to diabetes devices.³

Cyanoacrylate-based tissue adhesives (eg, 2‐octyl cyanoacrylate) are now well documented to cause postoperative ACD.^33,34 Although robust prospective data are limited, studies suggest that 2% to 14% of patients develop postoperative skin reactions following 2-octyl cyanoacrylate application.^35-37 It has been shown that sensitization to tissue adhesives often occurs after the first application, followed by an eruption of ACD as long as a month later, which can create confusion about the nature of the rash for patients and health care providers alike, who may for instance attribute it to infection rather than allergy.³⁸ In the orthopedic literature, a woman with a known history of acrylic nail ACD had knee arthroplasty failure attributed to acrylic bone cement with resolution of the joint symptoms after changing to a cementless device.³⁹

Awareness of the common use of acrylates is important to identify the cause of reactions from products that would otherwise seem nonallergenic. A case of occupational ACD to isobornyl acrylate in UV-cured phone screen protectors has been reported⁴⁰; several cases of ACD to acrylates in headphones^41,42 as well as one related to a wearable fitness device also have been reported.⁴³ Given all these possible sources of exposure, ACD to acrylates should be on your radar.

When to Consider Acrylate ACD

When working up a patient with dermatitis, it is essential to ask about occupational history and hobbies to get a sense of potential contact allergen exposures. The typical presentation of occupational acrylate-associated ACD is hand eczema, specifically involving the fingertips.^5,24,25,44 Acrylate ACD should be considered in patients with nail dystrophy and a history of wearing acrylic nails.⁴⁵ There can even be involvement of the face and eyelids secondary to airborne contact or ectopic spread from the hands.²⁴ Spreading vesicular eruptions associated with adhesives also should raise concern. The Figure depicts several possible presentations of ACD to acrylates. In a time of abundant access to products containing acrylates, dermatologists should consider this allergy in their differential diagnosis and consider patch testing.

Photographs courtesy of Brandon L. Adler, MD.

Patch Testing to Acrylates

The gold standard for ACD diagnosis is patch testing. It should be noted that no acrylates are included in the thin-layer rapid use epicutaneous (T.R.U.E.) test series. Several acrylates are tested in expanded patch test series including the American Contact Dermatitis Society Core Allergen series and North American 80 Comprehensive Series. 2-Hydroxyethyl methacrylate is thought to be the most important screening allergen to test. Ramos et al¹⁶ reported a positive patch test to HEMA in 81% (30/37) of patients who had any type of acrylate allergy.

If initial testing to a limited number of acrylates is negative but clinical suspicion remains high, expanded acrylates/plastics and glue series also are available from commercial patch test suppliers. Testing to an expanded panel of acrylates is especially pertinent to consider in suspected occupational cases given the risk of workplace absenteeism and even disability that come with continued exposure to the allergen. Of note, isobornyl acrylate is not included in the baseline patch test series and must be tested separately, particularly because it usually does not cross-react with other acrylates, and therefore allergy could be missed if not tested on its own.

Acrylates are volatile substances that have been shown to degrade at room temperature and to a lesser degree when refrigerated. Ideally, they should be stored in a freezer and not used beyond their expiration date. Furthermore, it is advised that acrylate patch tests be prepared immediately prior to placement on the patient and to discard the initial extrusion from the syringe, as the concentration at the tip may be decreased.^46,47

With regard to tissue adhesives, the actual product should be tested as-is because these are not commercially available patch test substances.⁴⁸ Occasionally, patients who are sensitized to the tissue adhesive will not react when patch tested on intact skin. If clinical suspicion remains high, scratch patch testing may confirm contact allergy in cases of negative testing on intact skin.⁴⁹

Management and Prevention

Once a diagnosis of ACD secondary to acrylates has been established, counseling patients on allergen avoidance strategies is essential. For (meth)acrylate-allergic patients who want to continue using modern nail products, cyanoacrylate-based options (eg, dipped, press-on nails) can be considered as an alternative, as they do not cross-react, though independent sensitization is still possible. However, traditional nail polish is the safest option to recommend.

The concern with acrylate sensitization extends beyond the immediate issue that brought the patient into your clinic. Dermatologists must counsel patients who are sensitized to acrylates on the possible sequelae of acrylate-containing dental or orthopedic procedures. Oral lichenoid lesions, denture stomatitis, burning mouth syndrome, or even acute facial swelling have been reported following dental work in patients with acrylate allergy.^50-53 Dentists of patients with acrylate ACD should be informed of the diagnosis so acrylates can be avoided during dental work; if unavoidable, all possible steps should be taken to ensure complete curing of the monomers. In the surgical setting, patients sensitized to cyanoacrylate-based tissue adhesives should be offered wound closure alternatives such as sutures or staples.³⁴

In patients with diabetes mellitus who develop ACD to their glucose monitor or insulin pump, ideally they should be switched to a device that does not contain acrylates. Problematically, these devices are constantly being reformulated, and manufacturers do not always divulge their components, which can make it challenging to determine safe alternative options.^32,54 Various barrier products may help on a case-by-case basis.⁵⁵Preventative measures should be implemented in workplaces that utilize acrylates, including dental practices and nail salons. Acrylic monomers have been shown to penetrate most gloves within minutes of exposure.^56,57 Double gloving with nitrile gloves affords some protection for no longer than 60 minutes.⁶ 4H gloves have been shown to provide true protection but result in a loss of dexterity.⁵⁸ The fingerstall technique involves removing the fingers from a 4H glove, inserting them on the fingers, and applying a more flexible glove on top to hold them in place; this offers a hybrid between protection and finger dexterity.⁵⁹

Final Interpretation

In a world characterized by technological advancements and increasing accessibility to acrylate-containing products, we hope this brief review serves as a resource and reminder to dermatologists to consider acrylates as a potential cause of ACD with diverse presentations and important future implications for affected individuals. The rising trend of acrylate allergy necessitates comprehensive assessment and shared decision-making between physicians and patients. As we navigate the ever-changing landscape of materials and technologies, clinicians must remain vigilant to avoid some potentially sticky situations for patients.