MDedge Dermatology

Spironolactone is an aldosterone antagonist that first was used as a potassium-sparing diuretic to treat heart failure and hypertension. It also possesses antiandrogenic mechanisms including competitively inhibiting androgen receptors, increasing steroid hormone–binding globulin production, and decreasing 5α-reductase activity.¹ These properties have been leveraged in off-label use for dermatologic conditions including acne, hidradenitis suppurativa, androgenic alopecia, and hirsutism.^1,2 Despite being used off-label to treat acne for more than 40 years, spironolactone has not received US Food and Drug Administration approval for this indication.³ Herein, we review the current evidence for use of spironolactone in acne management.

Spironolactone Efficacy

Spironolactone is efficacious for facial and truncal acne in adult females; it cannot be used in males given its anti-androgenic effects.^4,5 In 2 large studies, spironolactone completely or partially cleared facial acne in 75.5% to 85.1% of patients.^4,5 In the first study, which included 395 patients on a median dose of 100 mg/d (range, 25-200 mg/d), clearance of comedonal, papulopustular, and nodulocystic acne was observed.⁴ The second study included 403 patients, most of whom started on spironolactone at 100 mg/d (range, 25-200 mg/d). In addition to facial clearance, patients in this study demonstrated similar rates of partial or complete clearance of acne on the chest (84.0%) and back (80.2%) assessed via a comprehensive acne severity scale.⁵ In both studies, doses of 100 mg/d or higher were most effective, and the median time to initial acne improvement was 3 months, with peak effects occurring after 4 to 6 months of treatment.^4,5 Most patients were using spironolactone monotherapy or spironolactone in combination with topical therapies; however, a minority used it concurrently with oral antibiotics and/or combined oral contraceptives.

Spironolactone has demonstrated comparable efficacy to tetracycline antibiotics. A study comparing the rate of switching to another systemic therapy within 1 year of treatment initiation identified similar rates in patients started on spironolactone (n=962) and those started on tetracyclines (n=4236)(14.4% vs 13.4%, respectively). As switching may indicate treatment failure due to insufficient efficacy, adverse effects, or other causes, these findings may suggest similar effectiveness for spironolactone and tetracyclines.⁶ These treatments also were compared in a randomized controlled trial of 133 patients receiving topical benzoyl peroxide 5% for 6 months and either spironolactone 150 mg/d for 6 months or doxycycline 100 mg/d for 3 months followed by oral placebo for 3 months. At 4 months, spironolactone performed better than doxycycline as assessed using the Adult Female Acne Scoring Tool.³ Although doxycycline was stopped after 3 months and only topical therapy was continued, this finding is notable because guidelines from the American Academy of Dermatology recommend limiting tetracycline use to 3 to 4 months, whereas spironolactone may be continued for prolonged durations.^1,4

While most studies have evaluated the efficacy of spironolactone in adult females, it is increasingly being prescribed in adolescents.⁷ In a study that included 80 females aged 14 to 20 years, 80% (64/80) experienced acne improvement on a median dose of 100 mg/d.⁸ Additionally, in the study evaluating treatment switching rates, more than 80% of 1139 adolescents who were started on spironolactone were not switched to a different systemic therapy within the first year of treatment, demonstrating the efficacy of spironolactone in this demographic.⁶ However, treatment switching was more common among adolescents started on spironolactone compared with those who started on tetracyclines. As noted for adults, the treatment switching rates were the same for spironolactone and tetracycline users; the difference in adolescents may be due to lower influence of hormonal factors or higher therapeutic expectations in this population.⁶

Spironolactone Safety

Spironolactone is well tolerated at doses of 25 to 200 mg/d for acne management. Common adverse effects include diuresis (29% [26/90]), menstrual irregularities (22% [20/90]), fatigue (17% [15/90]), headache (14% [13/90]), and dizziness (12% [11/90]), but they infrequently lead to treatment discontinuation.^4,9 Rates of adverse effects are lower in adolescents compared to adults, although the effects of spironolactone on early endocrine development in adolescents are unknown.⁷ Spironolactone should not be used during pregnancy, and concurrent contraception use is advised because spironolactone has caused feminization of male fetuses in animal studies.^1,10-11

While concerns about potentially severe adverse effects including hypotension, hyperkalemia, and tumorigenicity have been raised, their occurrence in the literature is rare.^5,12-18 In a study evaluating hypotension in 2084 patients taking spironolactone 50 to 200 mg/day for acne, hair loss, and/or hirsutism, 3.1% experienced absolute hypotension, and only 0.26% required dose reduction or discontinuation.¹² Another study of 403 patients taking spironolactone for acne reported a statistically significant but clinically insignificant mean reduction in systolic blood pressure of 3.5 mm Hg.⁵ While clinically relevant hypotension is unlikely to occur, some authors still recommend measuring baseline blood pressure before spironolactone initiation.¹²

Many large studies have demonstrated that hyperkalemia with spironolactone use is rare in young healthy women.^13-15 In one study of patients aged 18 to 45 years treated with spironolactone for acne, only 0.72% of 1802 serum potassium measurements fell within the range of mild hyperkalemia.¹³ Another study found a significantly greater incidence of hyperkalemia in healthy women aged 46 to 65 years compared with women younger than 45 years (16.7% vs <1%; P=.0245).¹⁴ Additionally, among 27 patients taking spironolactone and oral contraceptives containing drospirenone (a spironolactone analog), none had elevated potassium levels.¹⁵ Given these findings, American Academy of Dermatology guidelines suggest that monitoring potassium in young healthy women has low utility but should be considered in those with risk factors including older age; renal and cardiovascular disease; and concurrent medications that interfere with renal, adrenal, and hepatic function.¹ If performed, monitoring should be done within the first few weeks of initiating spironolactone for early detection of hyperkalemia.¹⁶

Spironolactone has a US Food and Drug Administration warning for tumorigenicity based on studies in rats that were given up to 150 times the amount for human therapeutic doses and subsequently developed thyroid, hepatic, testicular, and breast adenomas.¹ However, several large studies in humans have not found an association between spironolactone and breast cancer (BC) development.^1,17,18 Furthermore, a large retrospective study found no increased risk for recurrence in BC survivors treated with spironolactone.² Most carcinogenicity studies include older women, which may limit generalizability of the findings to younger women, who comprise the majority of patients being treated for acne. Recently, however, a retrospective study evaluating healthy females aged 9 to 40 years with acne identified no significant increased risk for BC in patients treated with spironolactone.¹⁷ When compared to tetracyclines, there was a slightly decreased BC risk with spironolactone, providing further support for the latter’s safety. Finally, a large systematic review identified no association between spironolactone and ovarian, bladder, kidney, gastric, or esophageal cancers.¹⁸

Final Thoughts

Over the past several years, an ever-expanding body of literature supporting the efficacy and safety of spironolactone has emerged. While spironolactone has been used off label for decades to treat acne in healthy adult females, there are now strong data to support its efficacy in adolescent females. Notably, spironolactone consistently demonstrates similar effectiveness to first-line tetracycline antibiotics. Additionally, data suggest that spironolactone is safe in patients with a history of BC. Overall, spironolactone is a safe, comparable, and promising alternative to antibiotics for acne management in adult and adolescent females.

Spironolactone is an aldosterone antagonist that first was used as a potassium-sparing diuretic to treat heart failure and hypertension. It also possesses antiandrogenic mechanisms including competitively inhibiting androgen receptors, increasing steroid hormone–binding globulin production, and decreasing 5α-reductase activity.¹ These properties have been leveraged in off-label use for dermatologic conditions including acne, hidradenitis suppurativa, androgenic alopecia, and hirsutism.^1,2 Despite being used off-label to treat acne for more than 40 years, spironolactone has not received US Food and Drug Administration approval for this indication.³ Herein, we review the current evidence for use of spironolactone in acne management.

Spironolactone Efficacy

Spironolactone is efficacious for facial and truncal acne in adult females; it cannot be used in males given its anti-androgenic effects.^4,5 In 2 large studies, spironolactone completely or partially cleared facial acne in 75.5% to 85.1% of patients.^4,5 In the first study, which included 395 patients on a median dose of 100 mg/d (range, 25-200 mg/d), clearance of comedonal, papulopustular, and nodulocystic acne was observed.⁴ The second study included 403 patients, most of whom started on spironolactone at 100 mg/d (range, 25-200 mg/d). In addition to facial clearance, patients in this study demonstrated similar rates of partial or complete clearance of acne on the chest (84.0%) and back (80.2%) assessed via a comprehensive acne severity scale.⁵ In both studies, doses of 100 mg/d or higher were most effective, and the median time to initial acne improvement was 3 months, with peak effects occurring after 4 to 6 months of treatment.^4,5 Most patients were using spironolactone monotherapy or spironolactone in combination with topical therapies; however, a minority used it concurrently with oral antibiotics and/or combined oral contraceptives.

Spironolactone has demonstrated comparable efficacy to tetracycline antibiotics. A study comparing the rate of switching to another systemic therapy within 1 year of treatment initiation identified similar rates in patients started on spironolactone (n=962) and those started on tetracyclines (n=4236)(14.4% vs 13.4%, respectively). As switching may indicate treatment failure due to insufficient efficacy, adverse effects, or other causes, these findings may suggest similar effectiveness for spironolactone and tetracyclines.⁶ These treatments also were compared in a randomized controlled trial of 133 patients receiving topical benzoyl peroxide 5% for 6 months and either spironolactone 150 mg/d for 6 months or doxycycline 100 mg/d for 3 months followed by oral placebo for 3 months. At 4 months, spironolactone performed better than doxycycline as assessed using the Adult Female Acne Scoring Tool.³ Although doxycycline was stopped after 3 months and only topical therapy was continued, this finding is notable because guidelines from the American Academy of Dermatology recommend limiting tetracycline use to 3 to 4 months, whereas spironolactone may be continued for prolonged durations.^1,4

While most studies have evaluated the efficacy of spironolactone in adult females, it is increasingly being prescribed in adolescents.⁷ In a study that included 80 females aged 14 to 20 years, 80% (64/80) experienced acne improvement on a median dose of 100 mg/d.⁸ Additionally, in the study evaluating treatment switching rates, more than 80% of 1139 adolescents who were started on spironolactone were not switched to a different systemic therapy within the first year of treatment, demonstrating the efficacy of spironolactone in this demographic.⁶ However, treatment switching was more common among adolescents started on spironolactone compared with those who started on tetracyclines. As noted for adults, the treatment switching rates were the same for spironolactone and tetracycline users; the difference in adolescents may be due to lower influence of hormonal factors or higher therapeutic expectations in this population.⁶

Spironolactone Safety

Spironolactone is well tolerated at doses of 25 to 200 mg/d for acne management. Common adverse effects include diuresis (29% [26/90]), menstrual irregularities (22% [20/90]), fatigue (17% [15/90]), headache (14% [13/90]), and dizziness (12% [11/90]), but they infrequently lead to treatment discontinuation.^4,9 Rates of adverse effects are lower in adolescents compared to adults, although the effects of spironolactone on early endocrine development in adolescents are unknown.⁷ Spironolactone should not be used during pregnancy, and concurrent contraception use is advised because spironolactone has caused feminization of male fetuses in animal studies.^1,10-11

While concerns about potentially severe adverse effects including hypotension, hyperkalemia, and tumorigenicity have been raised, their occurrence in the literature is rare.^5,12-18 In a study evaluating hypotension in 2084 patients taking spironolactone 50 to 200 mg/day for acne, hair loss, and/or hirsutism, 3.1% experienced absolute hypotension, and only 0.26% required dose reduction or discontinuation.¹² Another study of 403 patients taking spironolactone for acne reported a statistically significant but clinically insignificant mean reduction in systolic blood pressure of 3.5 mm Hg.⁵ While clinically relevant hypotension is unlikely to occur, some authors still recommend measuring baseline blood pressure before spironolactone initiation.¹²

Many large studies have demonstrated that hyperkalemia with spironolactone use is rare in young healthy women.^13-15 In one study of patients aged 18 to 45 years treated with spironolactone for acne, only 0.72% of 1802 serum potassium measurements fell within the range of mild hyperkalemia.¹³ Another study found a significantly greater incidence of hyperkalemia in healthy women aged 46 to 65 years compared with women younger than 45 years (16.7% vs <1%; P=.0245).¹⁴ Additionally, among 27 patients taking spironolactone and oral contraceptives containing drospirenone (a spironolactone analog), none had elevated potassium levels.¹⁵ Given these findings, American Academy of Dermatology guidelines suggest that monitoring potassium in young healthy women has low utility but should be considered in those with risk factors including older age; renal and cardiovascular disease; and concurrent medications that interfere with renal, adrenal, and hepatic function.¹ If performed, monitoring should be done within the first few weeks of initiating spironolactone for early detection of hyperkalemia.¹⁶

Spironolactone has a US Food and Drug Administration warning for tumorigenicity based on studies in rats that were given up to 150 times the amount for human therapeutic doses and subsequently developed thyroid, hepatic, testicular, and breast adenomas.¹ However, several large studies in humans have not found an association between spironolactone and breast cancer (BC) development.^1,17,18 Furthermore, a large retrospective study found no increased risk for recurrence in BC survivors treated with spironolactone.² Most carcinogenicity studies include older women, which may limit generalizability of the findings to younger women, who comprise the majority of patients being treated for acne. Recently, however, a retrospective study evaluating healthy females aged 9 to 40 years with acne identified no significant increased risk for BC in patients treated with spironolactone.¹⁷ When compared to tetracyclines, there was a slightly decreased BC risk with spironolactone, providing further support for the latter’s safety. Finally, a large systematic review identified no association between spironolactone and ovarian, bladder, kidney, gastric, or esophageal cancers.¹⁸

Final Thoughts

Over the past several years, an ever-expanding body of literature supporting the efficacy and safety of spironolactone has emerged. While spironolactone has been used off label for decades to treat acne in healthy adult females, there are now strong data to support its efficacy in adolescent females. Notably, spironolactone consistently demonstrates similar effectiveness to first-line tetracycline antibiotics. Additionally, data suggest that spironolactone is safe in patients with a history of BC. Overall, spironolactone is a safe, comparable, and promising alternative to antibiotics for acne management in adult and adolescent females.

Spironolactone is an aldosterone antagonist that first was used as a potassium-sparing diuretic to treat heart failure and hypertension. It also possesses antiandrogenic mechanisms including competitively inhibiting androgen receptors, increasing steroid hormone–binding globulin production, and decreasing 5α-reductase activity.¹ These properties have been leveraged in off-label use for dermatologic conditions including acne, hidradenitis suppurativa, androgenic alopecia, and hirsutism.^1,2 Despite being used off-label to treat acne for more than 40 years, spironolactone has not received US Food and Drug Administration approval for this indication.³ Herein, we review the current evidence for use of spironolactone in acne management.

Spironolactone Efficacy

Spironolactone is efficacious for facial and truncal acne in adult females; it cannot be used in males given its anti-androgenic effects.^4,5 In 2 large studies, spironolactone completely or partially cleared facial acne in 75.5% to 85.1% of patients.^4,5 In the first study, which included 395 patients on a median dose of 100 mg/d (range, 25-200 mg/d), clearance of comedonal, papulopustular, and nodulocystic acne was observed.⁴ The second study included 403 patients, most of whom started on spironolactone at 100 mg/d (range, 25-200 mg/d). In addition to facial clearance, patients in this study demonstrated similar rates of partial or complete clearance of acne on the chest (84.0%) and back (80.2%) assessed via a comprehensive acne severity scale.⁵ In both studies, doses of 100 mg/d or higher were most effective, and the median time to initial acne improvement was 3 months, with peak effects occurring after 4 to 6 months of treatment.^4,5 Most patients were using spironolactone monotherapy or spironolactone in combination with topical therapies; however, a minority used it concurrently with oral antibiotics and/or combined oral contraceptives.

Spironolactone has demonstrated comparable efficacy to tetracycline antibiotics. A study comparing the rate of switching to another systemic therapy within 1 year of treatment initiation identified similar rates in patients started on spironolactone (n=962) and those started on tetracyclines (n=4236)(14.4% vs 13.4%, respectively). As switching may indicate treatment failure due to insufficient efficacy, adverse effects, or other causes, these findings may suggest similar effectiveness for spironolactone and tetracyclines.⁶ These treatments also were compared in a randomized controlled trial of 133 patients receiving topical benzoyl peroxide 5% for 6 months and either spironolactone 150 mg/d for 6 months or doxycycline 100 mg/d for 3 months followed by oral placebo for 3 months. At 4 months, spironolactone performed better than doxycycline as assessed using the Adult Female Acne Scoring Tool.³ Although doxycycline was stopped after 3 months and only topical therapy was continued, this finding is notable because guidelines from the American Academy of Dermatology recommend limiting tetracycline use to 3 to 4 months, whereas spironolactone may be continued for prolonged durations.^1,4

While most studies have evaluated the efficacy of spironolactone in adult females, it is increasingly being prescribed in adolescents.⁷ In a study that included 80 females aged 14 to 20 years, 80% (64/80) experienced acne improvement on a median dose of 100 mg/d.⁸ Additionally, in the study evaluating treatment switching rates, more than 80% of 1139 adolescents who were started on spironolactone were not switched to a different systemic therapy within the first year of treatment, demonstrating the efficacy of spironolactone in this demographic.⁶ However, treatment switching was more common among adolescents started on spironolactone compared with those who started on tetracyclines. As noted for adults, the treatment switching rates were the same for spironolactone and tetracycline users; the difference in adolescents may be due to lower influence of hormonal factors or higher therapeutic expectations in this population.⁶

Spironolactone Safety

Spironolactone is well tolerated at doses of 25 to 200 mg/d for acne management. Common adverse effects include diuresis (29% [26/90]), menstrual irregularities (22% [20/90]), fatigue (17% [15/90]), headache (14% [13/90]), and dizziness (12% [11/90]), but they infrequently lead to treatment discontinuation.^4,9 Rates of adverse effects are lower in adolescents compared to adults, although the effects of spironolactone on early endocrine development in adolescents are unknown.⁷ Spironolactone should not be used during pregnancy, and concurrent contraception use is advised because spironolactone has caused feminization of male fetuses in animal studies.^1,10-11

While concerns about potentially severe adverse effects including hypotension, hyperkalemia, and tumorigenicity have been raised, their occurrence in the literature is rare.^5,12-18 In a study evaluating hypotension in 2084 patients taking spironolactone 50 to 200 mg/day for acne, hair loss, and/or hirsutism, 3.1% experienced absolute hypotension, and only 0.26% required dose reduction or discontinuation.¹² Another study of 403 patients taking spironolactone for acne reported a statistically significant but clinically insignificant mean reduction in systolic blood pressure of 3.5 mm Hg.⁵ While clinically relevant hypotension is unlikely to occur, some authors still recommend measuring baseline blood pressure before spironolactone initiation.¹²

Many large studies have demonstrated that hyperkalemia with spironolactone use is rare in young healthy women.^13-15 In one study of patients aged 18 to 45 years treated with spironolactone for acne, only 0.72% of 1802 serum potassium measurements fell within the range of mild hyperkalemia.¹³ Another study found a significantly greater incidence of hyperkalemia in healthy women aged 46 to 65 years compared with women younger than 45 years (16.7% vs <1%; P=.0245).¹⁴ Additionally, among 27 patients taking spironolactone and oral contraceptives containing drospirenone (a spironolactone analog), none had elevated potassium levels.¹⁵ Given these findings, American Academy of Dermatology guidelines suggest that monitoring potassium in young healthy women has low utility but should be considered in those with risk factors including older age; renal and cardiovascular disease; and concurrent medications that interfere with renal, adrenal, and hepatic function.¹ If performed, monitoring should be done within the first few weeks of initiating spironolactone for early detection of hyperkalemia.¹⁶

Spironolactone has a US Food and Drug Administration warning for tumorigenicity based on studies in rats that were given up to 150 times the amount for human therapeutic doses and subsequently developed thyroid, hepatic, testicular, and breast adenomas.¹ However, several large studies in humans have not found an association between spironolactone and breast cancer (BC) development.^1,17,18 Furthermore, a large retrospective study found no increased risk for recurrence in BC survivors treated with spironolactone.² Most carcinogenicity studies include older women, which may limit generalizability of the findings to younger women, who comprise the majority of patients being treated for acne. Recently, however, a retrospective study evaluating healthy females aged 9 to 40 years with acne identified no significant increased risk for BC in patients treated with spironolactone.¹⁷ When compared to tetracyclines, there was a slightly decreased BC risk with spironolactone, providing further support for the latter’s safety. Finally, a large systematic review identified no association between spironolactone and ovarian, bladder, kidney, gastric, or esophageal cancers.¹⁸

Final Thoughts

Over the past several years, an ever-expanding body of literature supporting the efficacy and safety of spironolactone has emerged. While spironolactone has been used off label for decades to treat acne in healthy adult females, there are now strong data to support its efficacy in adolescent females. Notably, spironolactone consistently demonstrates similar effectiveness to first-line tetracycline antibiotics. Additionally, data suggest that spironolactone is safe in patients with a history of BC. Overall, spironolactone is a safe, comparable, and promising alternative to antibiotics for acne management in adult and adolescent females.

