Cutis

Practice Gap

Brown macules on the feet can pose diagnostic challenges, often raising suspicion of acral melanoma. Talon noir, which is benign and self-resolving, is characterized by dark patches on the skin of the feet due to hemorrhage within the stratum corneum and commonly is observed in athletes who sustain repetitive foot trauma. In one study, nearly 50% (9/20) of talon noir cases initially were misdiagnosed as acral melanoma or melanocytic nevi.¹ Accurate identification of talon noir is essential to prevent unnecessary interventions or delayed treatment of malignant lesions. Here, we describe a low-risk, cost-effective, and time-efficient diagnostic technique for talon noir using a disposable curette to potentially avoid more invasive procedures.

The Technique

A 34-year-old man presented to the dermatology department with a new brown macule on the second toe. The lesion had been present and stable for more than 4 months, showing no changes in shape or color. The patient reported that he was a frequent runner but did not recall any trauma to the toe, and he denied any associated pain, pruritus, or bleeding. Physical examination revealed a 6-mm dark-brown macule on the hyponychium of the left second toe, with numerous petechiae noted on dermoscopic examination. The findings were consistent with talon noir.

Given the clinical suspicion of talon noir, we used a 5-mm disposable curette to gently pare the superficial epidermis. The superficial curettage effectively removed the lesion, leaving behind a healthy epidermis with no pinpoint bleeding, which confirmed the diagnosis of talon noir (Figure). Pathologic changes from acral melanoma reside deeper than talon noir and consequently cannot be effectively removed by superficial curettage alone. Curettage acts as a curative technique for talon noir, but also as a low-risk, cost-effective, and time-efficient diagnostic technique to rule out insidious diagnoses, including acral melanoma.² A follow-up examination performed several weeks later showed no pigmentation or recurrence of the lesion in our patient, further supporting the diagnosis of talon noir.

Practice Implications

Talon noir refers to localized accumulation of blood within the epidermis due to repetitive trauma, pressure, and shearing forces on the skin that results in pigmented macules.^3-5 Repetitive trauma damages the microvasculature in areas of the skin with minimal subcutaneous adipose tissue.⁶ Talon noir also is known as subcorneal hematoma, intracorneal hematoma, black heel, hyperkeratosis hemorrhagica, and basketball heel.^1,3 First described by Crissey and Peachey³ in 1961 as calcaneal petechiae, the condition was identified in basketball players with well-circumscribed, deep-red lesions on the posterior lateral heels, located between the Achilles tendon insertion and calcaneal fat pad.³ Subsequent reports have documented talon noir in athletes from a range of sports such as tennis and football, whose activities involve rapid directional changes and shearing forces on the feet.⁶ Similar lesions, termed tache noir, have been observed on the hands of athletes including gymnasts, weightlifters, golfers, and climbers due to repetitive hand trauma.⁶ Gross examination reveals blood collecting in the thickened stratum corneum.⁵

The cutaneous manifestations of talon noir can mimic acral melanoma, highlighting the need for dermatologists to understand its clinical, dermoscopic, and microscopic features. Poor patient recall can complicate diagnosis; for instance, in one study only 20% (4/20) of patients remembered the inciting trauma that caused the subcorneal hematomas.¹ Balancing vigilance for melanoma with recognition of more benign conditions such as talon noir—particularly in younger active populations—is essential to minimize patient anxiety and avoid invasive procedures.

Further investigation is warranted in lesions that persist without obvious cause or in those that demonstrate concerning features such as extensive growth. One case of talon noir in a patient with diabetes required an excisional biopsy due to its atypical progression over 1 year with considerable hyperpigmentation and friability.⁷ Additional investigation such as dermoscopy may be required with paring of the skin to establish a diagnosis.¹ Using a curette to pare the thickened stratum corneum, which has no nerve endings, does not require anesthetics.⁸ In talon noir, paring completely removes the lesion, leaving behind unaffected skin, while melanomas would retain their pigmentation due to melanin in the basal layer.²

Talon noir is a benign condition frequently misdiagnosed due to its resemblance to more serious pathologies such as melanoma. Awareness of its clinical and dermoscopic features can promote cost-effective care while reducing unnecessary procedures. Diagnostic paring of the skin with a curette offers a simple and reliable means of distinguishing talon noir from acral melanoma and other potential conditions.

Practice Gap

Brown macules on the feet can pose diagnostic challenges, often raising suspicion of acral melanoma. Talon noir, which is benign and self-resolving, is characterized by dark patches on the skin of the feet due to hemorrhage within the stratum corneum and commonly is observed in athletes who sustain repetitive foot trauma. In one study, nearly 50% (9/20) of talon noir cases initially were misdiagnosed as acral melanoma or melanocytic nevi.¹ Accurate identification of talon noir is essential to prevent unnecessary interventions or delayed treatment of malignant lesions. Here, we describe a low-risk, cost-effective, and time-efficient diagnostic technique for talon noir using a disposable curette to potentially avoid more invasive procedures.