THE DIAGNOSIS: Cutaneous Cryptococcosis

Biopsy of the ulcerated nodule showed numerous yeastlike organisms within clear mucinous capsules and with some surrounding inflammation. On Grocott methenamine silver staining, the organisms stained black. Workup for disseminated cryptococcus was negative, leading to a diagnosis of primary cutaneous cryptococcosis in the setting of immunosuppression. Notably, cryptococcosis infection has been reported in patients taking fingolimod (a sphingosine-1-phosphate receptor) for multiple sclerosis, which was the case for our patient.¹

The genus Cryptococcus comprises more than 30 species of encapsulated basidiomycetous fungi distributed ubiquitously in nature. Currently, only 2 species are known to cause infectious disease in humans: Cryptococcus neoformans, which affects both immunocompromised and immunocompetent patients and frequently is isolated from pigeon droppings, as well as Cryptococcus gatti, which primarily affects immunocompetent patients and is more commonly isolated from soil and decaying wood.²

Primary cutaneous cryptococcosis (PCC), characterized by direct inoculation of C neoformans or C gatti via skin injury, is rare and typically is seen in patients with decreased cell-mediated immunity, such as those on chronic corticosteroid therapy, solid-organ transplant recipients, and those with HIV.³ Primary cutaneous cryptococcosis typically manifests as a solitary or confined lesion on exposed areas of the skin and often is accompanied by regional lymphadenopathy.^4,5 The most common cutaneous findings associated with PCC include ulceration, cellulitis, and whitlow.⁵ In immunocompetent hosts, frequently affected sites include the arms, fingers, and face, while the trunk and lower extremities are more commonly affected in immunocompromised hosts.³ Secondary cutaneous cryptococcosis occurs through hematologic spread in patients with disseminated cryptococcosis after inhalation of Cryptococcosis spores and differs from PCC in that it typically manifests as multiple lesions scattered on both exposed and covered areas of the skin. Patients also may have signs and symptoms of disseminated cryptococcosis such as pneumonia and/or meningitis at presentation.⁵

Despite the difference between PCC and secondary cutaneous cryptococcosis, almost every type of skin lesion has been observed in cryptococcosis, including pustules, nodules, vesicles, acneform lesions, purpura, ulcers, abscesses, molluscumlike lesions, granulomas, draining sinuses, and cellulitis.^6,7

Cutaneous cryptococcosis generally is associated with 2 types of histologic reactions: gelatinous and granulomatous. The gelatinous reaction shows numerous yeastlike organisms ranging from 4 μm to 12 μm in diameter with large mucinous polysaccharide capsules and scant inflammation. Organisms may be seen in mucoid sheets.⁸ The granulomatous type shows a more pronounced reaction with fewer organisms ranging from 2 μm to 4 μm in diameter found within giant cells, histiocytes, and lymphocytes.^6,9 Areas of necrosis occasionally can be observed.⁸

It is important to consider infection with Blastomyces dermatitidis and Histoplasma capsulatum in the differential Both entities can manifest as necrotizing granulomas on histology (Figures 1 and 2).¹⁰ Microscopic morphology can help differentiate these pathogenic fungi from Cryptococcus diagnosis of cryptococcosis. species which show pleomorphic, narrow-based budding yeast with wide capsules. In contrast, H capsulatum is characterized by small, intracellular, yeastlike cells with microconidia and macroconidia, while B dermatitidis is distinguished by spherical, thick-walled cells with broad-based budding.¹¹ Capsular material also can help distinguish Cryptococcus from other pathogenic fungi. Special stains highlighting the polysaccharide capsule of Cryptococcus can best identify the yeast. The capsule stains red with periodic acid–Schiff, blue with Alcian blue, and black with Grocott methenamine silver. Mucicarmine is especially useful as it can stain the mucinous capsule pinkish red and typically does not stain other pathogenic fungi.¹² Capsule-deficient organisms can lead to considerable difficulties in diagnosis given the organisms can vary in size and may mimic H capsulatum or B dermatitidis. The Fontana-Masson stain is a valuable tool in identifying capsule-deficient organisms, as melanin is found in Cryptococcus cell walls; thus, positive staining excludes H capsulatum and B dermatitidis.¹³

Cutaneous foreign body granuloma, which refers to a granulomatous inflammatory reaction to a foreign body in the skin, is another differential diagnosis that is important to distinguish from cutaneous cryptococcosis. On histology, a collection of histiocytes surround the inert material, forming giant cells without an immune response (Figure 3).¹⁰ In contrast, granulomas caused by infectious etiologies (eg, Cryptococcus species) have an associated adaptive immune response and can be further classified as necrotizing or non-necrotizing. Necrotizing granulomas have a distinct central necrosis with a surrounding lymphohistiocytic reaction with peripheral chronic inflammation.¹⁰

Sweet syndrome is another mimicker of cutaneous cryptococcosis. A histologic variant of Sweet syndrome has been reported that has characteristic cutaneous lesions clinically but shows basophilic bodies with a surrounding halo on pathology that can be mistaken for Cryptococcus yeast. Classic histopathology of Sweet syndrome features papillary dermal edema with neutrophil or histiocytelike inflammatory infiltrate (Figure 4). Identification of Sweet syndrome can be aided by positive myeloperoxidase staining and negative periodic acid–Schiff staining.^14,15

THE DIAGNOSIS: Cutaneous Cryptococcosis

Biopsy of the ulcerated nodule showed numerous yeastlike organisms within clear mucinous capsules and with some surrounding inflammation. On Grocott methenamine silver staining, the organisms stained black. Workup for disseminated cryptococcus was negative, leading to a diagnosis of primary cutaneous cryptococcosis in the setting of immunosuppression. Notably, cryptococcosis infection has been reported in patients taking fingolimod (a sphingosine-1-phosphate receptor) for multiple sclerosis, which was the case for our patient.¹

The genus Cryptococcus comprises more than 30 species of encapsulated basidiomycetous fungi distributed ubiquitously in nature. Currently, only 2 species are known to cause infectious disease in humans: Cryptococcus neoformans, which affects both immunocompromised and immunocompetent patients and frequently is isolated from pigeon droppings, as well as Cryptococcus gatti, which primarily affects immunocompetent patients and is more commonly isolated from soil and decaying wood.²

Primary cutaneous cryptococcosis (PCC), characterized by direct inoculation of C neoformans or C gatti via skin injury, is rare and typically is seen in patients with decreased cell-mediated immunity, such as those on chronic corticosteroid therapy, solid-organ transplant recipients, and those with HIV.³ Primary cutaneous cryptococcosis typically manifests as a solitary or confined lesion on exposed areas of the skin and often is accompanied by regional lymphadenopathy.^4,5 The most common cutaneous findings associated with PCC include ulceration, cellulitis, and whitlow.⁵ In immunocompetent hosts, frequently affected sites include the arms, fingers, and face, while the trunk and lower extremities are more commonly affected in immunocompromised hosts.³ Secondary cutaneous cryptococcosis occurs through hematologic spread in patients with disseminated cryptococcosis after inhalation of Cryptococcosis spores and differs from PCC in that it typically manifests as multiple lesions scattered on both exposed and covered areas of the skin. Patients also may have signs and symptoms of disseminated cryptococcosis such as pneumonia and/or meningitis at presentation.⁵

Despite the difference between PCC and secondary cutaneous cryptococcosis, almost every type of skin lesion has been observed in cryptococcosis, including pustules, nodules, vesicles, acneform lesions, purpura, ulcers, abscesses, molluscumlike lesions, granulomas, draining sinuses, and cellulitis.^6,7

Cutaneous cryptococcosis generally is associated with 2 types of histologic reactions: gelatinous and granulomatous. The gelatinous reaction shows numerous yeastlike organisms ranging from 4 μm to 12 μm in diameter with large mucinous polysaccharide capsules and scant inflammation. Organisms may be seen in mucoid sheets.⁸ The granulomatous type shows a more pronounced reaction with fewer organisms ranging from 2 μm to 4 μm in diameter found within giant cells, histiocytes, and lymphocytes.^6,9 Areas of necrosis occasionally can be observed.⁸

It is important to consider infection with Blastomyces dermatitidis and Histoplasma capsulatum in the differential Both entities can manifest as necrotizing granulomas on histology (Figures 1 and 2).¹⁰ Microscopic morphology can help differentiate these pathogenic fungi from Cryptococcus diagnosis of cryptococcosis. species which show pleomorphic, narrow-based budding yeast with wide capsules. In contrast, H capsulatum is characterized by small, intracellular, yeastlike cells with microconidia and macroconidia, while B dermatitidis is distinguished by spherical, thick-walled cells with broad-based budding.¹¹ Capsular material also can help distinguish Cryptococcus from other pathogenic fungi. Special stains highlighting the polysaccharide capsule of Cryptococcus can best identify the yeast. The capsule stains red with periodic acid–Schiff, blue with Alcian blue, and black with Grocott methenamine silver. Mucicarmine is especially useful as it can stain the mucinous capsule pinkish red and typically does not stain other pathogenic fungi.¹² Capsule-deficient organisms can lead to considerable difficulties in diagnosis given the organisms can vary in size and may mimic H capsulatum or B dermatitidis. The Fontana-Masson stain is a valuable tool in identifying capsule-deficient organisms, as melanin is found in Cryptococcus cell walls; thus, positive staining excludes H capsulatum and B dermatitidis.¹³

Cutaneous foreign body granuloma, which refers to a granulomatous inflammatory reaction to a foreign body in the skin, is another differential diagnosis that is important to distinguish from cutaneous cryptococcosis. On histology, a collection of histiocytes surround the inert material, forming giant cells without an immune response (Figure 3).¹⁰ In contrast, granulomas caused by infectious etiologies (eg, Cryptococcus species) have an associated adaptive immune response and can be further classified as necrotizing or non-necrotizing. Necrotizing granulomas have a distinct central necrosis with a surrounding lymphohistiocytic reaction with peripheral chronic inflammation.¹⁰

Sweet syndrome is another mimicker of cutaneous cryptococcosis. A histologic variant of Sweet syndrome has been reported that has characteristic cutaneous lesions clinically but shows basophilic bodies with a surrounding halo on pathology that can be mistaken for Cryptococcus yeast. Classic histopathology of Sweet syndrome features papillary dermal edema with neutrophil or histiocytelike inflammatory infiltrate (Figure 4). Identification of Sweet syndrome can be aided by positive myeloperoxidase staining and negative periodic acid–Schiff staining.^14,15

THE DIAGNOSIS: Cutaneous Cryptococcosis

Biopsy of the ulcerated nodule showed numerous yeastlike organisms within clear mucinous capsules and with some surrounding inflammation. On Grocott methenamine silver staining, the organisms stained black. Workup for disseminated cryptococcus was negative, leading to a diagnosis of primary cutaneous cryptococcosis in the setting of immunosuppression. Notably, cryptococcosis infection has been reported in patients taking fingolimod (a sphingosine-1-phosphate receptor) for multiple sclerosis, which was the case for our patient.¹

The genus Cryptococcus comprises more than 30 species of encapsulated basidiomycetous fungi distributed ubiquitously in nature. Currently, only 2 species are known to cause infectious disease in humans: Cryptococcus neoformans, which affects both immunocompromised and immunocompetent patients and frequently is isolated from pigeon droppings, as well as Cryptococcus gatti, which primarily affects immunocompetent patients and is more commonly isolated from soil and decaying wood.²

Primary cutaneous cryptococcosis (PCC), characterized by direct inoculation of C neoformans or C gatti via skin injury, is rare and typically is seen in patients with decreased cell-mediated immunity, such as those on chronic corticosteroid therapy, solid-organ transplant recipients, and those with HIV.³ Primary cutaneous cryptococcosis typically manifests as a solitary or confined lesion on exposed areas of the skin and often is accompanied by regional lymphadenopathy.^4,5 The most common cutaneous findings associated with PCC include ulceration, cellulitis, and whitlow.⁵ In immunocompetent hosts, frequently affected sites include the arms, fingers, and face, while the trunk and lower extremities are more commonly affected in immunocompromised hosts.³ Secondary cutaneous cryptococcosis occurs through hematologic spread in patients with disseminated cryptococcosis after inhalation of Cryptococcosis spores and differs from PCC in that it typically manifests as multiple lesions scattered on both exposed and covered areas of the skin. Patients also may have signs and symptoms of disseminated cryptococcosis such as pneumonia and/or meningitis at presentation.⁵

Despite the difference between PCC and secondary cutaneous cryptococcosis, almost every type of skin lesion has been observed in cryptococcosis, including pustules, nodules, vesicles, acneform lesions, purpura, ulcers, abscesses, molluscumlike lesions, granulomas, draining sinuses, and cellulitis.^6,7

Cutaneous cryptococcosis generally is associated with 2 types of histologic reactions: gelatinous and granulomatous. The gelatinous reaction shows numerous yeastlike organisms ranging from 4 μm to 12 μm in diameter with large mucinous polysaccharide capsules and scant inflammation. Organisms may be seen in mucoid sheets.⁸ The granulomatous type shows a more pronounced reaction with fewer organisms ranging from 2 μm to 4 μm in diameter found within giant cells, histiocytes, and lymphocytes.^6,9 Areas of necrosis occasionally can be observed.⁸

It is important to consider infection with Blastomyces dermatitidis and Histoplasma capsulatum in the differential Both entities can manifest as necrotizing granulomas on histology (Figures 1 and 2).¹⁰ Microscopic morphology can help differentiate these pathogenic fungi from Cryptococcus diagnosis of cryptococcosis. species which show pleomorphic, narrow-based budding yeast with wide capsules. In contrast, H capsulatum is characterized by small, intracellular, yeastlike cells with microconidia and macroconidia, while B dermatitidis is distinguished by spherical, thick-walled cells with broad-based budding.¹¹ Capsular material also can help distinguish Cryptococcus from other pathogenic fungi. Special stains highlighting the polysaccharide capsule of Cryptococcus can best identify the yeast. The capsule stains red with periodic acid–Schiff, blue with Alcian blue, and black with Grocott methenamine silver. Mucicarmine is especially useful as it can stain the mucinous capsule pinkish red and typically does not stain other pathogenic fungi.¹² Capsule-deficient organisms can lead to considerable difficulties in diagnosis given the organisms can vary in size and may mimic H capsulatum or B dermatitidis. The Fontana-Masson stain is a valuable tool in identifying capsule-deficient organisms, as melanin is found in Cryptococcus cell walls; thus, positive staining excludes H capsulatum and B dermatitidis.¹³

Cutaneous foreign body granuloma, which refers to a granulomatous inflammatory reaction to a foreign body in the skin, is another differential diagnosis that is important to distinguish from cutaneous cryptococcosis. On histology, a collection of histiocytes surround the inert material, forming giant cells without an immune response (Figure 3).¹⁰ In contrast, granulomas caused by infectious etiologies (eg, Cryptococcus species) have an associated adaptive immune response and can be further classified as necrotizing or non-necrotizing. Necrotizing granulomas have a distinct central necrosis with a surrounding lymphohistiocytic reaction with peripheral chronic inflammation.¹⁰

Sweet syndrome is another mimicker of cutaneous cryptococcosis. A histologic variant of Sweet syndrome has been reported that has characteristic cutaneous lesions clinically but shows basophilic bodies with a surrounding halo on pathology that can be mistaken for Cryptococcus yeast. Classic histopathology of Sweet syndrome features papillary dermal edema with neutrophil or histiocytelike inflammatory infiltrate (Figure 4). Identification of Sweet syndrome can be aided by positive myeloperoxidase staining and negative periodic acid–Schiff staining.^14,15

To the Editor:

Uveitis associated with tattoos is common, yet the etiology and optimal treatment options for this phenomenon remain unclear. Possible causes include a delayed hypersensitivity reaction to tattoo ink antigen or systemic sarcoidosis localized to the skin.¹ Long-term treatment options include topical, intralesional, and systemic corticosteroids or immunosuppressants.² Short-term options often include direct surgical excision and laser treatment. However, laser removal of tattoo pigment typically involves multiple sessions over the course of years, and there is a risk for antigen dispersal that may lead to anaphylaxis. Determining the most effective and safe treatment for a patient with progressive and severe ocular symptoms can be challenging. We describe a patient with cutaneous blue ink tattoos who developed chronic bilateral glaucoma, iritis, uveitis, and ocular hypertension that was refractory to multiple systemic medications and ophthalmologic procedures but responded to CO₂ laser ablation.

A 27-year-old man with an active smoking history presented to our laser surgery center with a rash of approximately 4 years’ duration in areas with blue tattoo ink on both forearms. He was referred by his ophthalmologist due to bilateral uveitis and iritis and subsequent ocular hypertension and glaucoma that developed approximately 5 years after tattoo placement on the bilateral forearms. When the rash first appeared, the skin in the areas of the blue tattoo ink had hyperpigmented pruritic plaques. The patient was treated by a dermatologist with topical steroids to help reduce the itching and inflammation. Around the same time, he also started having ocular symptoms—vitreous floaters, erythema, eye pain, and blurriness—and was diagnosed with iritis of unclear etiology by ophthalmology. Figure 1 documents the patient’s clinical course. Due to escalating intraocular pressure and symptoms, he was referred to a glaucoma specialist and a rheumatologist. Systemic and rheumatologic medical conditions were ruled out with negative results on a series of blood tests (eg, rheumatoid factor, HLA-B27, antinuclear antibody, lysozyme, interferon gamma release assay, erythrocyte sedimentation rate, C-reactive protein, hepatitis B/C virus, Treponema pallidum, HIV), and magnetic resonance imaging of the brain was negative, ruling out demyelinating disease. Laboratory workup for sarcoidosis also was performed. The angiotensin-converting enzyme level was 30 U/L (reference range, 9-67 U/L), and a chest radiograph and computed tomography with contrast indicated no evidence of cardiopulmonary involvement. Although sarcoidosis could not be definitively ruled out, no other cause could be determined, and the patient’s glaucoma specialist diagnosed him with tattoo-associated uveitis. The patient was started on brimonidine, latanoprost, prednisolone, and dorzolamidetimolol eye drops, as well as acetazolamide (500 mg twice daily) and oral prednisone (various doses). Over the next 3 years, the patient continued to have symptoms, and immunosuppressant medications—methotrexate 20-25 mg weekly and adalimumab 40 mg every 2 weeks—were added to his treatment regimen. The patient also underwent bilateral ophthalmologic procedures, including a Baerveldt glaucoma implant procedure in the left eye and circumferential trabeculectomy in the right eye.

Despite these medications and procedures, the patient’s symptoms and intraocular pressure had not improved. At the current visit, punch biopsy of the tattooed skin and histologic examination showed dermal lymphoplasmacytic inflammation with scattered foreign-body giant cells associated with blue tattoo ink and overlying hyperkeratosis and spongiosis, consistent with allergic contact dermatitis (Figure 2). Because both immunosuppressant medications and ophthalmologic procedures had failed to control the progression of the ocular symptoms and the patient was at risk for permanent blindness, surgical excision and laser tattoo removal were considered as potential treatment options. Due to the large surface area and circumferential nature of the tattoos, there was a notable risk for disfiguring scars at both recipient and donor sites with surgical excision followed by graft placement. Thus, CO₂ laser ablation was the preferred treatment option. However, this procedure was not without risk for anaphylaxis if the tattoo pigment were to be released into systemic circulation. Thus, at the first visit, ablation was performed on 3 test spots and the patient was prescribed cetirizine, diphenhydramine, and prophylactic prednisone for a few days. The patient then received a total of 5 fully ablative CO₂ laser sessions (pulse energy: 200 mJ [15 J/cm²]; computerized pattern generator: 2-8-9 [85.2 J/cm²]; rate: 200 Hz [20 W], 3 passes) over 13 months to remove all visible blue ink in stages (Figure 3). Even with a shortened time course (as more time between laser sessions typically is preferred), the treatments were well tolerated with only mild hypertrophic scarring that responded to intralesional steroids (triamcinolone 10 mg/mL). On repeat skin biopsy during the treatment course, the superficial dermis demonstrated mostly scar tissue and near-total pigment removal—a 90% to 95% reduction in blue ink from prior biopsy—and minimal inflammation (Figure 4). Scant fine to coarse pigment deposition was seen in the deep dermis next to subcutaneous fat, which was unchanged from the previous biopsy. The patient’s ophthalmologic symptoms were tracked via improvement in intraocular pressure and stabilization of his vision, indicating rapid and complete resolution of the glaucoma after the last laser treatment. With resolution of his ocular symptoms, the patient was tapered off all immunosuppressant medications. The patient was lost to follow-up approximately 2 years after the final laser treatment.

Tattoo-associated uveitis initially was described in 1969 in 3 patients with light blue tattoos who developed tattoo granulomas and simultaneous uveitis. These cases were successfully treated with excision.³ Multiple cases have been reported since, often with bilateral uveitis and tattoos demonstrating noncaseating granulomatous inflammation that were treated with steroids.⁴ In 2018, a diagnosis of exclusion was proposed for uveitis associated with granulomatous tattoo reaction without sarcoidosis: tattoo granulomas with uveitis (TAGU).¹

In this case, sarcoidosis initially was high on the differential diagnosis. Sarcoidosis is an immune-mediated systemic disease of unknown etiology characterized by the presence of widespread noncaseating epithelioid cell granulomas, primarily seen in the pulmonary and lymphatic systems. However, it often initially manifests with cutaneous involvement with noncaseating “naked” granulomas in the dermis and subcutaneous tissue. Although TAGU cases have demonstrated noncaseating granulomas in association with dermal tattoo pigment on histopathology,^1,4 dermal lymphoplasmacytic inflammation with scattered foreign body giant cells was noted in our patient, which was more consistent with allergic contact dermatitis. Thus, it is important to consider that TAGU can be seen with varying histologic patterns. In patients with tattoos, sarcoidosis can manifest grossly as a papulonodular cutaneous reaction.⁵ Active smoking is associated with a decreased risk for sarcoidosis, and those who smoke are statistically more likely to have tattoos than the general population,^6,7 so our patient’s smoking history may be relevant. However, sarcoidosis was an unlikely diagnosis due to the serum angiotensin-converting enzyme level; results of a chest radiograph (bilateral adenopathy and coarse reticular opacities) and computed tomography (hilar and mediastinal adenopathy); and nonsarcoidal histopathology.

An allergic reaction to tattoo ink is caused by a delayed-type hypersensitivity reaction to a pigment hapten that can develop abruptly months to years after tattoo placement—1 year after tattoo placement in our patient. This reaction was seen in our patient’s blue pigment tattoos, although it is more commonly seen in red pigment tattoos.⁸ Although the etiology of TAGU is poorly understood, it also is hypothesized to be a delayed-type hypersensitivity response to tattoo ink particles, suggested by the pattern of lymphocytes infiltrating the tattoo and atypical T-cell infiltrate on vitreous biopsy.^9,10 Further research is required to elucidate the relationship between tattoos and uveitis.

Q-switched lasers (eg, 532-nm or 1064-nm Nd:YAG, alexandrite, or ruby lasers) are the standard treatment options for uncomplicated tattoo removal and employ a high-intensity, ultrashort pulse duration.¹¹ However Q-switched lasers require multiple sessions and target pigment-containing cells, releasing the tattoo particles into systemic circulation, which can potentially induce a severe allergic response.¹² In contrast, CO₂ lasers use a different mechanism, emitting energy at a wavelength of 10,600 nm, which is absorbed by intracellular water and allows for the ablation of the superficial epidermis along with the embedded ink with subsequent re-epithelialization, as well as heat-mediated thermal injury to allow for dermal collagen remodeling.¹³ In a 2021 retrospective study of ablative laser therapy for allergic tattoo reactions, patients were treated with the 10,600-nm ablative CO₂ laser and noted improvements in itching and burning with minimal adverse events.¹² Although using a CO₂ laser may not be considered a firstline treatment option for TAGU, the refractory clinical course and notable morbidity of surgical excision necessitated the use of ablative laser in our case.

Tattoo granulomas with uveitis is a rare diagnosis with the potential for serious permanent sequelae including blindness. Existing treatments such as topical and oral corticosteroids, immunosuppressants, surgical excision, and Q-switched lasers all are possible options, but in a patient with progressive ocular symptoms with other potential rheumatologic conditions and sarcoidosis ruled out, fully ablative CO₂ laser may be an effective treatment option. Our case demonstrated the successful treatment of TAGU with CO₂ laser ablation. Given the unclear etiology of TAGU and the limited evidence on treatment options and efficacy, our case contributes to the body of literature that can inform clinical management of this unusual and serious reaction.

To the Editor:

Uveitis associated with tattoos is common, yet the etiology and optimal treatment options for this phenomenon remain unclear. Possible causes include a delayed hypersensitivity reaction to tattoo ink antigen or systemic sarcoidosis localized to the skin.¹ Long-term treatment options include topical, intralesional, and systemic corticosteroids or immunosuppressants.² Short-term options often include direct surgical excision and laser treatment. However, laser removal of tattoo pigment typically involves multiple sessions over the course of years, and there is a risk for antigen dispersal that may lead to anaphylaxis. Determining the most effective and safe treatment for a patient with progressive and severe ocular symptoms can be challenging. We describe a patient with cutaneous blue ink tattoos who developed chronic bilateral glaucoma, iritis, uveitis, and ocular hypertension that was refractory to multiple systemic medications and ophthalmologic procedures but responded to CO₂ laser ablation.

A 27-year-old man with an active smoking history presented to our laser surgery center with a rash of approximately 4 years’ duration in areas with blue tattoo ink on both forearms. He was referred by his ophthalmologist due to bilateral uveitis and iritis and subsequent ocular hypertension and glaucoma that developed approximately 5 years after tattoo placement on the bilateral forearms. When the rash first appeared, the skin in the areas of the blue tattoo ink had hyperpigmented pruritic plaques. The patient was treated by a dermatologist with topical steroids to help reduce the itching and inflammation. Around the same time, he also started having ocular symptoms—vitreous floaters, erythema, eye pain, and blurriness—and was diagnosed with iritis of unclear etiology by ophthalmology. Figure 1 documents the patient’s clinical course. Due to escalating intraocular pressure and symptoms, he was referred to a glaucoma specialist and a rheumatologist. Systemic and rheumatologic medical conditions were ruled out with negative results on a series of blood tests (eg, rheumatoid factor, HLA-B27, antinuclear antibody, lysozyme, interferon gamma release assay, erythrocyte sedimentation rate, C-reactive protein, hepatitis B/C virus, Treponema pallidum, HIV), and magnetic resonance imaging of the brain was negative, ruling out demyelinating disease. Laboratory workup for sarcoidosis also was performed. The angiotensin-converting enzyme level was 30 U/L (reference range, 9-67 U/L), and a chest radiograph and computed tomography with contrast indicated no evidence of cardiopulmonary involvement. Although sarcoidosis could not be definitively ruled out, no other cause could be determined, and the patient’s glaucoma specialist diagnosed him with tattoo-associated uveitis. The patient was started on brimonidine, latanoprost, prednisolone, and dorzolamidetimolol eye drops, as well as acetazolamide (500 mg twice daily) and oral prednisone (various doses). Over the next 3 years, the patient continued to have symptoms, and immunosuppressant medications—methotrexate 20-25 mg weekly and adalimumab 40 mg every 2 weeks—were added to his treatment regimen. The patient also underwent bilateral ophthalmologic procedures, including a Baerveldt glaucoma implant procedure in the left eye and circumferential trabeculectomy in the right eye.

Despite these medications and procedures, the patient’s symptoms and intraocular pressure had not improved. At the current visit, punch biopsy of the tattooed skin and histologic examination showed dermal lymphoplasmacytic inflammation with scattered foreign-body giant cells associated with blue tattoo ink and overlying hyperkeratosis and spongiosis, consistent with allergic contact dermatitis (Figure 2). Because both immunosuppressant medications and ophthalmologic procedures had failed to control the progression of the ocular symptoms and the patient was at risk for permanent blindness, surgical excision and laser tattoo removal were considered as potential treatment options. Due to the large surface area and circumferential nature of the tattoos, there was a notable risk for disfiguring scars at both recipient and donor sites with surgical excision followed by graft placement. Thus, CO₂ laser ablation was the preferred treatment option. However, this procedure was not without risk for anaphylaxis if the tattoo pigment were to be released into systemic circulation. Thus, at the first visit, ablation was performed on 3 test spots and the patient was prescribed cetirizine, diphenhydramine, and prophylactic prednisone for a few days. The patient then received a total of 5 fully ablative CO₂ laser sessions (pulse energy: 200 mJ [15 J/cm²]; computerized pattern generator: 2-8-9 [85.2 J/cm²]; rate: 200 Hz [20 W], 3 passes) over 13 months to remove all visible blue ink in stages (Figure 3). Even with a shortened time course (as more time between laser sessions typically is preferred), the treatments were well tolerated with only mild hypertrophic scarring that responded to intralesional steroids (triamcinolone 10 mg/mL). On repeat skin biopsy during the treatment course, the superficial dermis demonstrated mostly scar tissue and near-total pigment removal—a 90% to 95% reduction in blue ink from prior biopsy—and minimal inflammation (Figure 4). Scant fine to coarse pigment deposition was seen in the deep dermis next to subcutaneous fat, which was unchanged from the previous biopsy. The patient’s ophthalmologic symptoms were tracked via improvement in intraocular pressure and stabilization of his vision, indicating rapid and complete resolution of the glaucoma after the last laser treatment. With resolution of his ocular symptoms, the patient was tapered off all immunosuppressant medications. The patient was lost to follow-up approximately 2 years after the final laser treatment.

Tattoo-associated uveitis initially was described in 1969 in 3 patients with light blue tattoos who developed tattoo granulomas and simultaneous uveitis. These cases were successfully treated with excision.³ Multiple cases have been reported since, often with bilateral uveitis and tattoos demonstrating noncaseating granulomatous inflammation that were treated with steroids.⁴ In 2018, a diagnosis of exclusion was proposed for uveitis associated with granulomatous tattoo reaction without sarcoidosis: tattoo granulomas with uveitis (TAGU).¹

In this case, sarcoidosis initially was high on the differential diagnosis. Sarcoidosis is an immune-mediated systemic disease of unknown etiology characterized by the presence of widespread noncaseating epithelioid cell granulomas, primarily seen in the pulmonary and lymphatic systems. However, it often initially manifests with cutaneous involvement with noncaseating “naked” granulomas in the dermis and subcutaneous tissue. Although TAGU cases have demonstrated noncaseating granulomas in association with dermal tattoo pigment on histopathology,^1,4 dermal lymphoplasmacytic inflammation with scattered foreign body giant cells was noted in our patient, which was more consistent with allergic contact dermatitis. Thus, it is important to consider that TAGU can be seen with varying histologic patterns. In patients with tattoos, sarcoidosis can manifest grossly as a papulonodular cutaneous reaction.⁵ Active smoking is associated with a decreased risk for sarcoidosis, and those who smoke are statistically more likely to have tattoos than the general population,^6,7 so our patient’s smoking history may be relevant. However, sarcoidosis was an unlikely diagnosis due to the serum angiotensin-converting enzyme level; results of a chest radiograph (bilateral adenopathy and coarse reticular opacities) and computed tomography (hilar and mediastinal adenopathy); and nonsarcoidal histopathology.

An allergic reaction to tattoo ink is caused by a delayed-type hypersensitivity reaction to a pigment hapten that can develop abruptly months to years after tattoo placement—1 year after tattoo placement in our patient. This reaction was seen in our patient’s blue pigment tattoos, although it is more commonly seen in red pigment tattoos.⁸ Although the etiology of TAGU is poorly understood, it also is hypothesized to be a delayed-type hypersensitivity response to tattoo ink particles, suggested by the pattern of lymphocytes infiltrating the tattoo and atypical T-cell infiltrate on vitreous biopsy.^9,10 Further research is required to elucidate the relationship between tattoos and uveitis.

Q-switched lasers (eg, 532-nm or 1064-nm Nd:YAG, alexandrite, or ruby lasers) are the standard treatment options for uncomplicated tattoo removal and employ a high-intensity, ultrashort pulse duration.¹¹ However Q-switched lasers require multiple sessions and target pigment-containing cells, releasing the tattoo particles into systemic circulation, which can potentially induce a severe allergic response.¹² In contrast, CO₂ lasers use a different mechanism, emitting energy at a wavelength of 10,600 nm, which is absorbed by intracellular water and allows for the ablation of the superficial epidermis along with the embedded ink with subsequent re-epithelialization, as well as heat-mediated thermal injury to allow for dermal collagen remodeling.¹³ In a 2021 retrospective study of ablative laser therapy for allergic tattoo reactions, patients were treated with the 10,600-nm ablative CO₂ laser and noted improvements in itching and burning with minimal adverse events.¹² Although using a CO₂ laser may not be considered a firstline treatment option for TAGU, the refractory clinical course and notable morbidity of surgical excision necessitated the use of ablative laser in our case.

Tattoo granulomas with uveitis is a rare diagnosis with the potential for serious permanent sequelae including blindness. Existing treatments such as topical and oral corticosteroids, immunosuppressants, surgical excision, and Q-switched lasers all are possible options, but in a patient with progressive ocular symptoms with other potential rheumatologic conditions and sarcoidosis ruled out, fully ablative CO₂ laser may be an effective treatment option. Our case demonstrated the successful treatment of TAGU with CO₂ laser ablation. Given the unclear etiology of TAGU and the limited evidence on treatment options and efficacy, our case contributes to the body of literature that can inform clinical management of this unusual and serious reaction.

To the Editor:

Uveitis associated with tattoos is common, yet the etiology and optimal treatment options for this phenomenon remain unclear. Possible causes include a delayed hypersensitivity reaction to tattoo ink antigen or systemic sarcoidosis localized to the skin.¹ Long-term treatment options include topical, intralesional, and systemic corticosteroids or immunosuppressants.² Short-term options often include direct surgical excision and laser treatment. However, laser removal of tattoo pigment typically involves multiple sessions over the course of years, and there is a risk for antigen dispersal that may lead to anaphylaxis. Determining the most effective and safe treatment for a patient with progressive and severe ocular symptoms can be challenging. We describe a patient with cutaneous blue ink tattoos who developed chronic bilateral glaucoma, iritis, uveitis, and ocular hypertension that was refractory to multiple systemic medications and ophthalmologic procedures but responded to CO₂ laser ablation.

A 27-year-old man with an active smoking history presented to our laser surgery center with a rash of approximately 4 years’ duration in areas with blue tattoo ink on both forearms. He was referred by his ophthalmologist due to bilateral uveitis and iritis and subsequent ocular hypertension and glaucoma that developed approximately 5 years after tattoo placement on the bilateral forearms. When the rash first appeared, the skin in the areas of the blue tattoo ink had hyperpigmented pruritic plaques. The patient was treated by a dermatologist with topical steroids to help reduce the itching and inflammation. Around the same time, he also started having ocular symptoms—vitreous floaters, erythema, eye pain, and blurriness—and was diagnosed with iritis of unclear etiology by ophthalmology. Figure 1 documents the patient’s clinical course. Due to escalating intraocular pressure and symptoms, he was referred to a glaucoma specialist and a rheumatologist. Systemic and rheumatologic medical conditions were ruled out with negative results on a series of blood tests (eg, rheumatoid factor, HLA-B27, antinuclear antibody, lysozyme, interferon gamma release assay, erythrocyte sedimentation rate, C-reactive protein, hepatitis B/C virus, Treponema pallidum, HIV), and magnetic resonance imaging of the brain was negative, ruling out demyelinating disease. Laboratory workup for sarcoidosis also was performed. The angiotensin-converting enzyme level was 30 U/L (reference range, 9-67 U/L), and a chest radiograph and computed tomography with contrast indicated no evidence of cardiopulmonary involvement. Although sarcoidosis could not be definitively ruled out, no other cause could be determined, and the patient’s glaucoma specialist diagnosed him with tattoo-associated uveitis. The patient was started on brimonidine, latanoprost, prednisolone, and dorzolamidetimolol eye drops, as well as acetazolamide (500 mg twice daily) and oral prednisone (various doses). Over the next 3 years, the patient continued to have symptoms, and immunosuppressant medications—methotrexate 20-25 mg weekly and adalimumab 40 mg every 2 weeks—were added to his treatment regimen. The patient also underwent bilateral ophthalmologic procedures, including a Baerveldt glaucoma implant procedure in the left eye and circumferential trabeculectomy in the right eye.

Despite these medications and procedures, the patient’s symptoms and intraocular pressure had not improved. At the current visit, punch biopsy of the tattooed skin and histologic examination showed dermal lymphoplasmacytic inflammation with scattered foreign-body giant cells associated with blue tattoo ink and overlying hyperkeratosis and spongiosis, consistent with allergic contact dermatitis (Figure 2). Because both immunosuppressant medications and ophthalmologic procedures had failed to control the progression of the ocular symptoms and the patient was at risk for permanent blindness, surgical excision and laser tattoo removal were considered as potential treatment options. Due to the large surface area and circumferential nature of the tattoos, there was a notable risk for disfiguring scars at both recipient and donor sites with surgical excision followed by graft placement. Thus, CO₂ laser ablation was the preferred treatment option. However, this procedure was not without risk for anaphylaxis if the tattoo pigment were to be released into systemic circulation. Thus, at the first visit, ablation was performed on 3 test spots and the patient was prescribed cetirizine, diphenhydramine, and prophylactic prednisone for a few days. The patient then received a total of 5 fully ablative CO₂ laser sessions (pulse energy: 200 mJ [15 J/cm²]; computerized pattern generator: 2-8-9 [85.2 J/cm²]; rate: 200 Hz [20 W], 3 passes) over 13 months to remove all visible blue ink in stages (Figure 3). Even with a shortened time course (as more time between laser sessions typically is preferred), the treatments were well tolerated with only mild hypertrophic scarring that responded to intralesional steroids (triamcinolone 10 mg/mL). On repeat skin biopsy during the treatment course, the superficial dermis demonstrated mostly scar tissue and near-total pigment removal—a 90% to 95% reduction in blue ink from prior biopsy—and minimal inflammation (Figure 4). Scant fine to coarse pigment deposition was seen in the deep dermis next to subcutaneous fat, which was unchanged from the previous biopsy. The patient’s ophthalmologic symptoms were tracked via improvement in intraocular pressure and stabilization of his vision, indicating rapid and complete resolution of the glaucoma after the last laser treatment. With resolution of his ocular symptoms, the patient was tapered off all immunosuppressant medications. The patient was lost to follow-up approximately 2 years after the final laser treatment.

Tattoo-associated uveitis initially was described in 1969 in 3 patients with light blue tattoos who developed tattoo granulomas and simultaneous uveitis. These cases were successfully treated with excision.³ Multiple cases have been reported since, often with bilateral uveitis and tattoos demonstrating noncaseating granulomatous inflammation that were treated with steroids.⁴ In 2018, a diagnosis of exclusion was proposed for uveitis associated with granulomatous tattoo reaction without sarcoidosis: tattoo granulomas with uveitis (TAGU).¹

In this case, sarcoidosis initially was high on the differential diagnosis. Sarcoidosis is an immune-mediated systemic disease of unknown etiology characterized by the presence of widespread noncaseating epithelioid cell granulomas, primarily seen in the pulmonary and lymphatic systems. However, it often initially manifests with cutaneous involvement with noncaseating “naked” granulomas in the dermis and subcutaneous tissue. Although TAGU cases have demonstrated noncaseating granulomas in association with dermal tattoo pigment on histopathology,^1,4 dermal lymphoplasmacytic inflammation with scattered foreign body giant cells was noted in our patient, which was more consistent with allergic contact dermatitis. Thus, it is important to consider that TAGU can be seen with varying histologic patterns. In patients with tattoos, sarcoidosis can manifest grossly as a papulonodular cutaneous reaction.⁵ Active smoking is associated with a decreased risk for sarcoidosis, and those who smoke are statistically more likely to have tattoos than the general population,^6,7 so our patient’s smoking history may be relevant. However, sarcoidosis was an unlikely diagnosis due to the serum angiotensin-converting enzyme level; results of a chest radiograph (bilateral adenopathy and coarse reticular opacities) and computed tomography (hilar and mediastinal adenopathy); and nonsarcoidal histopathology.

An allergic reaction to tattoo ink is caused by a delayed-type hypersensitivity reaction to a pigment hapten that can develop abruptly months to years after tattoo placement—1 year after tattoo placement in our patient. This reaction was seen in our patient’s blue pigment tattoos, although it is more commonly seen in red pigment tattoos.⁸ Although the etiology of TAGU is poorly understood, it also is hypothesized to be a delayed-type hypersensitivity response to tattoo ink particles, suggested by the pattern of lymphocytes infiltrating the tattoo and atypical T-cell infiltrate on vitreous biopsy.^9,10 Further research is required to elucidate the relationship between tattoos and uveitis.

Q-switched lasers (eg, 532-nm or 1064-nm Nd:YAG, alexandrite, or ruby lasers) are the standard treatment options for uncomplicated tattoo removal and employ a high-intensity, ultrashort pulse duration.¹¹ However Q-switched lasers require multiple sessions and target pigment-containing cells, releasing the tattoo particles into systemic circulation, which can potentially induce a severe allergic response.¹² In contrast, CO₂ lasers use a different mechanism, emitting energy at a wavelength of 10,600 nm, which is absorbed by intracellular water and allows for the ablation of the superficial epidermis along with the embedded ink with subsequent re-epithelialization, as well as heat-mediated thermal injury to allow for dermal collagen remodeling.¹³ In a 2021 retrospective study of ablative laser therapy for allergic tattoo reactions, patients were treated with the 10,600-nm ablative CO₂ laser and noted improvements in itching and burning with minimal adverse events.¹² Although using a CO₂ laser may not be considered a firstline treatment option for TAGU, the refractory clinical course and notable morbidity of surgical excision necessitated the use of ablative laser in our case.

Tattoo granulomas with uveitis is a rare diagnosis with the potential for serious permanent sequelae including blindness. Existing treatments such as topical and oral corticosteroids, immunosuppressants, surgical excision, and Q-switched lasers all are possible options, but in a patient with progressive ocular symptoms with other potential rheumatologic conditions and sarcoidosis ruled out, fully ablative CO₂ laser may be an effective treatment option. Our case demonstrated the successful treatment of TAGU with CO₂ laser ablation. Given the unclear etiology of TAGU and the limited evidence on treatment options and efficacy, our case contributes to the body of literature that can inform clinical management of this unusual and serious reaction.

Celery (Apium graveolens)—that lowly vegetable that often languishes in the refrigerator crisper and apparently supplies fewer calories than are required to consume it—contains a myriad of photosensitizing chemicals known as furocoumarins and psoralens that can cause phytophotodermatitis (PPD) when handled prior to exposure to UV light.¹ Individuals who are most likely to develop PPD caused by repeated contact with celery include food industry workers (eg, grocery store workers, farmers) who pick, handle, or prepare celery for consumption. While eating celery as part of a standard diet is highly unlikely to cause PPD, celery infected with Sclerotinia sclerotiorum (known as pink rot) causes more severe generalized sun sensitivity due to an increased amount of furocoumarins produced in response to the fungus.² Contact with celery also can induce cutaneous manifestations unrelated to sun exposure in some individuals, including urticaria, allergic contact dermatitis, and anaphylaxis.³ In this article, we provide an overview of the life cycle and origin of celery as well as its irritant and allergic properties. We also describe cutaneous rashes associated with PPD caused by exposure to celery and highlight treatment options.

Morphology and Distribution

The Apiaceae family features aromatic flowering plants that comprise more than 3500 species, including many economically important vegetables, herbs, and spices.⁴ It also includes many alkaloid-containing species that are known to be poisonous to humans, such as poison hemlock (Conium maculatum) and water hemlock (Cicuta maculate). Most Apiaceae plants that are consumed by humans originate from the Mediterranean region.⁵ While known for their diversity of flavor and aroma, most of the plants from this family have low caloric value and provide minimal amounts of energy.

Members of the Apiaceae family have flowers that create a classic umbel shape mimicking the appearance of an upside-down umbrella (thus the former name for this family, Umbelliferae). The pedicles—the small stems attached to the base of each flower—spread from a common center to form the umbel.⁵ The Apiaceae family also includes the greatest number of plants that cause PPD due to their high concentration of furocoumarins, which deter fungus from harming the plants.⁶

A biennial plant, celery completes its life cycle in 2 years. During the first season, the stems, roots, and leaves sprout; in the second and final year, the flowers, fruits, and seeds proliferate, followed by decomposition. Apium graveolens approaches heights of 2 to 3 ft, growing upright and displaying grooved stems. Each stem terminates in a basal rosette of leaves. The second season brings white flower blooms in terminal or axillary umbels.⁷

Celery originated in the temperate Mediterranean regions of Europe, but farmers now cultivate it globally.⁸ It grows best in rich moist soil with full exposure to sunlight. Plants multiply their numbers through self-seeding. Celery commonly is found in suburban and rural homes, both in refrigerators for consumption as well as in medicine cabinets in capsule form for the treatment of arthritis.⁴

Irritant and Allergenic Properties

Despite the potential health benefits of celery, the Apiaceae family, which includes hogweed, dill, and fennel, prevails as the most common culprit for phytotoxic reactions. The Rutaceae family, including citrus plants and rue, remains runner-up for causes of PPD.⁹ Phytophotodermatitis is not an immunologic reaction, making anyone susceptible to formation of the cutaneous lesions when exposed to UV light after handling celery. Pruritis rarely occurs, unlike in allergic phytodermatitis.¹⁰ Upon photoexcitation from exposure to UVA light, individual psoralen molecules covalently bind to pyrimidine bases, causing interstrand cross-linking that prevents DNA replication and triggering a cascade leading to apoptosis of the cell. Apoptosis induces cell membrane edema, which manifests as cutaneous vesicles and bullae on the skin.¹⁰ Regardless of plant species, PPD reactions have similar appearance.

Celery roots contain the greatest concentration of psoralens, making it the most likely part of the plant to induce PPD.⁶ Phytophotodermatitis caused by celery can occur at any time of the year, but most eruptions occur during the summer months due to increased sunlight exposure and intensity. Among 320 randomly selected Michigan celery harvesters, 163 (51%) displayed evidence of vesicular and bullous dermatitis on the fingers, hands, and forearms.¹¹ In this study, celery infected with pink rot fungus induced an erythematous eruption with vesicles and bullae within 48 hours of contact after just 30 seconds of summer sunlight exposure; however, eruptions are not limited to summer months, as the cutaneous presentation depends solely on exposure to UVA light, which can occur year-round.

Use of tanning beds is a major risk factor for PPD.¹² Tanning beds utilize fluorescent bulbs that primarily emit UVA light, with UVB light emitted to a lesser degree. The UVA radiation produced by tanning beds is more than 3 times as intense as natural sunlight.¹² Among grocery store employees, the combination of these 2 risk factors—regular contact with celery and tanning bed use—resulted in a prevalence ratio for PPD more than 40 times greater than that of individuals with neither risk factor.¹³

Cutaneous Manifestations of PPD

Phytophotodermatitis is a nonimmunologic dermatitis that forms via the interaction between UV light exposure and the photosensitizing chemicals inherent to some plant species. Development of PPD following contact with celery may be caused by the photoactive substances in celery, including the psoralens 8-methoxypsoralen and 5-methoxypsoralen.¹⁴ The psoralens must become activated by UV light with wavelengths between 320 nm and 400 nm (UVA) to initiate biologic effects.¹⁵

Once chemically activated, the photoactive mediators cause an erythematous and edematous sunburnlike reaction. Current hypotheses state that psoralen plus UVA generates reactive oxygen species, which damage the DNA within cells and alter receptors on cell membranes within the epidermis.¹⁴ The cutaneous eruption usually appears between 12 and 36 hours after sun exposure. Although they generally are not pruritic, the eruptions may induce pain. Within 7 to 10 days following development of the rash, hyperpigmentation occurs in the affected area and often persists for months to years.¹⁶ Ingestion of large amounts of celery has been cited to cause generalized phototoxic reactions; however, PPD rarely arises solely after ingestion, unless excessive amounts are consumed with concomitant exposure to psoralen plus UVA or tanning beds.¹⁷ In these cases, patients develop diffuse redness with superficial scaling, pain, and blistering if severe.

Treatment of PPD

Prevention remains the best form of treatment for PPD caused by exposure to celery. Postcontact management includes washing the affected area with soap and water and changing clothes promptly. Topical corticosteroids have mild utility in treatment of PPD.¹⁸ Oral steroid tapers, which reduce acute inflammation, also are an option for treatment. Alternatively, intramuscular triamcinolone acetonide 1 mg/kg mixed with budesonide 0.1 mg/kg is an option and is associated with a reduced risk for adverse effects compared to oral steroids. The resulting hyperpigmentation develops 1 to 2 weeks postepithelialization.¹⁹ Hyperpigmentation often fades slowly over several months in lighter-skinned individuals but may last for years or indefinitely in darker-skinned patients.

Final Thoughts

Dermatologists should be knowledgeable about the various plant culprits that can induce PPD. Understanding the mechanism and pathophysiology can help guide both therapeutic interventions and preventive counseling. Understanding that even readily available vegetables such as celery can induce cutaneous eruptions should put PPD in the differential diagnosis more commonly when unspecified dermatitides are present.

Celery (Apium graveolens)—that lowly vegetable that often languishes in the refrigerator crisper and apparently supplies fewer calories than are required to consume it—contains a myriad of photosensitizing chemicals known as furocoumarins and psoralens that can cause phytophotodermatitis (PPD) when handled prior to exposure to UV light.¹ Individuals who are most likely to develop PPD caused by repeated contact with celery include food industry workers (eg, grocery store workers, farmers) who pick, handle, or prepare celery for consumption. While eating celery as part of a standard diet is highly unlikely to cause PPD, celery infected with Sclerotinia sclerotiorum (known as pink rot) causes more severe generalized sun sensitivity due to an increased amount of furocoumarins produced in response to the fungus.² Contact with celery also can induce cutaneous manifestations unrelated to sun exposure in some individuals, including urticaria, allergic contact dermatitis, and anaphylaxis.³ In this article, we provide an overview of the life cycle and origin of celery as well as its irritant and allergic properties. We also describe cutaneous rashes associated with PPD caused by exposure to celery and highlight treatment options.

Morphology and Distribution

The Apiaceae family features aromatic flowering plants that comprise more than 3500 species, including many economically important vegetables, herbs, and spices.⁴ It also includes many alkaloid-containing species that are known to be poisonous to humans, such as poison hemlock (Conium maculatum) and water hemlock (Cicuta maculate). Most Apiaceae plants that are consumed by humans originate from the Mediterranean region.⁵ While known for their diversity of flavor and aroma, most of the plants from this family have low caloric value and provide minimal amounts of energy.

Members of the Apiaceae family have flowers that create a classic umbel shape mimicking the appearance of an upside-down umbrella (thus the former name for this family, Umbelliferae). The pedicles—the small stems attached to the base of each flower—spread from a common center to form the umbel.⁵ The Apiaceae family also includes the greatest number of plants that cause PPD due to their high concentration of furocoumarins, which deter fungus from harming the plants.⁶

A biennial plant, celery completes its life cycle in 2 years. During the first season, the stems, roots, and leaves sprout; in the second and final year, the flowers, fruits, and seeds proliferate, followed by decomposition. Apium graveolens approaches heights of 2 to 3 ft, growing upright and displaying grooved stems. Each stem terminates in a basal rosette of leaves. The second season brings white flower blooms in terminal or axillary umbels.⁷

Celery originated in the temperate Mediterranean regions of Europe, but farmers now cultivate it globally.⁸ It grows best in rich moist soil with full exposure to sunlight. Plants multiply their numbers through self-seeding. Celery commonly is found in suburban and rural homes, both in refrigerators for consumption as well as in medicine cabinets in capsule form for the treatment of arthritis.⁴

Irritant and Allergenic Properties

Despite the potential health benefits of celery, the Apiaceae family, which includes hogweed, dill, and fennel, prevails as the most common culprit for phytotoxic reactions. The Rutaceae family, including citrus plants and rue, remains runner-up for causes of PPD.⁹ Phytophotodermatitis is not an immunologic reaction, making anyone susceptible to formation of the cutaneous lesions when exposed to UV light after handling celery. Pruritis rarely occurs, unlike in allergic phytodermatitis.¹⁰ Upon photoexcitation from exposure to UVA light, individual psoralen molecules covalently bind to pyrimidine bases, causing interstrand cross-linking that prevents DNA replication and triggering a cascade leading to apoptosis of the cell. Apoptosis induces cell membrane edema, which manifests as cutaneous vesicles and bullae on the skin.¹⁰ Regardless of plant species, PPD reactions have similar appearance.