The Technique

A 34-year-old man presented to the dermatology department with a new brown macule on the second toe. The lesion had been present and stable for more than 4 months, showing no changes in shape or color. The patient reported that he was a frequent runner but did not recall any trauma to the toe, and he denied any associated pain, pruritus, or bleeding. Physical examination revealed a 6-mm dark-brown macule on the hyponychium of the left second toe, with numerous petechiae noted on dermoscopic examination. The findings were consistent with talon noir.

Given the clinical suspicion of talon noir, we used a 5-mm disposable curette to gently pare the superficial epidermis. The superficial curettage effectively removed the lesion, leaving behind a healthy epidermis with no pinpoint bleeding, which confirmed the diagnosis of talon noir (Figure). Pathologic changes from acral melanoma reside deeper than talon noir and consequently cannot be effectively removed by superficial curettage alone. Curettage acts as a curative technique for talon noir, but also as a low-risk, cost-effective, and time-efficient diagnostic technique to rule out insidious diagnoses, including acral melanoma.² A follow-up examination performed several weeks later showed no pigmentation or recurrence of the lesion in our patient, further supporting the diagnosis of talon noir.

Practice Implications

Talon noir refers to localized accumulation of blood within the epidermis due to repetitive trauma, pressure, and shearing forces on the skin that results in pigmented macules.^3-5 Repetitive trauma damages the microvasculature in areas of the skin with minimal subcutaneous adipose tissue.⁶ Talon noir also is known as subcorneal hematoma, intracorneal hematoma, black heel, hyperkeratosis hemorrhagica, and basketball heel.^1,3 First described by Crissey and Peachey³ in 1961 as calcaneal petechiae, the condition was identified in basketball players with well-circumscribed, deep-red lesions on the posterior lateral heels, located between the Achilles tendon insertion and calcaneal fat pad.³ Subsequent reports have documented talon noir in athletes from a range of sports such as tennis and football, whose activities involve rapid directional changes and shearing forces on the feet.⁶ Similar lesions, termed tache noir, have been observed on the hands of athletes including gymnasts, weightlifters, golfers, and climbers due to repetitive hand trauma.⁶ Gross examination reveals blood collecting in the thickened stratum corneum.⁵

The cutaneous manifestations of talon noir can mimic acral melanoma, highlighting the need for dermatologists to understand its clinical, dermoscopic, and microscopic features. Poor patient recall can complicate diagnosis; for instance, in one study only 20% (4/20) of patients remembered the inciting trauma that caused the subcorneal hematomas.¹ Balancing vigilance for melanoma with recognition of more benign conditions such as talon noir—particularly in younger active populations—is essential to minimize patient anxiety and avoid invasive procedures.

Further investigation is warranted in lesions that persist without obvious cause or in those that demonstrate concerning features such as extensive growth. One case of talon noir in a patient with diabetes required an excisional biopsy due to its atypical progression over 1 year with considerable hyperpigmentation and friability.⁷ Additional investigation such as dermoscopy may be required with paring of the skin to establish a diagnosis.¹ Using a curette to pare the thickened stratum corneum, which has no nerve endings, does not require anesthetics.⁸ In talon noir, paring completely removes the lesion, leaving behind unaffected skin, while melanomas would retain their pigmentation due to melanin in the basal layer.²

Talon noir is a benign condition frequently misdiagnosed due to its resemblance to more serious pathologies such as melanoma. Awareness of its clinical and dermoscopic features can promote cost-effective care while reducing unnecessary procedures. Diagnostic paring of the skin with a curette offers a simple and reliable means of distinguishing talon noir from acral melanoma and other potential conditions.

Practice Gap

Brown macules on the feet can pose diagnostic challenges, often raising suspicion of acral melanoma. Talon noir, which is benign and self-resolving, is characterized by dark patches on the skin of the feet due to hemorrhage within the stratum corneum and commonly is observed in athletes who sustain repetitive foot trauma. In one study, nearly 50% (9/20) of talon noir cases initially were misdiagnosed as acral melanoma or melanocytic nevi.¹ Accurate identification of talon noir is essential to prevent unnecessary interventions or delayed treatment of malignant lesions. Here, we describe a low-risk, cost-effective, and time-efficient diagnostic technique for talon noir using a disposable curette to potentially avoid more invasive procedures.