Celery roots contain the greatest concentration of psoralens, making it the most likely part of the plant to induce PPD.⁶ Phytophotodermatitis caused by celery can occur at any time of the year, but most eruptions occur during the summer months due to increased sunlight exposure and intensity. Among 320 randomly selected Michigan celery harvesters, 163 (51%) displayed evidence of vesicular and bullous dermatitis on the fingers, hands, and forearms.¹¹ In this study, celery infected with pink rot fungus induced an erythematous eruption with vesicles and bullae within 48 hours of contact after just 30 seconds of summer sunlight exposure; however, eruptions are not limited to summer months, as the cutaneous presentation depends solely on exposure to UVA light, which can occur year-round.

Use of tanning beds is a major risk factor for PPD.¹² Tanning beds utilize fluorescent bulbs that primarily emit UVA light, with UVB light emitted to a lesser degree. The UVA radiation produced by tanning beds is more than 3 times as intense as natural sunlight.¹² Among grocery store employees, the combination of these 2 risk factors—regular contact with celery and tanning bed use—resulted in a prevalence ratio for PPD more than 40 times greater than that of individuals with neither risk factor.¹³

Cutaneous Manifestations of PPD

Phytophotodermatitis is a nonimmunologic dermatitis that forms via the interaction between UV light exposure and the photosensitizing chemicals inherent to some plant species. Development of PPD following contact with celery may be caused by the photoactive substances in celery, including the psoralens 8-methoxypsoralen and 5-methoxypsoralen.¹⁴ The psoralens must become activated by UV light with wavelengths between 320 nm and 400 nm (UVA) to initiate biologic effects.¹⁵

Once chemically activated, the photoactive mediators cause an erythematous and edematous sunburnlike reaction. Current hypotheses state that psoralen plus UVA generates reactive oxygen species, which damage the DNA within cells and alter receptors on cell membranes within the epidermis.¹⁴ The cutaneous eruption usually appears between 12 and 36 hours after sun exposure. Although they generally are not pruritic, the eruptions may induce pain. Within 7 to 10 days following development of the rash, hyperpigmentation occurs in the affected area and often persists for months to years.¹⁶ Ingestion of large amounts of celery has been cited to cause generalized phototoxic reactions; however, PPD rarely arises solely after ingestion, unless excessive amounts are consumed with concomitant exposure to psoralen plus UVA or tanning beds.¹⁷ In these cases, patients develop diffuse redness with superficial scaling, pain, and blistering if severe.

Treatment of PPD

Prevention remains the best form of treatment for PPD caused by exposure to celery. Postcontact management includes washing the affected area with soap and water and changing clothes promptly. Topical corticosteroids have mild utility in treatment of PPD.¹⁸ Oral steroid tapers, which reduce acute inflammation, also are an option for treatment. Alternatively, intramuscular triamcinolone acetonide 1 mg/kg mixed with budesonide 0.1 mg/kg is an option and is associated with a reduced risk for adverse effects compared to oral steroids. The resulting hyperpigmentation develops 1 to 2 weeks postepithelialization.¹⁹ Hyperpigmentation often fades slowly over several months in lighter-skinned individuals but may last for years or indefinitely in darker-skinned patients.

Final Thoughts

Dermatologists should be knowledgeable about the various plant culprits that can induce PPD. Understanding the mechanism and pathophysiology can help guide both therapeutic interventions and preventive counseling. Understanding that even readily available vegetables such as celery can induce cutaneous eruptions should put PPD in the differential diagnosis more commonly when unspecified dermatitides are present.

Celery (Apium graveolens)—that lowly vegetable that often languishes in the refrigerator crisper and apparently supplies fewer calories than are required to consume it—contains a myriad of photosensitizing chemicals known as furocoumarins and psoralens that can cause phytophotodermatitis (PPD) when handled prior to exposure to UV light.¹ Individuals who are most likely to develop PPD caused by repeated contact with celery include food industry workers (eg, grocery store workers, farmers) who pick, handle, or prepare celery for consumption. While eating celery as part of a standard diet is highly unlikely to cause PPD, celery infected with Sclerotinia sclerotiorum (known as pink rot) causes more severe generalized sun sensitivity due to an increased amount of furocoumarins produced in response to the fungus.² Contact with celery also can induce cutaneous manifestations unrelated to sun exposure in some individuals, including urticaria, allergic contact dermatitis, and anaphylaxis.³ In this article, we provide an overview of the life cycle and origin of celery as well as its irritant and allergic properties. We also describe cutaneous rashes associated with PPD caused by exposure to celery and highlight treatment options.

Morphology and Distribution

The Apiaceae family features aromatic flowering plants that comprise more than 3500 species, including many economically important vegetables, herbs, and spices.⁴ It also includes many alkaloid-containing species that are known to be poisonous to humans, such as poison hemlock (Conium maculatum) and water hemlock (Cicuta maculate). Most Apiaceae plants that are consumed by humans originate from the Mediterranean region.⁵ While known for their diversity of flavor and aroma, most of the plants from this family have low caloric value and provide minimal amounts of energy.

Members of the Apiaceae family have flowers that create a classic umbel shape mimicking the appearance of an upside-down umbrella (thus the former name for this family, Umbelliferae). The pedicles—the small stems attached to the base of each flower—spread from a common center to form the umbel.⁵ The Apiaceae family also includes the greatest number of plants that cause PPD due to their high concentration of furocoumarins, which deter fungus from harming the plants.⁶

A biennial plant, celery completes its life cycle in 2 years. During the first season, the stems, roots, and leaves sprout; in the second and final year, the flowers, fruits, and seeds proliferate, followed by decomposition. Apium graveolens approaches heights of 2 to 3 ft, growing upright and displaying grooved stems. Each stem terminates in a basal rosette of leaves. The second season brings white flower blooms in terminal or axillary umbels.⁷

Celery originated in the temperate Mediterranean regions of Europe, but farmers now cultivate it globally.⁸ It grows best in rich moist soil with full exposure to sunlight. Plants multiply their numbers through self-seeding. Celery commonly is found in suburban and rural homes, both in refrigerators for consumption as well as in medicine cabinets in capsule form for the treatment of arthritis.⁴

Irritant and Allergenic Properties

Despite the potential health benefits of celery, the Apiaceae family, which includes hogweed, dill, and fennel, prevails as the most common culprit for phytotoxic reactions. The Rutaceae family, including citrus plants and rue, remains runner-up for causes of PPD.⁹ Phytophotodermatitis is not an immunologic reaction, making anyone susceptible to formation of the cutaneous lesions when exposed to UV light after handling celery. Pruritis rarely occurs, unlike in allergic phytodermatitis.¹⁰ Upon photoexcitation from exposure to UVA light, individual psoralen molecules covalently bind to pyrimidine bases, causing interstrand cross-linking that prevents DNA replication and triggering a cascade leading to apoptosis of the cell. Apoptosis induces cell membrane edema, which manifests as cutaneous vesicles and bullae on the skin.¹⁰ Regardless of plant species, PPD reactions have similar appearance.

Celery roots contain the greatest concentration of psoralens, making it the most likely part of the plant to induce PPD.⁶ Phytophotodermatitis caused by celery can occur at any time of the year, but most eruptions occur during the summer months due to increased sunlight exposure and intensity. Among 320 randomly selected Michigan celery harvesters, 163 (51%) displayed evidence of vesicular and bullous dermatitis on the fingers, hands, and forearms.¹¹ In this study, celery infected with pink rot fungus induced an erythematous eruption with vesicles and bullae within 48 hours of contact after just 30 seconds of summer sunlight exposure; however, eruptions are not limited to summer months, as the cutaneous presentation depends solely on exposure to UVA light, which can occur year-round.

Use of tanning beds is a major risk factor for PPD.¹² Tanning beds utilize fluorescent bulbs that primarily emit UVA light, with UVB light emitted to a lesser degree. The UVA radiation produced by tanning beds is more than 3 times as intense as natural sunlight.¹² Among grocery store employees, the combination of these 2 risk factors—regular contact with celery and tanning bed use—resulted in a prevalence ratio for PPD more than 40 times greater than that of individuals with neither risk factor.¹³

Cutaneous Manifestations of PPD

Phytophotodermatitis is a nonimmunologic dermatitis that forms via the interaction between UV light exposure and the photosensitizing chemicals inherent to some plant species. Development of PPD following contact with celery may be caused by the photoactive substances in celery, including the psoralens 8-methoxypsoralen and 5-methoxypsoralen.¹⁴ The psoralens must become activated by UV light with wavelengths between 320 nm and 400 nm (UVA) to initiate biologic effects.¹⁵

Once chemically activated, the photoactive mediators cause an erythematous and edematous sunburnlike reaction. Current hypotheses state that psoralen plus UVA generates reactive oxygen species, which damage the DNA within cells and alter receptors on cell membranes within the epidermis.¹⁴ The cutaneous eruption usually appears between 12 and 36 hours after sun exposure. Although they generally are not pruritic, the eruptions may induce pain. Within 7 to 10 days following development of the rash, hyperpigmentation occurs in the affected area and often persists for months to years.¹⁶ Ingestion of large amounts of celery has been cited to cause generalized phototoxic reactions; however, PPD rarely arises solely after ingestion, unless excessive amounts are consumed with concomitant exposure to psoralen plus UVA or tanning beds.¹⁷ In these cases, patients develop diffuse redness with superficial scaling, pain, and blistering if severe.

Treatment of PPD

Prevention remains the best form of treatment for PPD caused by exposure to celery. Postcontact management includes washing the affected area with soap and water and changing clothes promptly. Topical corticosteroids have mild utility in treatment of PPD.¹⁸ Oral steroid tapers, which reduce acute inflammation, also are an option for treatment. Alternatively, intramuscular triamcinolone acetonide 1 mg/kg mixed with budesonide 0.1 mg/kg is an option and is associated with a reduced risk for adverse effects compared to oral steroids. The resulting hyperpigmentation develops 1 to 2 weeks postepithelialization.¹⁹ Hyperpigmentation often fades slowly over several months in lighter-skinned individuals but may last for years or indefinitely in darker-skinned patients.

Final Thoughts

Dermatologists should be knowledgeable about the various plant culprits that can induce PPD. Understanding the mechanism and pathophysiology can help guide both therapeutic interventions and preventive counseling. Understanding that even readily available vegetables such as celery can induce cutaneous eruptions should put PPD in the differential diagnosis more commonly when unspecified dermatitides are present.

THE DIAGNOSIS: Metastatic Renal Cell Carcinoma

The shave biopsy revealed large cells with prominent nucleoli, clear cytoplasm, and thin cell borders in a nestlike arrangement (Figure 1). Immunohistochemical examination was negative for cytokeratin 5/6 and positive for PAX8 (Figure 2), which finalized the diagnosis of metastatic renal cell carcinoma (RCC). Later, our patient had a core biopsy-proven metastasis to the C6 spinous process, with concern for additional metastasis to the liver and lungs on positron emission tomography. Our patient’s treatment plan included pembrolizumab and axitinib to manage further cutaneous metastasis and radiation therapy for the C6 spinous process metastasis.

Renal cell carcinoma denotes cancer originating from the renal epithelium and is the most common kidney tumor in adults.¹ Renal cell carcinoma accounts for more than 90% of kidney malignancies in the United States and has 3 main subtypes: clear cell RCC, papillary RCC, and chromophobe RCC.² About 25% of cases metastasize, commonly to the lungs, liver, bones, lymph nodes, contralateral kidney, and adrenal glands.³

Cutaneous metastasis of RCC is rare, with an incidence of approximately 3.3%.⁴ Notably, 80% to 90% of patients with metastatic skin lesions had a prior diagnosis of RCC.² Skin metastases associated with RCC predominantly are found on the face and scalp, appearing as nodular, swiftly expanding, circular, or oval-shaped growths. The robust vascular element of these lesions can lead to confusion with regard to the proper diagnosis, as they often resemble hemangiomas, pyogenic granulomas, or Kaposi sarcomas.⁴

Many cutaneous metastases linked to RCC exhibit a histomorphologic pattern consistent with clear cell adenocarcinoma.² The malignant cells are large and possess transparent cytoplasm, round to oval nuclei, and prominent nucleoli. The cells can form glandular, acinar, or papillary arrangements; extravasated red blood cells frequently are found within the surrounding fibrovascular tissue.⁵ The presence of cytoplasmic glycogen can be revealed through periodic acid–Schiff staining. Other immunohistochemical markers commonly used to identify skin metastasis of RCC include epithelioid membrane antigen, carcinoembryonic antigen, and CD-10.¹

Various mechanisms are involved in the cutaneous metastases of RCC. The most common pathway involves infiltration of the skin directly overlying the malignant renal mass; additional potential mechanisms include the introduction of abnormal cells into the skin during surgical or diagnostic interventions and their dissemination through the lymphatic system or bloodstream.¹ Among urogenital malignancies other than RCC, skin metastases predominantly manifest in the abdominal region.² Conversely, the head and neck region are more frequently impacted in RCC. The vascular composition of these tumors plays a role in facilitating the extension of cancer cells through the bloodstream, fostering the emergence of distant metastases.⁶

The development of cutaneous metastasis in RCC is associated with a poor prognosis, as most patients die within 6 months of detection.³ Treatment options thus are limited and palliative. Although local excision is an alternative treatment for localized cutaneous metastasis, it often provides little benefit in the presence of extensive metastasis; radiotherapy also has been shown to have a limited effect on primary RCC, though its devascularization of the lesion may be effective in metastatic cases.⁵ Immune checkpoint inhibitors such as nivolumab and ipilimumab have improved progression-free survival in patients with metastatic RCC, though uncertainty remains regarding their efficacy in attenuating cutaneous metastasis.^5,6

THE DIAGNOSIS: Metastatic Renal Cell Carcinoma

The shave biopsy revealed large cells with prominent nucleoli, clear cytoplasm, and thin cell borders in a nestlike arrangement (Figure 1). Immunohistochemical examination was negative for cytokeratin 5/6 and positive for PAX8 (Figure 2), which finalized the diagnosis of metastatic renal cell carcinoma (RCC). Later, our patient had a core biopsy-proven metastasis to the C6 spinous process, with concern for additional metastasis to the liver and lungs on positron emission tomography. Our patient’s treatment plan included pembrolizumab and axitinib to manage further cutaneous metastasis and radiation therapy for the C6 spinous process metastasis.

Renal cell carcinoma denotes cancer originating from the renal epithelium and is the most common kidney tumor in adults.¹ Renal cell carcinoma accounts for more than 90% of kidney malignancies in the United States and has 3 main subtypes: clear cell RCC, papillary RCC, and chromophobe RCC.² About 25% of cases metastasize, commonly to the lungs, liver, bones, lymph nodes, contralateral kidney, and adrenal glands.³

Cutaneous metastasis of RCC is rare, with an incidence of approximately 3.3%.⁴ Notably, 80% to 90% of patients with metastatic skin lesions had a prior diagnosis of RCC.² Skin metastases associated with RCC predominantly are found on the face and scalp, appearing as nodular, swiftly expanding, circular, or oval-shaped growths. The robust vascular element of these lesions can lead to confusion with regard to the proper diagnosis, as they often resemble hemangiomas, pyogenic granulomas, or Kaposi sarcomas.⁴

Many cutaneous metastases linked to RCC exhibit a histomorphologic pattern consistent with clear cell adenocarcinoma.² The malignant cells are large and possess transparent cytoplasm, round to oval nuclei, and prominent nucleoli. The cells can form glandular, acinar, or papillary arrangements; extravasated red blood cells frequently are found within the surrounding fibrovascular tissue.⁵ The presence of cytoplasmic glycogen can be revealed through periodic acid–Schiff staining. Other immunohistochemical markers commonly used to identify skin metastasis of RCC include epithelioid membrane antigen, carcinoembryonic antigen, and CD-10.¹

Various mechanisms are involved in the cutaneous metastases of RCC. The most common pathway involves infiltration of the skin directly overlying the malignant renal mass; additional potential mechanisms include the introduction of abnormal cells into the skin during surgical or diagnostic interventions and their dissemination through the lymphatic system or bloodstream.¹ Among urogenital malignancies other than RCC, skin metastases predominantly manifest in the abdominal region.² Conversely, the head and neck region are more frequently impacted in RCC. The vascular composition of these tumors plays a role in facilitating the extension of cancer cells through the bloodstream, fostering the emergence of distant metastases.⁶

The development of cutaneous metastasis in RCC is associated with a poor prognosis, as most patients die within 6 months of detection.³ Treatment options thus are limited and palliative. Although local excision is an alternative treatment for localized cutaneous metastasis, it often provides little benefit in the presence of extensive metastasis; radiotherapy also has been shown to have a limited effect on primary RCC, though its devascularization of the lesion may be effective in metastatic cases.⁵ Immune checkpoint inhibitors such as nivolumab and ipilimumab have improved progression-free survival in patients with metastatic RCC, though uncertainty remains regarding their efficacy in attenuating cutaneous metastasis.^5,6

THE DIAGNOSIS: Metastatic Renal Cell Carcinoma

The shave biopsy revealed large cells with prominent nucleoli, clear cytoplasm, and thin cell borders in a nestlike arrangement (Figure 1). Immunohistochemical examination was negative for cytokeratin 5/6 and positive for PAX8 (Figure 2), which finalized the diagnosis of metastatic renal cell carcinoma (RCC). Later, our patient had a core biopsy-proven metastasis to the C6 spinous process, with concern for additional metastasis to the liver and lungs on positron emission tomography. Our patient’s treatment plan included pembrolizumab and axitinib to manage further cutaneous metastasis and radiation therapy for the C6 spinous process metastasis.

Renal cell carcinoma denotes cancer originating from the renal epithelium and is the most common kidney tumor in adults.¹ Renal cell carcinoma accounts for more than 90% of kidney malignancies in the United States and has 3 main subtypes: clear cell RCC, papillary RCC, and chromophobe RCC.² About 25% of cases metastasize, commonly to the lungs, liver, bones, lymph nodes, contralateral kidney, and adrenal glands.³

Cutaneous metastasis of RCC is rare, with an incidence of approximately 3.3%.⁴ Notably, 80% to 90% of patients with metastatic skin lesions had a prior diagnosis of RCC.² Skin metastases associated with RCC predominantly are found on the face and scalp, appearing as nodular, swiftly expanding, circular, or oval-shaped growths. The robust vascular element of these lesions can lead to confusion with regard to the proper diagnosis, as they often resemble hemangiomas, pyogenic granulomas, or Kaposi sarcomas.⁴

Many cutaneous metastases linked to RCC exhibit a histomorphologic pattern consistent with clear cell adenocarcinoma.² The malignant cells are large and possess transparent cytoplasm, round to oval nuclei, and prominent nucleoli. The cells can form glandular, acinar, or papillary arrangements; extravasated red blood cells frequently are found within the surrounding fibrovascular tissue.⁵ The presence of cytoplasmic glycogen can be revealed through periodic acid–Schiff staining. Other immunohistochemical markers commonly used to identify skin metastasis of RCC include epithelioid membrane antigen, carcinoembryonic antigen, and CD-10.¹

Various mechanisms are involved in the cutaneous metastases of RCC. The most common pathway involves infiltration of the skin directly overlying the malignant renal mass; additional potential mechanisms include the introduction of abnormal cells into the skin during surgical or diagnostic interventions and their dissemination through the lymphatic system or bloodstream.¹ Among urogenital malignancies other than RCC, skin metastases predominantly manifest in the abdominal region.² Conversely, the head and neck region are more frequently impacted in RCC. The vascular composition of these tumors plays a role in facilitating the extension of cancer cells through the bloodstream, fostering the emergence of distant metastases.⁶

The development of cutaneous metastasis in RCC is associated with a poor prognosis, as most patients die within 6 months of detection.³ Treatment options thus are limited and palliative. Although local excision is an alternative treatment for localized cutaneous metastasis, it often provides little benefit in the presence of extensive metastasis; radiotherapy also has been shown to have a limited effect on primary RCC, though its devascularization of the lesion may be effective in metastatic cases.⁵ Immune checkpoint inhibitors such as nivolumab and ipilimumab have improved progression-free survival in patients with metastatic RCC, though uncertainty remains regarding their efficacy in attenuating cutaneous metastasis.^5,6

The Diagnosis: Leiomyoma

Histopathology revealed a dermal mesenchymal tumor composed of fascicles of bland spindle cells with tapered nuclei, perinuclear vacuoles, eosinophilic cytoplasm, and low cellularity (Figure 1). Immunohistochemical studies of the cells stained strongly positive for smooth muscle actin and desmin, consistent with a smooth muscle neoplasm (Figure 2). Fumarate hydratase (FH) staining revealed loss of expression in tumor cells, consistent with FH deficiency (Figure 3). A diagnosis of cutaneous leiomyoma was made, and although the clinical and histologic findings suggested hereditary leiomyomatosis and renal cell cancer (HLRCC), genetic testing was negative for an FH gene mutation. This negative result indicated that HLRCC was unlikely despite the initial concerns based on the findings. 

Leiomyomas are benign neoplasms that are challenging to diagnose based on the clinical picture alone. Leiomyomas most commonly are found in the genitourinary and gastrointestinal systems, with cutaneous manifestation being the second most common presentation.¹ These benign smooth muscle tumors manifest as tender, firm, flesh-colored, pink or reddish-brown nodules that are subcategorized based on the derivation of the smooth muscle within the tumor.² Angioleiomyomas, the most common type, arise from the tunica media of blood vessels, whereas piloleiomyomas and genital leiomyomas arise from the arrector pili musculature of the hair follicle and the smooth muscle found in the scrotum, labia, or nipple.² Rare cases of cutaneous leiomyosarcomas and angioleiomyosarcomas have been reported in the literature.^3,4 Solitary leiomyomas tend to develop on the lower extremities, whereas multiple lesions frequently manifest on the extensor surfaces of extremities and the trunk. Lesions often are painful, either spontaneously or in association with applied pressure, emotional stress, or exposure to cold temperatures.² 

Although leiomyomas themselves are benign, patients with multiple cutaneous leiomyomas may have an underlying genetic mutation that increases their risk of developing HLRCC, an autosomal-dominant syndrome.⁵ Referral should be considered for individuals with a personal history of or a first-degree relative with cutaneous leiomyomas or renal cell carcinoma (RCC) with histology typical of hereditary leiomyomatosis and RCC, as recommended by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.⁶ In this case, the decision to refer the patient for genetic testing was based on her family history, specifically her paternal uncle having multiple similar lesions, which, while not a first-degree relative, still raised concerns about potential hereditary risks and warranted further evaluation. A germline mutation in the FH gene, which encodes an enzyme that converts fumarate to malate in the Krebs cycle and plays a role in tumor suppression, is the cause of HLRCC.^2,7 When part of this genetic condition, cutaneous leiomyomas tend to occur around 25 years of age (range, 10-50 years).² A diagnosis of HLRCC should be strongly considered if a patient displays multiple cutaneous leiomyomas with at least 1 histologically confirmed lesion or at least 2 of the following: solitary cutaneous leiomyoma with family history of HLRCC, onset of severely symptomatic uterine fibroids before age 40 years, type II papillary or collecting duct renal cell cancer before age 40 years, or a first-degree family member who meets 1 of these criteria.^5,8 

Diagnosis of cutaneous leiomyoma may be accomplished by microscopic examination of a tissue sample; however, further diagnostic workup is warranted due to the strong correlation with HLRCC.² A definitive diagnosis of HLRCC is confirmed with a germline mutation in the FH gene, and genetic screening should be offered to patients before renal cancer surveillance to avoid unwarranted investigations.⁸ Timely clinical diagnosis enables early genetic testing and enhanced outcomes for patients with confirmed HLRCC who may need a multidisciplinary approach of dermatologists, gynecologists, and urologic oncologists.^5,8 

Cutaneous leiomyomas can be excised, and this typically is the gold standard of care for small and localized lesions, although the use of cryosurgery and carbon dioxide lasers has been reported as well.^2,9,10 For more widespread lesions or for patients who are not appropriate candidates for surgery, pharmacologic therapies (α-blockers, calcium channel blockers, nitroglycerin), intralesional corticosteroids, and/or botulinum toxin injections can be utilized.^2,11 

The acronym BLEND AN EGG encompasses the clinical differential diagnosis for painful skin tumors: blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor. Blue rubber bleb nevi are deep blue in color, and angiolipomas sit under the skin and present as subcutaneous swellings. Dermatofibromas and neurofibromas also are included in the differential.¹² Dermatofibromas are firm solitary lesions that have a pathognomonic pinch sign. Neurofibromas are soft and rubbery, have a buttonhole sign, and stain positively for S-100 protein and SOX-10 but negatively for actin and desmin.¹²

The Diagnosis: Leiomyoma

Histopathology revealed a dermal mesenchymal tumor composed of fascicles of bland spindle cells with tapered nuclei, perinuclear vacuoles, eosinophilic cytoplasm, and low cellularity (Figure 1). Immunohistochemical studies of the cells stained strongly positive for smooth muscle actin and desmin, consistent with a smooth muscle neoplasm (Figure 2). Fumarate hydratase (FH) staining revealed loss of expression in tumor cells, consistent with FH deficiency (Figure 3). A diagnosis of cutaneous leiomyoma was made, and although the clinical and histologic findings suggested hereditary leiomyomatosis and renal cell cancer (HLRCC), genetic testing was negative for an FH gene mutation. This negative result indicated that HLRCC was unlikely despite the initial concerns based on the findings. 