The Technique

A 34-year-old man presented to the dermatology department with a new brown macule on the second toe. The lesion had been present and stable for more than 4 months, showing no changes in shape or color. The patient reported that he was a frequent runner but did not recall any trauma to the toe, and he denied any associated pain, pruritus, or bleeding. Physical examination revealed a 6-mm dark-brown macule on the hyponychium of the left second toe, with numerous petechiae noted on dermoscopic examination. The findings were consistent with talon noir.

Given the clinical suspicion of talon noir, we used a 5-mm disposable curette to gently pare the superficial epidermis. The superficial curettage effectively removed the lesion, leaving behind a healthy epidermis with no pinpoint bleeding, which confirmed the diagnosis of talon noir (Figure). Pathologic changes from acral melanoma reside deeper than talon noir and consequently cannot be effectively removed by superficial curettage alone. Curettage acts as a curative technique for talon noir, but also as a low-risk, cost-effective, and time-efficient diagnostic technique to rule out insidious diagnoses, including acral melanoma.² A follow-up examination performed several weeks later showed no pigmentation or recurrence of the lesion in our patient, further supporting the diagnosis of talon noir.

Practice Implications

Talon noir refers to localized accumulation of blood within the epidermis due to repetitive trauma, pressure, and shearing forces on the skin that results in pigmented macules.^3-5 Repetitive trauma damages the microvasculature in areas of the skin with minimal subcutaneous adipose tissue.⁶ Talon noir also is known as subcorneal hematoma, intracorneal hematoma, black heel, hyperkeratosis hemorrhagica, and basketball heel.^1,3 First described by Crissey and Peachey³ in 1961 as calcaneal petechiae, the condition was identified in basketball players with well-circumscribed, deep-red lesions on the posterior lateral heels, located between the Achilles tendon insertion and calcaneal fat pad.³ Subsequent reports have documented talon noir in athletes from a range of sports such as tennis and football, whose activities involve rapid directional changes and shearing forces on the feet.⁶ Similar lesions, termed tache noir, have been observed on the hands of athletes including gymnasts, weightlifters, golfers, and climbers due to repetitive hand trauma.⁶ Gross examination reveals blood collecting in the thickened stratum corneum.⁵

The cutaneous manifestations of talon noir can mimic acral melanoma, highlighting the need for dermatologists to understand its clinical, dermoscopic, and microscopic features. Poor patient recall can complicate diagnosis; for instance, in one study only 20% (4/20) of patients remembered the inciting trauma that caused the subcorneal hematomas.¹ Balancing vigilance for melanoma with recognition of more benign conditions such as talon noir—particularly in younger active populations—is essential to minimize patient anxiety and avoid invasive procedures.

Further investigation is warranted in lesions that persist without obvious cause or in those that demonstrate concerning features such as extensive growth. One case of talon noir in a patient with diabetes required an excisional biopsy due to its atypical progression over 1 year with considerable hyperpigmentation and friability.⁷ Additional investigation such as dermoscopy may be required with paring of the skin to establish a diagnosis.¹ Using a curette to pare the thickened stratum corneum, which has no nerve endings, does not require anesthetics.⁸ In talon noir, paring completely removes the lesion, leaving behind unaffected skin, while melanomas would retain their pigmentation due to melanin in the basal layer.²

Talon noir is a benign condition frequently misdiagnosed due to its resemblance to more serious pathologies such as melanoma. Awareness of its clinical and dermoscopic features can promote cost-effective care while reducing unnecessary procedures. Diagnostic paring of the skin with a curette offers a simple and reliable means of distinguishing talon noir from acral melanoma and other potential conditions.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful recurrent abscesses. Several autoimmune and endocrine diseases are associated with HS, including inflammatory bowel disease and diabetes mellitus (DM).¹ Notably, the association between HS and thyroid disorders is poorly characterized,² and there are no known nationwide studies exploring this potential association in the hospital setting. In this cross-sectional matched cohort study, we aimed to characterize HS patients with comorbid thyroid disorders as well as to explore whether thyroid disease is associated with comorbidities and hospital outcome measures in these patients.

The 2019 National Inpatient Sample (NIS) was weighted in accordance with NIS-assigned weight variables and queried for HS, hypothyroidism, and hyperthyroidism cases using International Classification of Diseases, Tenth Revision, codes L73.2, E03, and E05, respectively. Propensity score matching based on age and sex was performed using a nearest-neighbor method in the MatchIt statistical R package. Patient demographics, comorbidities, and outcome variables were collected. Univariable analysis of HS patients with thyroid disease vs those without thyroid disease vs controls without HS were performed using X² and t-test functions in SPSS statistical software (IBM). A series of multivariate analyses were performed using SPSS logistic and linear regression models to examine the effect of thyroid disease on hospital outcome measures and comorbidities in HS patients, with statistical significance set at P=.05.