Leiomyomas are benign neoplasms that are challenging to diagnose based on the clinical picture alone. Leiomyomas most commonly are found in the genitourinary and gastrointestinal systems, with cutaneous manifestation being the second most common presentation.¹ These benign smooth muscle tumors manifest as tender, firm, flesh-colored, pink or reddish-brown nodules that are subcategorized based on the derivation of the smooth muscle within the tumor.² Angioleiomyomas, the most common type, arise from the tunica media of blood vessels, whereas piloleiomyomas and genital leiomyomas arise from the arrector pili musculature of the hair follicle and the smooth muscle found in the scrotum, labia, or nipple.² Rare cases of cutaneous leiomyosarcomas and angioleiomyosarcomas have been reported in the literature.^3,4 Solitary leiomyomas tend to develop on the lower extremities, whereas multiple lesions frequently manifest on the extensor surfaces of extremities and the trunk. Lesions often are painful, either spontaneously or in association with applied pressure, emotional stress, or exposure to cold temperatures.² 

Although leiomyomas themselves are benign, patients with multiple cutaneous leiomyomas may have an underlying genetic mutation that increases their risk of developing HLRCC, an autosomal-dominant syndrome.⁵ Referral should be considered for individuals with a personal history of or a first-degree relative with cutaneous leiomyomas or renal cell carcinoma (RCC) with histology typical of hereditary leiomyomatosis and RCC, as recommended by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.⁶ In this case, the decision to refer the patient for genetic testing was based on her family history, specifically her paternal uncle having multiple similar lesions, which, while not a first-degree relative, still raised concerns about potential hereditary risks and warranted further evaluation. A germline mutation in the FH gene, which encodes an enzyme that converts fumarate to malate in the Krebs cycle and plays a role in tumor suppression, is the cause of HLRCC.^2,7 When part of this genetic condition, cutaneous leiomyomas tend to occur around 25 years of age (range, 10-50 years).² A diagnosis of HLRCC should be strongly considered if a patient displays multiple cutaneous leiomyomas with at least 1 histologically confirmed lesion or at least 2 of the following: solitary cutaneous leiomyoma with family history of HLRCC, onset of severely symptomatic uterine fibroids before age 40 years, type II papillary or collecting duct renal cell cancer before age 40 years, or a first-degree family member who meets 1 of these criteria.^5,8 

Diagnosis of cutaneous leiomyoma may be accomplished by microscopic examination of a tissue sample; however, further diagnostic workup is warranted due to the strong correlation with HLRCC.² A definitive diagnosis of HLRCC is confirmed with a germline mutation in the FH gene, and genetic screening should be offered to patients before renal cancer surveillance to avoid unwarranted investigations.⁸ Timely clinical diagnosis enables early genetic testing and enhanced outcomes for patients with confirmed HLRCC who may need a multidisciplinary approach of dermatologists, gynecologists, and urologic oncologists.^5,8 

Cutaneous leiomyomas can be excised, and this typically is the gold standard of care for small and localized lesions, although the use of cryosurgery and carbon dioxide lasers has been reported as well.^2,9,10 For more widespread lesions or for patients who are not appropriate candidates for surgery, pharmacologic therapies (α-blockers, calcium channel blockers, nitroglycerin), intralesional corticosteroids, and/or botulinum toxin injections can be utilized.^2,11 

The acronym BLEND AN EGG encompasses the clinical differential diagnosis for painful skin tumors: blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor. Blue rubber bleb nevi are deep blue in color, and angiolipomas sit under the skin and present as subcutaneous swellings. Dermatofibromas and neurofibromas also are included in the differential.¹² Dermatofibromas are firm solitary lesions that have a pathognomonic pinch sign. Neurofibromas are soft and rubbery, have a buttonhole sign, and stain positively for S-100 protein and SOX-10 but negatively for actin and desmin.¹²

The Diagnosis: Leiomyoma

Histopathology revealed a dermal mesenchymal tumor composed of fascicles of bland spindle cells with tapered nuclei, perinuclear vacuoles, eosinophilic cytoplasm, and low cellularity (Figure 1). Immunohistochemical studies of the cells stained strongly positive for smooth muscle actin and desmin, consistent with a smooth muscle neoplasm (Figure 2). Fumarate hydratase (FH) staining revealed loss of expression in tumor cells, consistent with FH deficiency (Figure 3). A diagnosis of cutaneous leiomyoma was made, and although the clinical and histologic findings suggested hereditary leiomyomatosis and renal cell cancer (HLRCC), genetic testing was negative for an FH gene mutation. This negative result indicated that HLRCC was unlikely despite the initial concerns based on the findings. 

Leiomyomas are benign neoplasms that are challenging to diagnose based on the clinical picture alone. Leiomyomas most commonly are found in the genitourinary and gastrointestinal systems, with cutaneous manifestation being the second most common presentation.¹ These benign smooth muscle tumors manifest as tender, firm, flesh-colored, pink or reddish-brown nodules that are subcategorized based on the derivation of the smooth muscle within the tumor.² Angioleiomyomas, the most common type, arise from the tunica media of blood vessels, whereas piloleiomyomas and genital leiomyomas arise from the arrector pili musculature of the hair follicle and the smooth muscle found in the scrotum, labia, or nipple.² Rare cases of cutaneous leiomyosarcomas and angioleiomyosarcomas have been reported in the literature.^3,4 Solitary leiomyomas tend to develop on the lower extremities, whereas multiple lesions frequently manifest on the extensor surfaces of extremities and the trunk. Lesions often are painful, either spontaneously or in association with applied pressure, emotional stress, or exposure to cold temperatures.² 

Although leiomyomas themselves are benign, patients with multiple cutaneous leiomyomas may have an underlying genetic mutation that increases their risk of developing HLRCC, an autosomal-dominant syndrome.⁵ Referral should be considered for individuals with a personal history of or a first-degree relative with cutaneous leiomyomas or renal cell carcinoma (RCC) with histology typical of hereditary leiomyomatosis and RCC, as recommended by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.⁶ In this case, the decision to refer the patient for genetic testing was based on her family history, specifically her paternal uncle having multiple similar lesions, which, while not a first-degree relative, still raised concerns about potential hereditary risks and warranted further evaluation. A germline mutation in the FH gene, which encodes an enzyme that converts fumarate to malate in the Krebs cycle and plays a role in tumor suppression, is the cause of HLRCC.^2,7 When part of this genetic condition, cutaneous leiomyomas tend to occur around 25 years of age (range, 10-50 years).² A diagnosis of HLRCC should be strongly considered if a patient displays multiple cutaneous leiomyomas with at least 1 histologically confirmed lesion or at least 2 of the following: solitary cutaneous leiomyoma with family history of HLRCC, onset of severely symptomatic uterine fibroids before age 40 years, type II papillary or collecting duct renal cell cancer before age 40 years, or a first-degree family member who meets 1 of these criteria.^5,8 

Diagnosis of cutaneous leiomyoma may be accomplished by microscopic examination of a tissue sample; however, further diagnostic workup is warranted due to the strong correlation with HLRCC.² A definitive diagnosis of HLRCC is confirmed with a germline mutation in the FH gene, and genetic screening should be offered to patients before renal cancer surveillance to avoid unwarranted investigations.⁸ Timely clinical diagnosis enables early genetic testing and enhanced outcomes for patients with confirmed HLRCC who may need a multidisciplinary approach of dermatologists, gynecologists, and urologic oncologists.^5,8 

Cutaneous leiomyomas can be excised, and this typically is the gold standard of care for small and localized lesions, although the use of cryosurgery and carbon dioxide lasers has been reported as well.^2,9,10 For more widespread lesions or for patients who are not appropriate candidates for surgery, pharmacologic therapies (α-blockers, calcium channel blockers, nitroglycerin), intralesional corticosteroids, and/or botulinum toxin injections can be utilized.^2,11 

The acronym BLEND AN EGG encompasses the clinical differential diagnosis for painful skin tumors: blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor. Blue rubber bleb nevi are deep blue in color, and angiolipomas sit under the skin and present as subcutaneous swellings. Dermatofibromas and neurofibromas also are included in the differential.¹² Dermatofibromas are firm solitary lesions that have a pathognomonic pinch sign. Neurofibromas are soft and rubbery, have a buttonhole sign, and stain positively for S-100 protein and SOX-10 but negatively for actin and desmin.¹²

To the Editor:

A 22-year-old man was referred to our dermatology outpatient department for wartlike growths that gradually developed around a postoperative enteroatmospheric fistula and stoma over the past 4 months. The patient presented for an emergency exploratory laparotomy with a history of perforation peritonitis 1.5 years prior to the current presentation. He also had a small bowel obstruction 5 months prior to the current presentation that resulted in the resection of a large segment of the small bowel. He underwent a diverting loop ileostomy when the abdominal closure was not achieved because of bowel edema, following which he developed a postoperative enteroatmospheric fistula. In addition, the stoma retracted and was followed by dermal dehiscence, which led to notable leakage and resulted in heavy fecal contamination of the midline wound.

At the current presentation, physical examination revealed multiple grayish-white, dome-shaped, moist papules coalescing to form a peristomal pseudoverrucous mass on the lower side of the stoma (Figure 1). The patient experienced mild itching. The lesion showed no signs of erosion, bleeding, or purulent discharge, and there were no nearby lumps or enlarged lymph nodes. The differential diagnosis included peristomal pyoderma gangrenosum, human papillomavirus (HPV) infection, pseudoverrucous papules and nodules (PPNs), squamous cell carcinoma, and exuberant granulation tissue. A skin biopsy was performed, and histopathology revealed hyperkeratosis, moderate papillomatosis, and marked acanthotic hyperplasia seen as downgrowths into the dermis (Figure 2). No koilocytes, atypia, or mitotic figures were present. Abundant neutrophils and few eosinophils were seen in the dermal infiltrate. A final diagnosis of PPN was made based on clinicopathologic correlation. The patient was advised to use a smaller stoma bag and to change the collection pouch frequently to reduce skin contact with fecal matter.

Peristomal skin conditions are reported in 18% to 55% of patients with stomas and include allergic contact dermatitis, mechanical dermatitis, infections, pyoderma gangrenosum, and irritant contact dermatitis.^1,2 Pseudoverrucous papules (also called chronic papillomatous dermatitis or pseudoverrucous lesions) is a rare dermatologic complication found on the skin around stomas,³ most commonly around urostomy stomas. The presence of PPNs around colostomy stomas and the perianal region is extremely rare.^2,4 This condition is the result of chronic irritant dermatitis from frequent exposure to urine or feces, leading to maceration and epidermal hyperplasia. It occurs because of improper sizing of the stoma bag or incorrect positioning or construction of the stoma.⁵

the overuse of topical benzocaine-resorcinol, leading to chronic irritation.⁶ It is clinically characterized by multiple grayish-white, wartlike, confluent papulonodules around areas chronically exposed to moisture. Differential diagnoses such as secondary neoplasms, HPV infection, exuberant granulation tissue, and candidal infections should be considered.³ Final diagnosis is based on clinicopathologic findings, similar to our case. Epidermal growth factor and transforming growth factor are thought to play a role in the pathophysiology of pseudoepitheliomatous hyperplasia. Increased expression of these mediators leads to proliferation of the epidermis into the dermis.⁷ The role of HPV in PPN remains unclear, as not all PPN lesions are positive for HPV and the cutaneous lesions resolve once the source of irritation is removed. Recommended treatment includes local skin care; stoma refitting; and, in severe cases, excision and revision of the stoma.² Dermatologists must be aware of this often-underdiagnosed condition.

To the Editor:

A 22-year-old man was referred to our dermatology outpatient department for wartlike growths that gradually developed around a postoperative enteroatmospheric fistula and stoma over the past 4 months. The patient presented for an emergency exploratory laparotomy with a history of perforation peritonitis 1.5 years prior to the current presentation. He also had a small bowel obstruction 5 months prior to the current presentation that resulted in the resection of a large segment of the small bowel. He underwent a diverting loop ileostomy when the abdominal closure was not achieved because of bowel edema, following which he developed a postoperative enteroatmospheric fistula. In addition, the stoma retracted and was followed by dermal dehiscence, which led to notable leakage and resulted in heavy fecal contamination of the midline wound.

At the current presentation, physical examination revealed multiple grayish-white, dome-shaped, moist papules coalescing to form a peristomal pseudoverrucous mass on the lower side of the stoma (Figure 1). The patient experienced mild itching. The lesion showed no signs of erosion, bleeding, or purulent discharge, and there were no nearby lumps or enlarged lymph nodes. The differential diagnosis included peristomal pyoderma gangrenosum, human papillomavirus (HPV) infection, pseudoverrucous papules and nodules (PPNs), squamous cell carcinoma, and exuberant granulation tissue. A skin biopsy was performed, and histopathology revealed hyperkeratosis, moderate papillomatosis, and marked acanthotic hyperplasia seen as downgrowths into the dermis (Figure 2). No koilocytes, atypia, or mitotic figures were present. Abundant neutrophils and few eosinophils were seen in the dermal infiltrate. A final diagnosis of PPN was made based on clinicopathologic correlation. The patient was advised to use a smaller stoma bag and to change the collection pouch frequently to reduce skin contact with fecal matter.

Peristomal skin conditions are reported in 18% to 55% of patients with stomas and include allergic contact dermatitis, mechanical dermatitis, infections, pyoderma gangrenosum, and irritant contact dermatitis.^1,2 Pseudoverrucous papules (also called chronic papillomatous dermatitis or pseudoverrucous lesions) is a rare dermatologic complication found on the skin around stomas,³ most commonly around urostomy stomas. The presence of PPNs around colostomy stomas and the perianal region is extremely rare.^2,4 This condition is the result of chronic irritant dermatitis from frequent exposure to urine or feces, leading to maceration and epidermal hyperplasia. It occurs because of improper sizing of the stoma bag or incorrect positioning or construction of the stoma.⁵

the overuse of topical benzocaine-resorcinol, leading to chronic irritation.⁶ It is clinically characterized by multiple grayish-white, wartlike, confluent papulonodules around areas chronically exposed to moisture. Differential diagnoses such as secondary neoplasms, HPV infection, exuberant granulation tissue, and candidal infections should be considered.³ Final diagnosis is based on clinicopathologic findings, similar to our case. Epidermal growth factor and transforming growth factor are thought to play a role in the pathophysiology of pseudoepitheliomatous hyperplasia. Increased expression of these mediators leads to proliferation of the epidermis into the dermis.⁷ The role of HPV in PPN remains unclear, as not all PPN lesions are positive for HPV and the cutaneous lesions resolve once the source of irritation is removed. Recommended treatment includes local skin care; stoma refitting; and, in severe cases, excision and revision of the stoma.² Dermatologists must be aware of this often-underdiagnosed condition.

To the Editor:

A 22-year-old man was referred to our dermatology outpatient department for wartlike growths that gradually developed around a postoperative enteroatmospheric fistula and stoma over the past 4 months. The patient presented for an emergency exploratory laparotomy with a history of perforation peritonitis 1.5 years prior to the current presentation. He also had a small bowel obstruction 5 months prior to the current presentation that resulted in the resection of a large segment of the small bowel. He underwent a diverting loop ileostomy when the abdominal closure was not achieved because of bowel edema, following which he developed a postoperative enteroatmospheric fistula. In addition, the stoma retracted and was followed by dermal dehiscence, which led to notable leakage and resulted in heavy fecal contamination of the midline wound.

At the current presentation, physical examination revealed multiple grayish-white, dome-shaped, moist papules coalescing to form a peristomal pseudoverrucous mass on the lower side of the stoma (Figure 1). The patient experienced mild itching. The lesion showed no signs of erosion, bleeding, or purulent discharge, and there were no nearby lumps or enlarged lymph nodes. The differential diagnosis included peristomal pyoderma gangrenosum, human papillomavirus (HPV) infection, pseudoverrucous papules and nodules (PPNs), squamous cell carcinoma, and exuberant granulation tissue. A skin biopsy was performed, and histopathology revealed hyperkeratosis, moderate papillomatosis, and marked acanthotic hyperplasia seen as downgrowths into the dermis (Figure 2). No koilocytes, atypia, or mitotic figures were present. Abundant neutrophils and few eosinophils were seen in the dermal infiltrate. A final diagnosis of PPN was made based on clinicopathologic correlation. The patient was advised to use a smaller stoma bag and to change the collection pouch frequently to reduce skin contact with fecal matter.

Peristomal skin conditions are reported in 18% to 55% of patients with stomas and include allergic contact dermatitis, mechanical dermatitis, infections, pyoderma gangrenosum, and irritant contact dermatitis.^1,2 Pseudoverrucous papules (also called chronic papillomatous dermatitis or pseudoverrucous lesions) is a rare dermatologic complication found on the skin around stomas,³ most commonly around urostomy stomas. The presence of PPNs around colostomy stomas and the perianal region is extremely rare.^2,4 This condition is the result of chronic irritant dermatitis from frequent exposure to urine or feces, leading to maceration and epidermal hyperplasia. It occurs because of improper sizing of the stoma bag or incorrect positioning or construction of the stoma.⁵

the overuse of topical benzocaine-resorcinol, leading to chronic irritation.⁶ It is clinically characterized by multiple grayish-white, wartlike, confluent papulonodules around areas chronically exposed to moisture. Differential diagnoses such as secondary neoplasms, HPV infection, exuberant granulation tissue, and candidal infections should be considered.³ Final diagnosis is based on clinicopathologic findings, similar to our case. Epidermal growth factor and transforming growth factor are thought to play a role in the pathophysiology of pseudoepitheliomatous hyperplasia. Increased expression of these mediators leads to proliferation of the epidermis into the dermis.⁷ The role of HPV in PPN remains unclear, as not all PPN lesions are positive for HPV and the cutaneous lesions resolve once the source of irritation is removed. Recommended treatment includes local skin care; stoma refitting; and, in severe cases, excision and revision of the stoma.² Dermatologists must be aware of this often-underdiagnosed condition.

North American venomous snakes traditionally are classified as members of either the Viperidae (eg, rattlesnakes, copperheads, cottonmouths) or Elapidae (eg, coral snakes) families and account for roughly 5000 to 10,000 reported envenomations annually.^1,2 In 2021, America’s Poison Centers reported 2287 calls related to copperheads, 71 related to coral snakes, 229 related to cottonmouths, 1184 related to rattlesnakes, and 524 related to unknown snakes.³ The majority of calls related to snake bites were for adult patients, resulting in absent to minor outcomes. Only 1 death due to a rattlesnake bite was reported.³ Death by envenomation from a North American snake species is considered rare and typically is attributed to a lapse in medical attention; however, rattlesnakes are the most common reported cause of death by snake envenomation (Figure 1).^1,3 A study comparing snake bites and hospital stays in the southeast vs southwest United States found that the southeast had the highest incidence of copperhead bites (37%), while the southwest had a higher incidence of rattlesnake bites (70%); those who were bitten by a rattlesnake were reported to have more severe symptoms and greater need for medical attention and antivenin.⁴ Some reports have linked pediatric and elderly patients to worse outcomes.⁵ However, one study examining 24,388 emergency department visits for snake bites from 2006 through 2014 found that the majority of pediatric cases were handled by non– trauma centers in the southern United States,⁶ supporting evidence found by Campbell et al⁷ indicating that most snake bites in children can be managed with conservative care. Though reported complications—including weakness, paralysis, hypovolemic shock, thrombocytopenia, and death—from North American venomous snake bites are low, they are still considered a medical emergency.⁸ It is essential for physicians to understand the clinical manifestations and treatment of North American venomous snake bites and to educate patients on how to protect themselves against and avoid provoking snakes, particularly in rural areas.² In this article, we review the characteristics of common North American venomous snakes and the clinical manifestations of their bites. We also discuss the appropriate measures for staging, evaluating, and treating snake envenomation to improve patient management and care.

Features of North American Venomous Snakes

Individual snakes within the Viperidae family vary in size, markings and coloration, activity, and region, and physicians should consult their local health departments regarding snakes that are common in their area.² Cottonmouth snakes are semiaquatic and traditionally are found within the southern and central United States. With a spade-shaped head and distinct two-tone coloration, cottonmouths may be mistaken for other nonvenomous water snakes in these regions (Figure 2).² Copperheads, true to their name, are red in color; they inhabit a large portion of the southeastern United States and eastern Texas regions and are the cause of the majority of venomous snake bites in North America (Figure 3). Both cottonmouths and copperheads are believed to bite and envenomate as a defensive mechanism when provoked.

Coral snakes, found in the eastern United States and Texas regions, are the only subspecies of the Elapidae family (Figure 4).^2,9 They can be distinguished from the nonvenomous milk snake by their characteristic banding, as coral snakes are patterned in a red-yellow-black band sequence and milk snakes are patterned in a red-black-yellow or white sequence. The differences in appearance of these snakes often is remembered by the phrase “red on yellow kills a fellow.”

Anatomic differences between the Viperidae and Elapidae families, including fang size, placement, and type, as well as venom composition, are directly linked to clinical manifestations of the bites. Viperidae fangs extend from the maxillary bones and are mobile, long, and hollow, making it easy for the snake to control fang movement and envenomation.⁹ Viperidae snakes are uniquely capable of inflicting puncture wounds without the injection of venom, known as dry bites. In contrast, Elapidae snakes have short, hollow, and fixed fangs, and thus patients can protect themselves by wearing appropriate clothing and covered footwear.⁹ Currently, identifying the type of snake responsible for the bite relies on visualization of the snake and/or the identification of clinical symptoms of envenomation by a dermatologist.

Clinical Manifestations of Venomous Snake Bites

Clinical manifestations and cutaneous findings often are used to grade the severity of venomous snake bites as well as to dictate treatment procedures. Grade 0 indicates a bite has occurred without envenomation, while grades I to V describe the progression and severity of envenomation.¹⁰ Grade I describes minimal erythema and edema around the site (fang marks may or may not be present) and no systemic symptoms. Grade II describes erythema and edema extending up the extremity to the first joint (eg, hand to wrist), pain, some systemic symptoms if there is rapid progression, and potential bleeding at the site. Grade III describes erythema and edema spreading to the second joint in the extremity, pain, and systemic symptoms, including coagulation defects. Grade IV describes erythema and edema of the whole extremity, a rapid reaction and progression following the bite, and risk for compartment syndrome. Grade V includes erythema and edema beyond the extremity and increasing systemic symptoms.¹⁰

Local pain and edema, usually on easily accessible or exposed extremities, are the most common clinical symptoms reported following a Viperidae snake bite.¹¹ Due to their capability of producing a dry bite, puncture markings alone do not indicate envenomation. Patients will need to be monitored for several hours for signs of envenomation, which may include swelling, pain, ecchymosis, and indications of systemic manifestation (eg, weakness, dizziness, nausea, severe hypotension, thrombocytopenia).¹¹ Viperidae venom hemorrhagic metalloproteinases act on capillary blood vessels by cleaving basement membrane proteins and allowing for extravasation of fluid into local tissue.¹² The inflammatory response produced at the site of envenomation likely is due to the release of tumor necrosis factor á and endogenous matrix metalloprotein.¹² There is a higher risk for death associated with bites from rattlesnakes within the Viperidae family because their venom contains a unique neurotoxin that works by blocking presynaptic junctions and causing a range of paralytic symptoms from ptosis to respiratory failure.¹³

The severity of Elapidae bites is thought to be related to the amount of venom injected, the size of the victim, and the length of the snake. Though clothing may offer protection, envenomation occurs in 75% of coral snake bites and can produce devastating consequences due to the venom content.¹⁴ In a retrospective study between 2002 and 2004, 90% of Elapidae snake bite patients (n=82) reported local pain, redness, and paresthesia, while around 7% developed systemic symptoms.¹⁵ Elapidae venom primarily is neurotoxic and is thought to spread via lymphatics.¹⁶ Delayed reactions are common and may take up to 12 hours to develop. Patients should be monitored, as local reactions may progress to weakness, fasciculations, extremity paralysis, and lastly, respiratory paralysis. Due to the risk for progression, all patients with likely coral snake bites should be given antivenin.^8,15,17

Much like the North American coral snake, the venomous snake species Gloydius blomhoffii—referred to as the salmosa or mamushi snake depending on the region of origin (ie, Korea or Japan)—is a frequent source of devastating rural snake bites due to neurotoxins (Figure 5). The species’ slender fangs are thought to directly inject the snake’s potent venom, which contains hemorrhagic toxins and α-neurotoxins and Β-neurotoxins, into the bloodstream; however, the salmosa is considered a viper like the North American cottonmouth and copperhead because of its triangular head shape and hollow fangs, which allow for the accommodation of venom-containing glands and mechanism of venom injection. Salmosa venom shares both Viperidae and Elapidae characteristics. Cutaneous findings such as progressive edema, erythema, and bleeding frequently are reported and are attributed to the proteases and hemorrhagic toxins characteristic of vipers (Figure 6). α-Neurotoxins and Β-neurotoxins, similar to the proteolytic venom of the Elapidae family, are responsible for the unique visual disturbances (binocular diplopia) caused by the salmosa.^12,18,19

Treatment

Treating snake bites begins with assessing the patient’s airway, breathing, and circulation, followed by a thorough medical and encounter history (including description of how the bite occurred). Due to the range of Viperidae symptoms, it generally is recommended that patients remove any restrictive clothing or jewelry near the bite and/or over the affected limb or body part, place the affected body part at the level of the heart, and go to the nearest medical facility for prompt care. Historically, empiric antibiotics often were used to prevent wound infections; however, studies have since demonstrated that antibiotics are not necessary and lack efficacy in uncomplicated snake bites.^16,20 In a study of 114 pediatric cases from 1995 to 2005, it was determined that most patients could be managed with conservative treatment directed at pain management and swelling reduction via elevation of the affected extremity.⁶ While conservative management may be all that is needed to care for the majority of cases, one retrospective study from Texas indicated that 70% of pediatric venomous snake bites were treated with either intravenous antibiotics and/or antivenin, highlighting the variability in management and opportunity for improvement.²¹

Antivenin, specifically antivenin (Crotalidae) polyvalent, is the indicated treatment for Viperidae hemorrhagic or coagulopathic envenomation.^13,22 Per guidelines from the World Health Organization, physical examination will yield a grading of the snake bite based on cutaneous findings. Grades III to V are considered moderate to severe and should be given antivenin.²³ Physicians should look for signs of progressive injury and coagulopathy, such as increased swelling, bruising, hypotension, or altered mental status.²² Due to the major neurotoxic risks associated with Elapidae venom, all coral snake bites should be treated with antivenin; early intubation and ventilation may be considered.¹³ Similarly, patients who report a salmosa snake bite require prompt treatment with antivenin and/or cepharanthine, an additive agent to reduce swelling and pain.¹⁸ Due to the nature of the neurotoxins contained in the salmosa venom (α-neurotoxin causing postsynaptic inhibition of the neuromuscular junction and Β-neurotoxin inhibiting neurotransmitter release from the presynaptic terminal), anticholinesterases, which work by blocking the enzymatic breakdown of the neurotransmitter acetylcholine, should not be used.¹⁹ While bleeding and skin and systemic changes may be reversed by antivenin, visual changes are unlikely to resolve with antivenin administration due to the presynaptic binding of Β-neurotoxin and the blockade of neuromuscular signaling.¹⁹

Antivenin should be administered intravenously for the fastest onset of action in a setting suitable for the management of anaphylaxis.²⁴ In situations when the benefits may outweigh the risks (eg, if the patient has had a prior allergic reaction or is not in an environment where they can be watched for at least 8 hours for progression of envenomation or adverse reactions), premedication with an antihistamine or epinephrine may be considered.17 Per the World Allergy Organization and World Health Organization, adverse reactions should be treated with crystalloid solutions and antihistamines, corticosteroids, or epinephrine as indicated.²⁵ In a qualitative analysis of emergency physicians’ attitudes toward antivenin, most expressed treatment hesitancy due to lack of knowledge and experience using the medication.²⁶ When possible, snake bites should thus be managed in consultation with a toxicologist.²

Conclusion

Snake bites and envenomation occur commonly in the United States due to exposure to a variety of venomous snakes in the North American Viperidae and Elapidae families. Appropriate and successful management of snake bites by physicians requires general knowledge of regional snakes, the cutaneous and systemic manifestations of snake bites and envenomation, and current treatment methods.

North American venomous snakes traditionally are classified as members of either the Viperidae (eg, rattlesnakes, copperheads, cottonmouths) or Elapidae (eg, coral snakes) families and account for roughly 5000 to 10,000 reported envenomations annually.^1,2 In 2021, America’s Poison Centers reported 2287 calls related to copperheads, 71 related to coral snakes, 229 related to cottonmouths, 1184 related to rattlesnakes, and 524 related to unknown snakes.³ The majority of calls related to snake bites were for adult patients, resulting in absent to minor outcomes. Only 1 death due to a rattlesnake bite was reported.³ Death by envenomation from a North American snake species is considered rare and typically is attributed to a lapse in medical attention; however, rattlesnakes are the most common reported cause of death by snake envenomation (Figure 1).^1,3 A study comparing snake bites and hospital stays in the southeast vs southwest United States found that the southeast had the highest incidence of copperhead bites (37%), while the southwest had a higher incidence of rattlesnake bites (70%); those who were bitten by a rattlesnake were reported to have more severe symptoms and greater need for medical attention and antivenin.⁴ Some reports have linked pediatric and elderly patients to worse outcomes.⁵ However, one study examining 24,388 emergency department visits for snake bites from 2006 through 2014 found that the majority of pediatric cases were handled by non– trauma centers in the southern United States,⁶ supporting evidence found by Campbell et al⁷ indicating that most snake bites in children can be managed with conservative care. Though reported complications—including weakness, paralysis, hypovolemic shock, thrombocytopenia, and death—from North American venomous snake bites are low, they are still considered a medical emergency.⁸ It is essential for physicians to understand the clinical manifestations and treatment of North American venomous snake bites and to educate patients on how to protect themselves against and avoid provoking snakes, particularly in rural areas.² In this article, we review the characteristics of common North American venomous snakes and the clinical manifestations of their bites. We also discuss the appropriate measures for staging, evaluating, and treating snake envenomation to improve patient management and care.

Features of North American Venomous Snakes

Individual snakes within the Viperidae family vary in size, markings and coloration, activity, and region, and physicians should consult their local health departments regarding snakes that are common in their area.² Cottonmouth snakes are semiaquatic and traditionally are found within the southern and central United States. With a spade-shaped head and distinct two-tone coloration, cottonmouths may be mistaken for other nonvenomous water snakes in these regions (Figure 2).² Copperheads, true to their name, are red in color; they inhabit a large portion of the southeastern United States and eastern Texas regions and are the cause of the majority of venomous snake bites in North America (Figure 3). Both cottonmouths and copperheads are believed to bite and envenomate as a defensive mechanism when provoked.

Coral snakes, found in the eastern United States and Texas regions, are the only subspecies of the Elapidae family (Figure 4).^2,9 They can be distinguished from the nonvenomous milk snake by their characteristic banding, as coral snakes are patterned in a red-yellow-black band sequence and milk snakes are patterned in a red-black-yellow or white sequence. The differences in appearance of these snakes often is remembered by the phrase “red on yellow kills a fellow.”

Anatomic differences between the Viperidae and Elapidae families, including fang size, placement, and type, as well as venom composition, are directly linked to clinical manifestations of the bites. Viperidae fangs extend from the maxillary bones and are mobile, long, and hollow, making it easy for the snake to control fang movement and envenomation.⁹ Viperidae snakes are uniquely capable of inflicting puncture wounds without the injection of venom, known as dry bites. In contrast, Elapidae snakes have short, hollow, and fixed fangs, and thus patients can protect themselves by wearing appropriate clothing and covered footwear.⁹ Currently, identifying the type of snake responsible for the bite relies on visualization of the snake and/or the identification of clinical symptoms of envenomation by a dermatologist.

Clinical Manifestations of Venomous Snake Bites

Clinical manifestations and cutaneous findings often are used to grade the severity of venomous snake bites as well as to dictate treatment procedures. Grade 0 indicates a bite has occurred without envenomation, while grades I to V describe the progression and severity of envenomation.¹⁰ Grade I describes minimal erythema and edema around the site (fang marks may or may not be present) and no systemic symptoms. Grade II describes erythema and edema extending up the extremity to the first joint (eg, hand to wrist), pain, some systemic symptoms if there is rapid progression, and potential bleeding at the site. Grade III describes erythema and edema spreading to the second joint in the extremity, pain, and systemic symptoms, including coagulation defects. Grade IV describes erythema and edema of the whole extremity, a rapid reaction and progression following the bite, and risk for compartment syndrome. Grade V includes erythema and edema beyond the extremity and increasing systemic symptoms.¹⁰

Local pain and edema, usually on easily accessible or exposed extremities, are the most common clinical symptoms reported following a Viperidae snake bite.¹¹ Due to their capability of producing a dry bite, puncture markings alone do not indicate envenomation. Patients will need to be monitored for several hours for signs of envenomation, which may include swelling, pain, ecchymosis, and indications of systemic manifestation (eg, weakness, dizziness, nausea, severe hypotension, thrombocytopenia).¹¹ Viperidae venom hemorrhagic metalloproteinases act on capillary blood vessels by cleaving basement membrane proteins and allowing for extravasation of fluid into local tissue.¹² The inflammatory response produced at the site of envenomation likely is due to the release of tumor necrosis factor á and endogenous matrix metalloprotein.¹² There is a higher risk for death associated with bites from rattlesnakes within the Viperidae family because their venom contains a unique neurotoxin that works by blocking presynaptic junctions and causing a range of paralytic symptoms from ptosis to respiratory failure.¹³

The severity of Elapidae bites is thought to be related to the amount of venom injected, the size of the victim, and the length of the snake. Though clothing may offer protection, envenomation occurs in 75% of coral snake bites and can produce devastating consequences due to the venom content.¹⁴ In a retrospective study between 2002 and 2004, 90% of Elapidae snake bite patients (n=82) reported local pain, redness, and paresthesia, while around 7% developed systemic symptoms.¹⁵ Elapidae venom primarily is neurotoxic and is thought to spread via lymphatics.¹⁶ Delayed reactions are common and may take up to 12 hours to develop. Patients should be monitored, as local reactions may progress to weakness, fasciculations, extremity paralysis, and lastly, respiratory paralysis. Due to the risk for progression, all patients with likely coral snake bites should be given antivenin.^8,15,17

Much like the North American coral snake, the venomous snake species Gloydius blomhoffii—referred to as the salmosa or mamushi snake depending on the region of origin (ie, Korea or Japan)—is a frequent source of devastating rural snake bites due to neurotoxins (Figure 5). The species’ slender fangs are thought to directly inject the snake’s potent venom, which contains hemorrhagic toxins and α-neurotoxins and Β-neurotoxins, into the bloodstream; however, the salmosa is considered a viper like the North American cottonmouth and copperhead because of its triangular head shape and hollow fangs, which allow for the accommodation of venom-containing glands and mechanism of venom injection. Salmosa venom shares both Viperidae and Elapidae characteristics. Cutaneous findings such as progressive edema, erythema, and bleeding frequently are reported and are attributed to the proteases and hemorrhagic toxins characteristic of vipers (Figure 6). α-Neurotoxins and Β-neurotoxins, similar to the proteolytic venom of the Elapidae family, are responsible for the unique visual disturbances (binocular diplopia) caused by the salmosa.^12,18,19

Treatment

Treating snake bites begins with assessing the patient’s airway, breathing, and circulation, followed by a thorough medical and encounter history (including description of how the bite occurred). Due to the range of Viperidae symptoms, it generally is recommended that patients remove any restrictive clothing or jewelry near the bite and/or over the affected limb or body part, place the affected body part at the level of the heart, and go to the nearest medical facility for prompt care. Historically, empiric antibiotics often were used to prevent wound infections; however, studies have since demonstrated that antibiotics are not necessary and lack efficacy in uncomplicated snake bites.^16,20 In a study of 114 pediatric cases from 1995 to 2005, it was determined that most patients could be managed with conservative treatment directed at pain management and swelling reduction via elevation of the affected extremity.⁶ While conservative management may be all that is needed to care for the majority of cases, one retrospective study from Texas indicated that 70% of pediatric venomous snake bites were treated with either intravenous antibiotics and/or antivenin, highlighting the variability in management and opportunity for improvement.²¹

Antivenin, specifically antivenin (Crotalidae) polyvalent, is the indicated treatment for Viperidae hemorrhagic or coagulopathic envenomation.^13,22 Per guidelines from the World Health Organization, physical examination will yield a grading of the snake bite based on cutaneous findings. Grades III to V are considered moderate to severe and should be given antivenin.²³ Physicians should look for signs of progressive injury and coagulopathy, such as increased swelling, bruising, hypotension, or altered mental status.²² Due to the major neurotoxic risks associated with Elapidae venom, all coral snake bites should be treated with antivenin; early intubation and ventilation may be considered.¹³ Similarly, patients who report a salmosa snake bite require prompt treatment with antivenin and/or cepharanthine, an additive agent to reduce swelling and pain.¹⁸ Due to the nature of the neurotoxins contained in the salmosa venom (α-neurotoxin causing postsynaptic inhibition of the neuromuscular junction and Β-neurotoxin inhibiting neurotransmitter release from the presynaptic terminal), anticholinesterases, which work by blocking the enzymatic breakdown of the neurotransmitter acetylcholine, should not be used.¹⁹ While bleeding and skin and systemic changes may be reversed by antivenin, visual changes are unlikely to resolve with antivenin administration due to the presynaptic binding of Β-neurotoxin and the blockade of neuromuscular signaling.¹⁹

Antivenin should be administered intravenously for the fastest onset of action in a setting suitable for the management of anaphylaxis.²⁴ In situations when the benefits may outweigh the risks (eg, if the patient has had a prior allergic reaction or is not in an environment where they can be watched for at least 8 hours for progression of envenomation or adverse reactions), premedication with an antihistamine or epinephrine may be considered.17 Per the World Allergy Organization and World Health Organization, adverse reactions should be treated with crystalloid solutions and antihistamines, corticosteroids, or epinephrine as indicated.²⁵ In a qualitative analysis of emergency physicians’ attitudes toward antivenin, most expressed treatment hesitancy due to lack of knowledge and experience using the medication.²⁶ When possible, snake bites should thus be managed in consultation with a toxicologist.²

Conclusion

Snake bites and envenomation occur commonly in the United States due to exposure to a variety of venomous snakes in the North American Viperidae and Elapidae families. Appropriate and successful management of snake bites by physicians requires general knowledge of regional snakes, the cutaneous and systemic manifestations of snake bites and envenomation, and current treatment methods.

North American venomous snakes traditionally are classified as members of either the Viperidae (eg, rattlesnakes, copperheads, cottonmouths) or Elapidae (eg, coral snakes) families and account for roughly 5000 to 10,000 reported envenomations annually.^1,2 In 2021, America’s Poison Centers reported 2287 calls related to copperheads, 71 related to coral snakes, 229 related to cottonmouths, 1184 related to rattlesnakes, and 524 related to unknown snakes.³ The majority of calls related to snake bites were for adult patients, resulting in absent to minor outcomes. Only 1 death due to a rattlesnake bite was reported.³ Death by envenomation from a North American snake species is considered rare and typically is attributed to a lapse in medical attention; however, rattlesnakes are the most common reported cause of death by snake envenomation (Figure 1).^1,3 A study comparing snake bites and hospital stays in the southeast vs southwest United States found that the southeast had the highest incidence of copperhead bites (37%), while the southwest had a higher incidence of rattlesnake bites (70%); those who were bitten by a rattlesnake were reported to have more severe symptoms and greater need for medical attention and antivenin.⁴ Some reports have linked pediatric and elderly patients to worse outcomes.⁵ However, one study examining 24,388 emergency department visits for snake bites from 2006 through 2014 found that the majority of pediatric cases were handled by non– trauma centers in the southern United States,⁶ supporting evidence found by Campbell et al⁷ indicating that most snake bites in children can be managed with conservative care. Though reported complications—including weakness, paralysis, hypovolemic shock, thrombocytopenia, and death—from North American venomous snake bites are low, they are still considered a medical emergency.⁸ It is essential for physicians to understand the clinical manifestations and treatment of North American venomous snake bites and to educate patients on how to protect themselves against and avoid provoking snakes, particularly in rural areas.² In this article, we review the characteristics of common North American venomous snakes and the clinical manifestations of their bites. We also discuss the appropriate measures for staging, evaluating, and treating snake envenomation to improve patient management and care.

Features of North American Venomous Snakes

Individual snakes within the Viperidae family vary in size, markings and coloration, activity, and region, and physicians should consult their local health departments regarding snakes that are common in their area.² Cottonmouth snakes are semiaquatic and traditionally are found within the southern and central United States. With a spade-shaped head and distinct two-tone coloration, cottonmouths may be mistaken for other nonvenomous water snakes in these regions (Figure 2).² Copperheads, true to their name, are red in color; they inhabit a large portion of the southeastern United States and eastern Texas regions and are the cause of the majority of venomous snake bites in North America (Figure 3). Both cottonmouths and copperheads are believed to bite and envenomate as a defensive mechanism when provoked.

Coral snakes, found in the eastern United States and Texas regions, are the only subspecies of the Elapidae family (Figure 4).^2,9 They can be distinguished from the nonvenomous milk snake by their characteristic banding, as coral snakes are patterned in a red-yellow-black band sequence and milk snakes are patterned in a red-black-yellow or white sequence. The differences in appearance of these snakes often is remembered by the phrase “red on yellow kills a fellow.”

Anatomic differences between the Viperidae and Elapidae families, including fang size, placement, and type, as well as venom composition, are directly linked to clinical manifestations of the bites. Viperidae fangs extend from the maxillary bones and are mobile, long, and hollow, making it easy for the snake to control fang movement and envenomation.⁹ Viperidae snakes are uniquely capable of inflicting puncture wounds without the injection of venom, known as dry bites. In contrast, Elapidae snakes have short, hollow, and fixed fangs, and thus patients can protect themselves by wearing appropriate clothing and covered footwear.⁹ Currently, identifying the type of snake responsible for the bite relies on visualization of the snake and/or the identification of clinical symptoms of envenomation by a dermatologist.

Clinical Manifestations of Venomous Snake Bites

Clinical manifestations and cutaneous findings often are used to grade the severity of venomous snake bites as well as to dictate treatment procedures. Grade 0 indicates a bite has occurred without envenomation, while grades I to V describe the progression and severity of envenomation.¹⁰ Grade I describes minimal erythema and edema around the site (fang marks may or may not be present) and no systemic symptoms. Grade II describes erythema and edema extending up the extremity to the first joint (eg, hand to wrist), pain, some systemic symptoms if there is rapid progression, and potential bleeding at the site. Grade III describes erythema and edema spreading to the second joint in the extremity, pain, and systemic symptoms, including coagulation defects. Grade IV describes erythema and edema of the whole extremity, a rapid reaction and progression following the bite, and risk for compartment syndrome. Grade V includes erythema and edema beyond the extremity and increasing systemic symptoms.¹⁰

Local pain and edema, usually on easily accessible or exposed extremities, are the most common clinical symptoms reported following a Viperidae snake bite.¹¹ Due to their capability of producing a dry bite, puncture markings alone do not indicate envenomation. Patients will need to be monitored for several hours for signs of envenomation, which may include swelling, pain, ecchymosis, and indications of systemic manifestation (eg, weakness, dizziness, nausea, severe hypotension, thrombocytopenia).¹¹ Viperidae venom hemorrhagic metalloproteinases act on capillary blood vessels by cleaving basement membrane proteins and allowing for extravasation of fluid into local tissue.¹² The inflammatory response produced at the site of envenomation likely is due to the release of tumor necrosis factor á and endogenous matrix metalloprotein.¹² There is a higher risk for death associated with bites from rattlesnakes within the Viperidae family because their venom contains a unique neurotoxin that works by blocking presynaptic junctions and causing a range of paralytic symptoms from ptosis to respiratory failure.¹³

The severity of Elapidae bites is thought to be related to the amount of venom injected, the size of the victim, and the length of the snake. Though clothing may offer protection, envenomation occurs in 75% of coral snake bites and can produce devastating consequences due to the venom content.¹⁴ In a retrospective study between 2002 and 2004, 90% of Elapidae snake bite patients (n=82) reported local pain, redness, and paresthesia, while around 7% developed systemic symptoms.¹⁵ Elapidae venom primarily is neurotoxic and is thought to spread via lymphatics.¹⁶ Delayed reactions are common and may take up to 12 hours to develop. Patients should be monitored, as local reactions may progress to weakness, fasciculations, extremity paralysis, and lastly, respiratory paralysis. Due to the risk for progression, all patients with likely coral snake bites should be given antivenin.^8,15,17

Much like the North American coral snake, the venomous snake species Gloydius blomhoffii—referred to as the salmosa or mamushi snake depending on the region of origin (ie, Korea or Japan)—is a frequent source of devastating rural snake bites due to neurotoxins (Figure 5). The species’ slender fangs are thought to directly inject the snake’s potent venom, which contains hemorrhagic toxins and α-neurotoxins and Β-neurotoxins, into the bloodstream; however, the salmosa is considered a viper like the North American cottonmouth and copperhead because of its triangular head shape and hollow fangs, which allow for the accommodation of venom-containing glands and mechanism of venom injection. Salmosa venom shares both Viperidae and Elapidae characteristics. Cutaneous findings such as progressive edema, erythema, and bleeding frequently are reported and are attributed to the proteases and hemorrhagic toxins characteristic of vipers (Figure 6). α-Neurotoxins and Β-neurotoxins, similar to the proteolytic venom of the Elapidae family, are responsible for the unique visual disturbances (binocular diplopia) caused by the salmosa.^12,18,19

Treatment

Treating snake bites begins with assessing the patient’s airway, breathing, and circulation, followed by a thorough medical and encounter history (including description of how the bite occurred). Due to the range of Viperidae symptoms, it generally is recommended that patients remove any restrictive clothing or jewelry near the bite and/or over the affected limb or body part, place the affected body part at the level of the heart, and go to the nearest medical facility for prompt care. Historically, empiric antibiotics often were used to prevent wound infections; however, studies have since demonstrated that antibiotics are not necessary and lack efficacy in uncomplicated snake bites.^16,20 In a study of 114 pediatric cases from 1995 to 2005, it was determined that most patients could be managed with conservative treatment directed at pain management and swelling reduction via elevation of the affected extremity.⁶ While conservative management may be all that is needed to care for the majority of cases, one retrospective study from Texas indicated that 70% of pediatric venomous snake bites were treated with either intravenous antibiotics and/or antivenin, highlighting the variability in management and opportunity for improvement.²¹

Antivenin, specifically antivenin (Crotalidae) polyvalent, is the indicated treatment for Viperidae hemorrhagic or coagulopathic envenomation.^13,22 Per guidelines from the World Health Organization, physical examination will yield a grading of the snake bite based on cutaneous findings. Grades III to V are considered moderate to severe and should be given antivenin.²³ Physicians should look for signs of progressive injury and coagulopathy, such as increased swelling, bruising, hypotension, or altered mental status.²² Due to the major neurotoxic risks associated with Elapidae venom, all coral snake bites should be treated with antivenin; early intubation and ventilation may be considered.¹³ Similarly, patients who report a salmosa snake bite require prompt treatment with antivenin and/or cepharanthine, an additive agent to reduce swelling and pain.¹⁸ Due to the nature of the neurotoxins contained in the salmosa venom (α-neurotoxin causing postsynaptic inhibition of the neuromuscular junction and Β-neurotoxin inhibiting neurotransmitter release from the presynaptic terminal), anticholinesterases, which work by blocking the enzymatic breakdown of the neurotransmitter acetylcholine, should not be used.¹⁹ While bleeding and skin and systemic changes may be reversed by antivenin, visual changes are unlikely to resolve with antivenin administration due to the presynaptic binding of Β-neurotoxin and the blockade of neuromuscular signaling.¹⁹

Antivenin should be administered intravenously for the fastest onset of action in a setting suitable for the management of anaphylaxis.²⁴ In situations when the benefits may outweigh the risks (eg, if the patient has had a prior allergic reaction or is not in an environment where they can be watched for at least 8 hours for progression of envenomation or adverse reactions), premedication with an antihistamine or epinephrine may be considered.17 Per the World Allergy Organization and World Health Organization, adverse reactions should be treated with crystalloid solutions and antihistamines, corticosteroids, or epinephrine as indicated.²⁵ In a qualitative analysis of emergency physicians’ attitudes toward antivenin, most expressed treatment hesitancy due to lack of knowledge and experience using the medication.²⁶ When possible, snake bites should thus be managed in consultation with a toxicologist.²

Conclusion

Snake bites and envenomation occur commonly in the United States due to exposure to a variety of venomous snakes in the North American Viperidae and Elapidae families. Appropriate and successful management of snake bites by physicians requires general knowledge of regional snakes, the cutaneous and systemic manifestations of snake bites and envenomation, and current treatment methods.

THE DIAGNOSIS: Tinea Corporis

Due to the scaly and acute nature of the rash, a potassium hydroxide (KOH) preparation was performed, and hyphal elements were floridly present. After further questioning, the patient reported finding a stray kitten a few weeks before the onset of the eruption and shared a picture of it lying on her chest in the area corresponding with the main distribution of the rash (Figure). Based on the patient’s personal history and the positive KOH preparation, a diagnosis of tinea corporis was made. She was immediately started on fluconazole 300 mg once weekly for 4 weeks and naftifine gel 1%, which she used for 6 to 8 weeks with complete resolution of the eruption.

Tinea corporis is a dermatophyte infection that typically affects exposed areas of the skin such as the chest, arms, and legs. Spread via human-to-human contact, Trichophyton rubrum is the most common cause worldwide. The second most common is Trichophyton mentagrophytes, which is spread through animal-to-human contact.^1,2

Symptoms of tinea corporis usually appear 1 to 3 weeks after exposure and manifest as itchy scaly papules that spread outward, forming annular, circinate, and petaloid erythematous plaques with central clearing. The condition most commonly is diagnosed through the examination of scale from the affected area using a KOH preparation, which will reveal hyphae when positive.^2-4 Cultures are the gold standard for identifying dermatophyte species,⁵ but results can take several weeks. Biopsy also can confirm the diagnosis by showing the presence of hyphae in the stratum corneum, which can be highlighted using periodic acid–Schiff or silver stains.³

Topical antifungals are the first-line treatment for cutaneous dermatophyte infections.^3-5 The most effective topical therapies are allylamines and azoles, which work by inhibiting the growth of the fungus. Allylamines are more effective than azoles due to their fungicidal properties and ability to penetrate the skin more effectively.^6,7 Topical medications should be applied at least 2 cm beyond the infected area for 2 to 4 weeks or until the infection has cleared.³ Systemic antifungals may be necessary in more complicated cases.

It is important to consider a broad differential and take into consideration the distribution of the plaques, the patient’s history, and other clinical features when differentiating tinea corporis from other conditions. Erythema annulare centrifugum more often presents as nonpruritic annular plaques with a trailing scale instead of a leading scale seen in tinea corporis. Biopsy exhibits a dense, perivascular, lymphocytic infiltrate in superficial vessels, resembling a coat sleeve.^3,8 Pemphigus foliaceous can manifest with painful crusted scaly plaques and vesicles in a seborrheic distribution. Biopsy reveals subcorneal acantholytic vesicles and can be confirmed on direct immunofluorescence.^3,8 Subacute cutaneous lupus erythematosus presents with annular plaques that often are symmetric and most prominent in sun-exposed areas, sparing the face.^3,9,10 It can be associated with other autoimmune conditions as well as medications such as thiazides, terbinafine, and calcium channel blockers. Additionally, 76% to 90% of patients are Ro/SSA antibody positive.³ Biopsy often demonstrates follicular plugging, perivascular and periadnexal lymphocytic infiltrates, and mucin.^3,10 Lastly, pityriasis rosea typically begins with a herald patch, followed by a widespread rash that often appears in a Christmas tree distribution.³

THE DIAGNOSIS: Tinea Corporis

Due to the scaly and acute nature of the rash, a potassium hydroxide (KOH) preparation was performed, and hyphal elements were floridly present. After further questioning, the patient reported finding a stray kitten a few weeks before the onset of the eruption and shared a picture of it lying on her chest in the area corresponding with the main distribution of the rash (Figure). Based on the patient’s personal history and the positive KOH preparation, a diagnosis of tinea corporis was made. She was immediately started on fluconazole 300 mg once weekly for 4 weeks and naftifine gel 1%, which she used for 6 to 8 weeks with complete resolution of the eruption.

Tinea corporis is a dermatophyte infection that typically affects exposed areas of the skin such as the chest, arms, and legs. Spread via human-to-human contact, Trichophyton rubrum is the most common cause worldwide. The second most common is Trichophyton mentagrophytes, which is spread through animal-to-human contact.^1,2

Symptoms of tinea corporis usually appear 1 to 3 weeks after exposure and manifest as itchy scaly papules that spread outward, forming annular, circinate, and petaloid erythematous plaques with central clearing. The condition most commonly is diagnosed through the examination of scale from the affected area using a KOH preparation, which will reveal hyphae when positive.^2-4 Cultures are the gold standard for identifying dermatophyte species,⁵ but results can take several weeks. Biopsy also can confirm the diagnosis by showing the presence of hyphae in the stratum corneum, which can be highlighted using periodic acid–Schiff or silver stains.³

Topical antifungals are the first-line treatment for cutaneous dermatophyte infections.^3-5 The most effective topical therapies are allylamines and azoles, which work by inhibiting the growth of the fungus. Allylamines are more effective than azoles due to their fungicidal properties and ability to penetrate the skin more effectively.^6,7 Topical medications should be applied at least 2 cm beyond the infected area for 2 to 4 weeks or until the infection has cleared.³ Systemic antifungals may be necessary in more complicated cases.

It is important to consider a broad differential and take into consideration the distribution of the plaques, the patient’s history, and other clinical features when differentiating tinea corporis from other conditions. Erythema annulare centrifugum more often presents as nonpruritic annular plaques with a trailing scale instead of a leading scale seen in tinea corporis. Biopsy exhibits a dense, perivascular, lymphocytic infiltrate in superficial vessels, resembling a coat sleeve.^3,8 Pemphigus foliaceous can manifest with painful crusted scaly plaques and vesicles in a seborrheic distribution. Biopsy reveals subcorneal acantholytic vesicles and can be confirmed on direct immunofluorescence.^3,8 Subacute cutaneous lupus erythematosus presents with annular plaques that often are symmetric and most prominent in sun-exposed areas, sparing the face.^3,9,10 It can be associated with other autoimmune conditions as well as medications such as thiazides, terbinafine, and calcium channel blockers. Additionally, 76% to 90% of patients are Ro/SSA antibody positive.³ Biopsy often demonstrates follicular plugging, perivascular and periadnexal lymphocytic infiltrates, and mucin.^3,10 Lastly, pityriasis rosea typically begins with a herald patch, followed by a widespread rash that often appears in a Christmas tree distribution.³

THE DIAGNOSIS: Tinea Corporis

Due to the scaly and acute nature of the rash, a potassium hydroxide (KOH) preparation was performed, and hyphal elements were floridly present. After further questioning, the patient reported finding a stray kitten a few weeks before the onset of the eruption and shared a picture of it lying on her chest in the area corresponding with the main distribution of the rash (Figure). Based on the patient’s personal history and the positive KOH preparation, a diagnosis of tinea corporis was made. She was immediately started on fluconazole 300 mg once weekly for 4 weeks and naftifine gel 1%, which she used for 6 to 8 weeks with complete resolution of the eruption.

Tinea corporis is a dermatophyte infection that typically affects exposed areas of the skin such as the chest, arms, and legs. Spread via human-to-human contact, Trichophyton rubrum is the most common cause worldwide. The second most common is Trichophyton mentagrophytes, which is spread through animal-to-human contact.^1,2

Symptoms of tinea corporis usually appear 1 to 3 weeks after exposure and manifest as itchy scaly papules that spread outward, forming annular, circinate, and petaloid erythematous plaques with central clearing. The condition most commonly is diagnosed through the examination of scale from the affected area using a KOH preparation, which will reveal hyphae when positive.^2-4 Cultures are the gold standard for identifying dermatophyte species,⁵ but results can take several weeks. Biopsy also can confirm the diagnosis by showing the presence of hyphae in the stratum corneum, which can be highlighted using periodic acid–Schiff or silver stains.³

Topical antifungals are the first-line treatment for cutaneous dermatophyte infections.^3-5 The most effective topical therapies are allylamines and azoles, which work by inhibiting the growth of the fungus. Allylamines are more effective than azoles due to their fungicidal properties and ability to penetrate the skin more effectively.^6,7 Topical medications should be applied at least 2 cm beyond the infected area for 2 to 4 weeks or until the infection has cleared.³ Systemic antifungals may be necessary in more complicated cases.

It is important to consider a broad differential and take into consideration the distribution of the plaques, the patient’s history, and other clinical features when differentiating tinea corporis from other conditions. Erythema annulare centrifugum more often presents as nonpruritic annular plaques with a trailing scale instead of a leading scale seen in tinea corporis. Biopsy exhibits a dense, perivascular, lymphocytic infiltrate in superficial vessels, resembling a coat sleeve.^3,8 Pemphigus foliaceous can manifest with painful crusted scaly plaques and vesicles in a seborrheic distribution. Biopsy reveals subcorneal acantholytic vesicles and can be confirmed on direct immunofluorescence.^3,8 Subacute cutaneous lupus erythematosus presents with annular plaques that often are symmetric and most prominent in sun-exposed areas, sparing the face.^3,9,10 It can be associated with other autoimmune conditions as well as medications such as thiazides, terbinafine, and calcium channel blockers. Additionally, 76% to 90% of patients are Ro/SSA antibody positive.³ Biopsy often demonstrates follicular plugging, perivascular and periadnexal lymphocytic infiltrates, and mucin.^3,10 Lastly, pityriasis rosea typically begins with a herald patch, followed by a widespread rash that often appears in a Christmas tree distribution.³

Patients often ask dermatologists how to best care for their specific hair type; however, there are no formal recommendations that apply to the many different hair care practices utilized by Black patients, as hair types in this community can range from wavy to tightly coiled.¹ Understanding the the history of hair care in those of African ancestry and various styling practices in this population is necessary to adequately counsel patients and gain trust in the doctor-patient relationship. In this article, we provide an overview of hair care recommendations based on common styling practices in Black women.

A PubMed search of articles indexed for MEDLINE using the terms Black hair care, African American hair management, hair loss prevention, hair care practices, natural hair, natural-hair styles, alopecia, hairdressing, hair breakage, hair fragility, heat-stressed hair, traction alopecia, and natural hair care yielded 305 results; 107 duplicates were identified and removed, leaving 198 articles to be screened for eligibility (ie, English-language studies created in the past 15 years). Sixty-eight full-text articles were screened against the exclusion criteria, which included case reports and case series, articles not focused on Afro-textured hair, and cancer-related hair loss. Three additional fulltext articles were identified via resources from Wayne State University library (Detroit, Michigan) that were not available on PubMed. A total of 29 full-text articles were included in our review.

Background on Hair Care and Styling in African Populations

It is difficult to understand the history of hair in those of African ancestry in the United States.² Prior to slavery, hair styling was considered a way of identification, classification, and communication as well as a medium through which to connect with the spiritual world in many parts of Africa. Hair-styling practices in Africa included elaborate cornrows, threading, and braiding with many accessories. Notable hair-styling products included natural butters, herbs, and powders to assist with moisture retention. Scarves also were used during this time for ceremonies or protection.³ During the mass enslavement of African populations and their transportation to the Americas by Europeans, slaveholders routinely cut off all the hair of both men and women in order to objectify and erase the culture of African hair styling passed down through generations.^4,5 Hair texture then was weaponized to create a caste system in plantation life, in which Black slaves with straight hair textures were granted the “privilege” of domestic work, while those with kinky hair were relegated to arduous manual labor in the fields.⁴ Years later, during the 1800s, laws were enacted in the United States to prohibit Black women from wearing tightly coiled natural hair in public places.⁵ Over the next few centuries from the 1800s to the early 2000s, various hair-styling trends such as the use of hot combs, perms, afros, and Jheri curls developed as a means for Black individuals to conform to societal pressure to adopt more European features; however, as time progressed, afros, braids, locs, and natural hair would become more dominant as statements against these same societal pressures.⁵

The natural hair movement, which emerged in the United States in the 2000s, encouraged Black women to abandon the use of toxic chemical hair straighteners, cultivate healthier hair care practices, disrupt Eurocentric standards of wearing straightened hair, and facilitate self-definition of beauty ideals from the Civil Rights Movement of the 1960s.^4,5 It is estimated that between 30% and 70% of all Black women in the United States wear natural hair, including 79% of millennial Black women younger than 30 years⁶; however, several new trends such as wigs and weaves have grown in popularity since the early 2000s due to mainstream pop culture and improvements in creating natural hairlines.^7,8

Key Features of Afro-Textured Hair

Individuals of African descent have the most diverse hair texture phenotypes, ranging from straight to tightly coiled.⁹ Although hair is chemically similar across various racial groups, differences are noted mainly in the shape of the hair shaft, with elliptical and curved shapes seen in Afrotextured hair. These differences yield more tightly curled strands than in other hair types; however, these features also contribute to fragility, as it creates points of weakness and decreases the tensile strength of the hair shaft.¹⁰ This inherent fragility leads to higher rates of hair breakage as well as lower moisture content and slower growth rates, which is why Afro-textured hair requires special care.⁹

Afro-textured hair generally falls into 2 main categories of the Andre Walker hair typing system: 4A-4C and 3A-3C.¹¹ In the 4A-4C category, hair is described as coily or kinky. Common concerns related to this hair type include dryness and brittleness with increased susceptibility to breakage. The 3A-3C category is described as loose to corkscrew curls, with a common concern of dryness.^11,12 Additionally, Loussouarn et al¹³ established a method to further define natural hair curliness using curve diameter and curl meters on glass plates to measure the curvature of hair strands. This method allows for assessing diversity and range of curliness within various races without relying on ethnic origin.¹³

Common Hair Care Practices

A description of each hair type and recommended styling practices with their levels of evidence can be found in the eTable.

Natural Hair—Natural hair is classified as hair that has not been chemically changed by perms, heat, or other straightening treatments.^12,14 For natural hair, retaining the moisture of the hair shaft should be the main focus, as moisture loss leads to considerable dryness.¹⁴ Generally, it is recommended to wash natural hair once per week or every other week; however, this can change based on hair length and oil production on the scalp. Washing daily may be ideal for shorter hair and monthly for longer hair to help prevent product build-up that can have a drying effect.¹⁵ Avoid shampoos that are drying (eg, sulfate and silicone products). The co-washing method also can be utilized, which entails washing the hair with a conditioning cleanser instead of shampoo and conditioner. However, this technique is not meant to completely replace shampoo.¹⁶ In fact, a clarifying shampoo is recommended after co-washing 3 or 4 times.¹⁶ The use of a hot oil treatment twice per month can promote moisture retention and reduce split-end formation.¹⁷ For maintenance between washes, many utilize the liquid, oil, cream (LOC) or liquid, cream, oil (LCO) methods, which describe regimens that utilize water, an oil of choice, and cream such as shea butter to lock in moisture.¹⁸ This method can be used as often as needed for dry hair.

Due to the susceptibility of Afro-textured hair to tangle and knot, using a wide-tooth comb, detangling brush, or detangling conditioners is a grade B recommendation for care (eTable). Though not widely documented in the literature, many of our patients have had anecdotal success detangling their hair simply by pulling hair strands apart by hand or “finger detangling” as well as using wide-tooth combs. Although both hair types are healthier in their natural states, kinky hair (type 4A-4C) is extremely fragile and more difficult to manage than less kinky hair (type 3A-3C).¹⁸

Special care is needed when detangling due to strands being weaker when wet.¹⁹ Detangling should be performed in a retrograde fashion. Deep conditioning can aid in moisture retention and should be performed weekly or biweekly.^17-20 Depending on the health of the hair, protein treatments can be considered on a monthly basis to help preserve the cuticle. Styling with braids, twists, or other protective styles can then be completed on an individual basis.

Thermal Straightening—A blowout involves straightening the hair after a wash with the use of a hair dryer.²¹ This common hair-styling method does not employ the use of chemicals beyond light hair oils and heat-protectant creams or sprays, typically resulting in a less kinky afro or semi-straight hair. Thermal straightening utilizes heat to temporarily straighten hair strands. Flat irons with heated metal plates then can be used after blow-drying the hair to fully straighten and smooth the strands. These processes combined commonly are known as a silk press.^21-22

For thermally straightened hair, it is recommended to either wrap the hair around the scalp to keep it flat or pin curl the hair and cover with a bonnet to sleep. Safe straightening techniques with the use of a flat iron include setting the temperature no higher than 175 °F or a low/medium setting while also limiting use to once per week if possible.²³ The number of passes of the flat iron also should be limited to 1 to 2 to reduce breakage. A heat-protectant cream or spray also can be applied to the hair before flat ironing to minimize damage. Applying heat protectant to the hair prior to styling will help minimize heat damage by distributing the heat along the hair fiber surface, avoiding water boiling in the hair shaft and the development of bubble hair leading to damage.²⁴

Chemical Straightening—Similar to how relaxers, perms, and Jheri curl treatments chemically modify hair texture using distinct chemicals yielding different curl patterns, the Brazilian blowout similarly straightens hair using a hair dryer and chemicals applied to hair strands after washing.^21-24 Relaxers utilize sodium or guanidine hydroxide for straightening, perms use ammonium thioglycolate for curling, and Jheri curl treatments employ thioglycolates or mercaptans for defined curls. However, these treatments generally are cautioned against due to potential hair damage and recent associations with uterine and breast cancer in Black women. Research has suggested that endocrine disrupters in these products, especially those marketed to Black women, contribute to hormone-related disease processes.^25,26 One study found higher concentrations of alkylphenols, the fragrance marker diethyl phthalate, and parabens in relaxers²⁷; however, more research is needed to determine specific chemicals associated with these cancers.

Braids and Locs—Braiding is a technique that involves interlocking 3 or more sections of hair that may or may not be fixated to the scalp like a cornrow,¹¹ and one can utilize extensions or natural hair depending on the desired outcome. Intended for long-term wear (ie, weeks to months), braids minimize breakage and reduce daily styling needs. Two popular styles—cornrows and individual braids—differ in preparation and weaving techniques. Cornrows are an Afro-centric style involving uniform, tightly woven braids that are close to the scalp, creating distinct patterns. Conversely, individual braids weave separate hair sections, offering diverse styling possibilities. Braiding practices should exclude hairline edges—often termed baby hairs—to prevent traction alopecia. Minimal use of edge gel, which helps to tame the vellus hairs at the frontotemporal scalp, as well as mindful weave volume, weight, and length are recommended to avert breakage. Braids that cause pain are too tight, can damage hair, and may cause traction alopecia.¹¹ Braids should not be worn for longer than 3 months at a time and require biweekly washing with diluted shampoo and conditioner. Proper drying by wringing the hair with a microfiber towel is essential to avoid frizz and mold formation.

Locs are a low-maintenance hairstyle considered permanent until cut.²⁸ This style involves twisting, palm rolling, or using tools such as crochet hooks to “lock” the hair. Regular maintenance with retwisting and cleaning is vital for loc health. Increased weight and tight twisting of locs can cause damage to the scalp and hair strands; however, locs are known to increase hair volume over time, often due to the accumulation of hairs that would otherwise have been shed in the telogen phase.²⁸

Wigs and Weaves—Wigs consist of synthetic or human hair that can be strapped to the head with an adjustable band or glued to the scalp depending on the desired style.²⁹ Wigs are removed daily, which allows for quick access to hair for cleansing and moisturizing. In contrast, weaves typically are sewn into the natural hair, which may make it difficult to reach the scalp for cleansing, leading to dryness and product build-up.²⁹ Notably, there is evidence of a relationship between long-term use of weaves and traction alopecia.³⁰

Wigs can have a fully synthetic hair line or lace hair line and can range from very affordable to expensive. When applied correctly, both styles offer an easy way to cover and protect the natural hair by reducing the amount of physical trauma related to daily hair styling. A lace-front wig contains a frontal thin mesh or lace that camouflages the natural frontal hairline.^29,30 A risk of lace-front wigs is that they can cause friction alopecia secondary to repeated use of adhesives and repeated friction against the hairline. Generally, wigs and weaves should be cared for as one would care for one’s own hair.

Hair Care in Black Children—Children’s hair care begins with washing the hair and scalp with shampoo, applying conditioner, and detangling as needed.³¹ After rinsing out the conditioner, a leave-in conditioner can assist with moisture retention and further detangling. The hair is then styled, either wet or dry. Recommendations for hair care practices in Black children include loose hairstyles that do not strain hair roots and nightly removal of root-securing accessories (eg, barrettes, elastic hairbeads). Frequent cornrow styling and friction on chemically straightened hair were identified by a survey as considerable traction alopecia risk factors.³² Thus, educating caregivers on appropriate hair-grooming practices for children is important.

Hair Protection—Proactive steps to reduce hair loss include wearing satin bonnets and/or using satin pillowcases while sleeping regardless of hairstyle. Although evidence is limited, it is thought that satin and silk allow the hair to retain its moisture and natural oils, preventing breakage and friction.^33,34 Frequent hair trimming every 2 to 4 months can reduce breakage when doing thermal treatments.^35,36 When prolonged or repetitive styles are used, it is encouraged to give the hair a break between styles to recover from the repeated stress. Wearing an intermittent updo or high bun—a hairstyle in which the hair is pulled upward—can prevent breakage by reducing heavy strain on the hair; however, it is important to avoid the use of rubber bands due to friction and risk for tangling of hair strands. Instead, the use of covered elastic ties and/or those without metal is preferred.¹¹ Alternatively, if a polished and neat appearance with slicked-back hair is desired, the practice of tautly pulling the hair is not recommended. Instead, use of an alcohol-free gel is suggested along with a satin scarf wrapped around the hairline to facilitate the setting of the hair in place.¹¹

A common practice to preserve curly hairstyles while sleeping is known as the pineapple method, which protects the hair and aids in preserving the freshness and style of the curls.³⁷ It consists of a loosely tied high ponytail at the top of the head allowing the curls to fall forward. This minimizes frizz and prevents the curls from forming knots.

Conclusion

Hair care recommendations in Black women can be complex due to a wide range of personal care preferences and styling techniques in this population. While evidence in the literature is limited, it still is important for dermatologists to be familiar with the different hair care practices utilized by Black women so they can effectively counsel patients and improve hair health. Knowledge of optimal hair care practices can aid in the prevention of common hair disorders that disproportionately affect this patient population, such as traction alopecia and trichorrhexis nodosa or breakage.

Patients often ask dermatologists how to best care for their specific hair type; however, there are no formal recommendations that apply to the many different hair care practices utilized by Black patients, as hair types in this community can range from wavy to tightly coiled.¹ Understanding the the history of hair care in those of African ancestry and various styling practices in this population is necessary to adequately counsel patients and gain trust in the doctor-patient relationship. In this article, we provide an overview of hair care recommendations based on common styling practices in Black women.

A PubMed search of articles indexed for MEDLINE using the terms Black hair care, African American hair management, hair loss prevention, hair care practices, natural hair, natural-hair styles, alopecia, hairdressing, hair breakage, hair fragility, heat-stressed hair, traction alopecia, and natural hair care yielded 305 results; 107 duplicates were identified and removed, leaving 198 articles to be screened for eligibility (ie, English-language studies created in the past 15 years). Sixty-eight full-text articles were screened against the exclusion criteria, which included case reports and case series, articles not focused on Afro-textured hair, and cancer-related hair loss. Three additional fulltext articles were identified via resources from Wayne State University library (Detroit, Michigan) that were not available on PubMed. A total of 29 full-text articles were included in our review.

Background on Hair Care and Styling in African Populations

It is difficult to understand the history of hair in those of African ancestry in the United States.² Prior to slavery, hair styling was considered a way of identification, classification, and communication as well as a medium through which to connect with the spiritual world in many parts of Africa. Hair-styling practices in Africa included elaborate cornrows, threading, and braiding with many accessories. Notable hair-styling products included natural butters, herbs, and powders to assist with moisture retention. Scarves also were used during this time for ceremonies or protection.³ During the mass enslavement of African populations and their transportation to the Americas by Europeans, slaveholders routinely cut off all the hair of both men and women in order to objectify and erase the culture of African hair styling passed down through generations.^4,5 Hair texture then was weaponized to create a caste system in plantation life, in which Black slaves with straight hair textures were granted the “privilege” of domestic work, while those with kinky hair were relegated to arduous manual labor in the fields.⁴ Years later, during the 1800s, laws were enacted in the United States to prohibit Black women from wearing tightly coiled natural hair in public places.⁵ Over the next few centuries from the 1800s to the early 2000s, various hair-styling trends such as the use of hot combs, perms, afros, and Jheri curls developed as a means for Black individuals to conform to societal pressure to adopt more European features; however, as time progressed, afros, braids, locs, and natural hair would become more dominant as statements against these same societal pressures.⁵

The natural hair movement, which emerged in the United States in the 2000s, encouraged Black women to abandon the use of toxic chemical hair straighteners, cultivate healthier hair care practices, disrupt Eurocentric standards of wearing straightened hair, and facilitate self-definition of beauty ideals from the Civil Rights Movement of the 1960s.^4,5 It is estimated that between 30% and 70% of all Black women in the United States wear natural hair, including 79% of millennial Black women younger than 30 years⁶; however, several new trends such as wigs and weaves have grown in popularity since the early 2000s due to mainstream pop culture and improvements in creating natural hairlines.^7,8

Key Features of Afro-Textured Hair

Individuals of African descent have the most diverse hair texture phenotypes, ranging from straight to tightly coiled.⁹ Although hair is chemically similar across various racial groups, differences are noted mainly in the shape of the hair shaft, with elliptical and curved shapes seen in Afrotextured hair. These differences yield more tightly curled strands than in other hair types; however, these features also contribute to fragility, as it creates points of weakness and decreases the tensile strength of the hair shaft.¹⁰ This inherent fragility leads to higher rates of hair breakage as well as lower moisture content and slower growth rates, which is why Afro-textured hair requires special care.⁹

Afro-textured hair generally falls into 2 main categories of the Andre Walker hair typing system: 4A-4C and 3A-3C.¹¹ In the 4A-4C category, hair is described as coily or kinky. Common concerns related to this hair type include dryness and brittleness with increased susceptibility to breakage. The 3A-3C category is described as loose to corkscrew curls, with a common concern of dryness.^11,12 Additionally, Loussouarn et al¹³ established a method to further define natural hair curliness using curve diameter and curl meters on glass plates to measure the curvature of hair strands. This method allows for assessing diversity and range of curliness within various races without relying on ethnic origin.¹³

Common Hair Care Practices

A description of each hair type and recommended styling practices with their levels of evidence can be found in the eTable.

Natural Hair—Natural hair is classified as hair that has not been chemically changed by perms, heat, or other straightening treatments.^12,14 For natural hair, retaining the moisture of the hair shaft should be the main focus, as moisture loss leads to considerable dryness.¹⁴ Generally, it is recommended to wash natural hair once per week or every other week; however, this can change based on hair length and oil production on the scalp. Washing daily may be ideal for shorter hair and monthly for longer hair to help prevent product build-up that can have a drying effect.¹⁵ Avoid shampoos that are drying (eg, sulfate and silicone products). The co-washing method also can be utilized, which entails washing the hair with a conditioning cleanser instead of shampoo and conditioner. However, this technique is not meant to completely replace shampoo.¹⁶ In fact, a clarifying shampoo is recommended after co-washing 3 or 4 times.¹⁶ The use of a hot oil treatment twice per month can promote moisture retention and reduce split-end formation.¹⁷ For maintenance between washes, many utilize the liquid, oil, cream (LOC) or liquid, cream, oil (LCO) methods, which describe regimens that utilize water, an oil of choice, and cream such as shea butter to lock in moisture.¹⁸ This method can be used as often as needed for dry hair.

Due to the susceptibility of Afro-textured hair to tangle and knot, using a wide-tooth comb, detangling brush, or detangling conditioners is a grade B recommendation for care (eTable). Though not widely documented in the literature, many of our patients have had anecdotal success detangling their hair simply by pulling hair strands apart by hand or “finger detangling” as well as using wide-tooth combs. Although both hair types are healthier in their natural states, kinky hair (type 4A-4C) is extremely fragile and more difficult to manage than less kinky hair (type 3A-3C).¹⁸

Special care is needed when detangling due to strands being weaker when wet.¹⁹ Detangling should be performed in a retrograde fashion. Deep conditioning can aid in moisture retention and should be performed weekly or biweekly.^17-20 Depending on the health of the hair, protein treatments can be considered on a monthly basis to help preserve the cuticle. Styling with braids, twists, or other protective styles can then be completed on an individual basis.

Thermal Straightening—A blowout involves straightening the hair after a wash with the use of a hair dryer.²¹ This common hair-styling method does not employ the use of chemicals beyond light hair oils and heat-protectant creams or sprays, typically resulting in a less kinky afro or semi-straight hair. Thermal straightening utilizes heat to temporarily straighten hair strands. Flat irons with heated metal plates then can be used after blow-drying the hair to fully straighten and smooth the strands. These processes combined commonly are known as a silk press.^21-22

For thermally straightened hair, it is recommended to either wrap the hair around the scalp to keep it flat or pin curl the hair and cover with a bonnet to sleep. Safe straightening techniques with the use of a flat iron include setting the temperature no higher than 175 °F or a low/medium setting while also limiting use to once per week if possible.²³ The number of passes of the flat iron also should be limited to 1 to 2 to reduce breakage. A heat-protectant cream or spray also can be applied to the hair before flat ironing to minimize damage. Applying heat protectant to the hair prior to styling will help minimize heat damage by distributing the heat along the hair fiber surface, avoiding water boiling in the hair shaft and the development of bubble hair leading to damage.²⁴

Chemical Straightening—Similar to how relaxers, perms, and Jheri curl treatments chemically modify hair texture using distinct chemicals yielding different curl patterns, the Brazilian blowout similarly straightens hair using a hair dryer and chemicals applied to hair strands after washing.^21-24 Relaxers utilize sodium or guanidine hydroxide for straightening, perms use ammonium thioglycolate for curling, and Jheri curl treatments employ thioglycolates or mercaptans for defined curls. However, these treatments generally are cautioned against due to potential hair damage and recent associations with uterine and breast cancer in Black women. Research has suggested that endocrine disrupters in these products, especially those marketed to Black women, contribute to hormone-related disease processes.^25,26 One study found higher concentrations of alkylphenols, the fragrance marker diethyl phthalate, and parabens in relaxers²⁷; however, more research is needed to determine specific chemicals associated with these cancers.

Braids and Locs—Braiding is a technique that involves interlocking 3 or more sections of hair that may or may not be fixated to the scalp like a cornrow,¹¹ and one can utilize extensions or natural hair depending on the desired outcome. Intended for long-term wear (ie, weeks to months), braids minimize breakage and reduce daily styling needs. Two popular styles—cornrows and individual braids—differ in preparation and weaving techniques. Cornrows are an Afro-centric style involving uniform, tightly woven braids that are close to the scalp, creating distinct patterns. Conversely, individual braids weave separate hair sections, offering diverse styling possibilities. Braiding practices should exclude hairline edges—often termed baby hairs—to prevent traction alopecia. Minimal use of edge gel, which helps to tame the vellus hairs at the frontotemporal scalp, as well as mindful weave volume, weight, and length are recommended to avert breakage. Braids that cause pain are too tight, can damage hair, and may cause traction alopecia.¹¹ Braids should not be worn for longer than 3 months at a time and require biweekly washing with diluted shampoo and conditioner. Proper drying by wringing the hair with a microfiber towel is essential to avoid frizz and mold formation.

Locs are a low-maintenance hairstyle considered permanent until cut.²⁸ This style involves twisting, palm rolling, or using tools such as crochet hooks to “lock” the hair. Regular maintenance with retwisting and cleaning is vital for loc health. Increased weight and tight twisting of locs can cause damage to the scalp and hair strands; however, locs are known to increase hair volume over time, often due to the accumulation of hairs that would otherwise have been shed in the telogen phase.²⁸

Wigs and Weaves—Wigs consist of synthetic or human hair that can be strapped to the head with an adjustable band or glued to the scalp depending on the desired style.²⁹ Wigs are removed daily, which allows for quick access to hair for cleansing and moisturizing. In contrast, weaves typically are sewn into the natural hair, which may make it difficult to reach the scalp for cleansing, leading to dryness and product build-up.²⁹ Notably, there is evidence of a relationship between long-term use of weaves and traction alopecia.³⁰

Wigs can have a fully synthetic hair line or lace hair line and can range from very affordable to expensive. When applied correctly, both styles offer an easy way to cover and protect the natural hair by reducing the amount of physical trauma related to daily hair styling. A lace-front wig contains a frontal thin mesh or lace that camouflages the natural frontal hairline.^29,30 A risk of lace-front wigs is that they can cause friction alopecia secondary to repeated use of adhesives and repeated friction against the hairline. Generally, wigs and weaves should be cared for as one would care for one’s own hair.

Hair Care in Black Children—Children’s hair care begins with washing the hair and scalp with shampoo, applying conditioner, and detangling as needed.³¹ After rinsing out the conditioner, a leave-in conditioner can assist with moisture retention and further detangling. The hair is then styled, either wet or dry. Recommendations for hair care practices in Black children include loose hairstyles that do not strain hair roots and nightly removal of root-securing accessories (eg, barrettes, elastic hairbeads). Frequent cornrow styling and friction on chemically straightened hair were identified by a survey as considerable traction alopecia risk factors.³² Thus, educating caregivers on appropriate hair-grooming practices for children is important.

Hair Protection—Proactive steps to reduce hair loss include wearing satin bonnets and/or using satin pillowcases while sleeping regardless of hairstyle. Although evidence is limited, it is thought that satin and silk allow the hair to retain its moisture and natural oils, preventing breakage and friction.^33,34 Frequent hair trimming every 2 to 4 months can reduce breakage when doing thermal treatments.^35,36 When prolonged or repetitive styles are used, it is encouraged to give the hair a break between styles to recover from the repeated stress. Wearing an intermittent updo or high bun—a hairstyle in which the hair is pulled upward—can prevent breakage by reducing heavy strain on the hair; however, it is important to avoid the use of rubber bands due to friction and risk for tangling of hair strands. Instead, the use of covered elastic ties and/or those without metal is preferred.¹¹ Alternatively, if a polished and neat appearance with slicked-back hair is desired, the practice of tautly pulling the hair is not recommended. Instead, use of an alcohol-free gel is suggested along with a satin scarf wrapped around the hairline to facilitate the setting of the hair in place.¹¹

A common practice to preserve curly hairstyles while sleeping is known as the pineapple method, which protects the hair and aids in preserving the freshness and style of the curls.³⁷ It consists of a loosely tied high ponytail at the top of the head allowing the curls to fall forward. This minimizes frizz and prevents the curls from forming knots.

Conclusion

Hair care recommendations in Black women can be complex due to a wide range of personal care preferences and styling techniques in this population. While evidence in the literature is limited, it still is important for dermatologists to be familiar with the different hair care practices utilized by Black women so they can effectively counsel patients and improve hair health. Knowledge of optimal hair care practices can aid in the prevention of common hair disorders that disproportionately affect this patient population, such as traction alopecia and trichorrhexis nodosa or breakage.

Patients often ask dermatologists how to best care for their specific hair type; however, there are no formal recommendations that apply to the many different hair care practices utilized by Black patients, as hair types in this community can range from wavy to tightly coiled.¹ Understanding the the history of hair care in those of African ancestry and various styling practices in this population is necessary to adequately counsel patients and gain trust in the doctor-patient relationship. In this article, we provide an overview of hair care recommendations based on common styling practices in Black women.

A PubMed search of articles indexed for MEDLINE using the terms Black hair care, African American hair management, hair loss prevention, hair care practices, natural hair, natural-hair styles, alopecia, hairdressing, hair breakage, hair fragility, heat-stressed hair, traction alopecia, and natural hair care yielded 305 results; 107 duplicates were identified and removed, leaving 198 articles to be screened for eligibility (ie, English-language studies created in the past 15 years). Sixty-eight full-text articles were screened against the exclusion criteria, which included case reports and case series, articles not focused on Afro-textured hair, and cancer-related hair loss. Three additional fulltext articles were identified via resources from Wayne State University library (Detroit, Michigan) that were not available on PubMed. A total of 29 full-text articles were included in our review.

Background on Hair Care and Styling in African Populations

It is difficult to understand the history of hair in those of African ancestry in the United States.² Prior to slavery, hair styling was considered a way of identification, classification, and communication as well as a medium through which to connect with the spiritual world in many parts of Africa. Hair-styling practices in Africa included elaborate cornrows, threading, and braiding with many accessories. Notable hair-styling products included natural butters, herbs, and powders to assist with moisture retention. Scarves also were used during this time for ceremonies or protection.³ During the mass enslavement of African populations and their transportation to the Americas by Europeans, slaveholders routinely cut off all the hair of both men and women in order to objectify and erase the culture of African hair styling passed down through generations.^4,5 Hair texture then was weaponized to create a caste system in plantation life, in which Black slaves with straight hair textures were granted the “privilege” of domestic work, while those with kinky hair were relegated to arduous manual labor in the fields.⁴ Years later, during the 1800s, laws were enacted in the United States to prohibit Black women from wearing tightly coiled natural hair in public places.⁵ Over the next few centuries from the 1800s to the early 2000s, various hair-styling trends such as the use of hot combs, perms, afros, and Jheri curls developed as a means for Black individuals to conform to societal pressure to adopt more European features; however, as time progressed, afros, braids, locs, and natural hair would become more dominant as statements against these same societal pressures.⁵

The natural hair movement, which emerged in the United States in the 2000s, encouraged Black women to abandon the use of toxic chemical hair straighteners, cultivate healthier hair care practices, disrupt Eurocentric standards of wearing straightened hair, and facilitate self-definition of beauty ideals from the Civil Rights Movement of the 1960s.^4,5 It is estimated that between 30% and 70% of all Black women in the United States wear natural hair, including 79% of millennial Black women younger than 30 years⁶; however, several new trends such as wigs and weaves have grown in popularity since the early 2000s due to mainstream pop culture and improvements in creating natural hairlines.^7,8

Key Features of Afro-Textured Hair

Individuals of African descent have the most diverse hair texture phenotypes, ranging from straight to tightly coiled.⁹ Although hair is chemically similar across various racial groups, differences are noted mainly in the shape of the hair shaft, with elliptical and curved shapes seen in Afrotextured hair. These differences yield more tightly curled strands than in other hair types; however, these features also contribute to fragility, as it creates points of weakness and decreases the tensile strength of the hair shaft.¹⁰ This inherent fragility leads to higher rates of hair breakage as well as lower moisture content and slower growth rates, which is why Afro-textured hair requires special care.⁹

Afro-textured hair generally falls into 2 main categories of the Andre Walker hair typing system: 4A-4C and 3A-3C.¹¹ In the 4A-4C category, hair is described as coily or kinky. Common concerns related to this hair type include dryness and brittleness with increased susceptibility to breakage. The 3A-3C category is described as loose to corkscrew curls, with a common concern of dryness.^11,12 Additionally, Loussouarn et al¹³ established a method to further define natural hair curliness using curve diameter and curl meters on glass plates to measure the curvature of hair strands. This method allows for assessing diversity and range of curliness within various races without relying on ethnic origin.¹³

Common Hair Care Practices

A description of each hair type and recommended styling practices with their levels of evidence can be found in the eTable.

Natural Hair—Natural hair is classified as hair that has not been chemically changed by perms, heat, or other straightening treatments.^12,14 For natural hair, retaining the moisture of the hair shaft should be the main focus, as moisture loss leads to considerable dryness.¹⁴ Generally, it is recommended to wash natural hair once per week or every other week; however, this can change based on hair length and oil production on the scalp. Washing daily may be ideal for shorter hair and monthly for longer hair to help prevent product build-up that can have a drying effect.¹⁵ Avoid shampoos that are drying (eg, sulfate and silicone products). The co-washing method also can be utilized, which entails washing the hair with a conditioning cleanser instead of shampoo and conditioner. However, this technique is not meant to completely replace shampoo.¹⁶ In fact, a clarifying shampoo is recommended after co-washing 3 or 4 times.¹⁶ The use of a hot oil treatment twice per month can promote moisture retention and reduce split-end formation.¹⁷ For maintenance between washes, many utilize the liquid, oil, cream (LOC) or liquid, cream, oil (LCO) methods, which describe regimens that utilize water, an oil of choice, and cream such as shea butter to lock in moisture.¹⁸ This method can be used as often as needed for dry hair.

Due to the susceptibility of Afro-textured hair to tangle and knot, using a wide-tooth comb, detangling brush, or detangling conditioners is a grade B recommendation for care (eTable). Though not widely documented in the literature, many of our patients have had anecdotal success detangling their hair simply by pulling hair strands apart by hand or “finger detangling” as well as using wide-tooth combs. Although both hair types are healthier in their natural states, kinky hair (type 4A-4C) is extremely fragile and more difficult to manage than less kinky hair (type 3A-3C).¹⁸

Special care is needed when detangling due to strands being weaker when wet.¹⁹ Detangling should be performed in a retrograde fashion. Deep conditioning can aid in moisture retention and should be performed weekly or biweekly.^17-20 Depending on the health of the hair, protein treatments can be considered on a monthly basis to help preserve the cuticle. Styling with braids, twists, or other protective styles can then be completed on an individual basis.

Thermal Straightening—A blowout involves straightening the hair after a wash with the use of a hair dryer.²¹ This common hair-styling method does not employ the use of chemicals beyond light hair oils and heat-protectant creams or sprays, typically resulting in a less kinky afro or semi-straight hair. Thermal straightening utilizes heat to temporarily straighten hair strands. Flat irons with heated metal plates then can be used after blow-drying the hair to fully straighten and smooth the strands. These processes combined commonly are known as a silk press.^21-22

For thermally straightened hair, it is recommended to either wrap the hair around the scalp to keep it flat or pin curl the hair and cover with a bonnet to sleep. Safe straightening techniques with the use of a flat iron include setting the temperature no higher than 175 °F or a low/medium setting while also limiting use to once per week if possible.²³ The number of passes of the flat iron also should be limited to 1 to 2 to reduce breakage. A heat-protectant cream or spray also can be applied to the hair before flat ironing to minimize damage. Applying heat protectant to the hair prior to styling will help minimize heat damage by distributing the heat along the hair fiber surface, avoiding water boiling in the hair shaft and the development of bubble hair leading to damage.²⁴

Chemical Straightening—Similar to how relaxers, perms, and Jheri curl treatments chemically modify hair texture using distinct chemicals yielding different curl patterns, the Brazilian blowout similarly straightens hair using a hair dryer and chemicals applied to hair strands after washing.^21-24 Relaxers utilize sodium or guanidine hydroxide for straightening, perms use ammonium thioglycolate for curling, and Jheri curl treatments employ thioglycolates or mercaptans for defined curls. However, these treatments generally are cautioned against due to potential hair damage and recent associations with uterine and breast cancer in Black women. Research has suggested that endocrine disrupters in these products, especially those marketed to Black women, contribute to hormone-related disease processes.^25,26 One study found higher concentrations of alkylphenols, the fragrance marker diethyl phthalate, and parabens in relaxers²⁷; however, more research is needed to determine specific chemicals associated with these cancers.

Braids and Locs—Braiding is a technique that involves interlocking 3 or more sections of hair that may or may not be fixated to the scalp like a cornrow,¹¹ and one can utilize extensions or natural hair depending on the desired outcome. Intended for long-term wear (ie, weeks to months), braids minimize breakage and reduce daily styling needs. Two popular styles—cornrows and individual braids—differ in preparation and weaving techniques. Cornrows are an Afro-centric style involving uniform, tightly woven braids that are close to the scalp, creating distinct patterns. Conversely, individual braids weave separate hair sections, offering diverse styling possibilities. Braiding practices should exclude hairline edges—often termed baby hairs—to prevent traction alopecia. Minimal use of edge gel, which helps to tame the vellus hairs at the frontotemporal scalp, as well as mindful weave volume, weight, and length are recommended to avert breakage. Braids that cause pain are too tight, can damage hair, and may cause traction alopecia.¹¹ Braids should not be worn for longer than 3 months at a time and require biweekly washing with diluted shampoo and conditioner. Proper drying by wringing the hair with a microfiber towel is essential to avoid frizz and mold formation.

Locs are a low-maintenance hairstyle considered permanent until cut.²⁸ This style involves twisting, palm rolling, or using tools such as crochet hooks to “lock” the hair. Regular maintenance with retwisting and cleaning is vital for loc health. Increased weight and tight twisting of locs can cause damage to the scalp and hair strands; however, locs are known to increase hair volume over time, often due to the accumulation of hairs that would otherwise have been shed in the telogen phase.²⁸

Wigs and Weaves—Wigs consist of synthetic or human hair that can be strapped to the head with an adjustable band or glued to the scalp depending on the desired style.²⁹ Wigs are removed daily, which allows for quick access to hair for cleansing and moisturizing. In contrast, weaves typically are sewn into the natural hair, which may make it difficult to reach the scalp for cleansing, leading to dryness and product build-up.²⁹ Notably, there is evidence of a relationship between long-term use of weaves and traction alopecia.³⁰

Wigs can have a fully synthetic hair line or lace hair line and can range from very affordable to expensive. When applied correctly, both styles offer an easy way to cover and protect the natural hair by reducing the amount of physical trauma related to daily hair styling. A lace-front wig contains a frontal thin mesh or lace that camouflages the natural frontal hairline.^29,30 A risk of lace-front wigs is that they can cause friction alopecia secondary to repeated use of adhesives and repeated friction against the hairline. Generally, wigs and weaves should be cared for as one would care for one’s own hair.

Hair Care in Black Children—Children’s hair care begins with washing the hair and scalp with shampoo, applying conditioner, and detangling as needed.³¹ After rinsing out the conditioner, a leave-in conditioner can assist with moisture retention and further detangling. The hair is then styled, either wet or dry. Recommendations for hair care practices in Black children include loose hairstyles that do not strain hair roots and nightly removal of root-securing accessories (eg, barrettes, elastic hairbeads). Frequent cornrow styling and friction on chemically straightened hair were identified by a survey as considerable traction alopecia risk factors.³² Thus, educating caregivers on appropriate hair-grooming practices for children is important.

Hair Protection—Proactive steps to reduce hair loss include wearing satin bonnets and/or using satin pillowcases while sleeping regardless of hairstyle. Although evidence is limited, it is thought that satin and silk allow the hair to retain its moisture and natural oils, preventing breakage and friction.^33,34 Frequent hair trimming every 2 to 4 months can reduce breakage when doing thermal treatments.^35,36 When prolonged or repetitive styles are used, it is encouraged to give the hair a break between styles to recover from the repeated stress. Wearing an intermittent updo or high bun—a hairstyle in which the hair is pulled upward—can prevent breakage by reducing heavy strain on the hair; however, it is important to avoid the use of rubber bands due to friction and risk for tangling of hair strands. Instead, the use of covered elastic ties and/or those without metal is preferred.¹¹ Alternatively, if a polished and neat appearance with slicked-back hair is desired, the practice of tautly pulling the hair is not recommended. Instead, use of an alcohol-free gel is suggested along with a satin scarf wrapped around the hairline to facilitate the setting of the hair in place.¹¹

A common practice to preserve curly hairstyles while sleeping is known as the pineapple method, which protects the hair and aids in preserving the freshness and style of the curls.³⁷ It consists of a loosely tied high ponytail at the top of the head allowing the curls to fall forward. This minimizes frizz and prevents the curls from forming knots.

Conclusion

Hair care recommendations in Black women can be complex due to a wide range of personal care preferences and styling techniques in this population. While evidence in the literature is limited, it still is important for dermatologists to be familiar with the different hair care practices utilized by Black women so they can effectively counsel patients and improve hair health. Knowledge of optimal hair care practices can aid in the prevention of common hair disorders that disproportionately affect this patient population, such as traction alopecia and trichorrhexis nodosa or breakage.