A total of 1720 HS patients with comorbid thyroid disease (hyperthyroidism/hypothyroidism), 23,785 HS patients without thyroid disease, and 25,497 age- and sex-matched controls were included in the analysis. On average, HS patients with comorbid thyroid disease were older than HS patients without thyroid disease and controls (49.36 years vs 42.17 years vs 42.66 years [P<.001]), more likely to be female (75.58% vs 58.67% vs 59.81% [P<.001]), more likely to be in the highest income quartile (17.52% vs 12.18% vs 8.14% [P<.001]), and more likely to be Medicare insured (39.07% vs 27.47% vs 18.02% [P<.001])(eTable).

On univariate analysis of hospital outcome measures, HS patients with comorbid thyroid disease had the highest frequency of extreme likelihood of dying compared with HS patients without thyroid disease and with controls (6.40% vs 5.38% vs 2.47% [P<.001]), the highest mean number of diagnoses (18.31 vs 14.14 vs 8.57 [P<.001]), and the longest mean length of hospital stay (6.03 days vs 5.94 days vs 3.73 days [P<.001]). On univariate analysis of comorbidities, HS patients with thyroid disease had the highest incidence of the following comorbidities compared with HS patients without thyroid disease and controls: hypertension (34.01% vs 28.55% vs 22.39% [P<.001]), DM (48.26% vs 35.63% vs 18.05% [P<.001]), obesity (46.80% vs 39.65% vs 11.70% [P<.001]), and acute kidney injury (AKI)(21.80% vs 13.10% vs 6.33% [P<.001])(eTable).

A multivariate analysis adjusting for multiple potential confounders including age, sex, race, median income quartile, disposition/discharge location, and primary payer was performed for hospital outcome measures and comorbidities. There were no significant differences in hospital outcome measures between HS patients with comorbid thyroid disease vs those without thyroid disease (P>.05)(Table 1). Thyroid disease was associated with increased odds of comorbid DM (odds ratio [OR], 1.242 [95% CI, 1.113-1.386]), obesity (OR, 1.173 [95% CI, 1.057-1.302]), and AKI (OR, 1.623 [95% CI, 1.423-1.851]) and decreased odds of comorbid nicotine dependence (OR, 0.609 [95% CI, 0.540-0.687]), skin and soft tissue infections (OR, 0.712 [95% CI, 0.637-0.797]), and sepsis (OR, 0.836 [95% CI, 0.717-0.973]) in HS patients (Table 2).

We found that HS patients with thyroid disease had increased odds of comorbid obesity, DM, and AKI compared with HS patients without thyroid disease when adjusting for potential confounders on multivariate analysis. A 2019 nationwide cross-sectional study of 18,224 patients with thyroid disease and 72,896 controls in Taiwan showed a higher prevalence of obesity (1.26% vs 0.57% [P<.0001]) and a higher hazard ratio (HR) of type 2 DM (HR, 1.23 [95% CI, 1.16-1.31]) in the thyroid disease group vs the controls.³ In a 2024 claims-based national cohort study of 4,152,830 patients with 2 or more consecutive thyroid-stimulating hormone measurements in the United States, patients with hypothyroidism and hyperthyroidism had a higher incidence risk for kidney dysfunction vs patients with euthyroidism (HRs, 1.37 [95% CI, 1.34–1.40] and 1.42 [95% CI, 1.39-1.45]).⁴ In addition, patients with and without DM and thyroid disease had increased risk for kidney disease compared to patients with and without DM and euthyroidism (hypothyroidism: HRs, 1.17 [95% CI, 1.13-1.22] and 1.52 [95% CI, 1.49-1.56]; hyperthyroidism: HRs, 1.34 [95% CI, 1.29-1.38] and 1.36 [95% CI, 1.33-1.39]). Furthermore, patients with and without obesity and thyroid disease had increased risk for kidney disease compared to patients with and without obesity and with euthyroidism (hypothyroidism: HRs, 1.40 [95% CI, 1.36-1.45] and 1.26 [95% CI, 1.21-1.32]; hyperthyroidism: HRs, 1.34 [95% CI, 1.30-1.39] and 1.35 [95% CI, 1.30-1.40]).⁴ However, these studies did not focus on HS patients.⁵

Hidradenitis suppurativa has a major comorbidity burden, including obesity, DM, and kidney disease.⁵ Our findings suggest a potential additive risk for these conditions in HS patients with comorbid thyroid disease; therefore, heightened surveillance for obesity, DM, and AKI in this population is encouraged. Prospective and retrospective studies in HS patients assessing the risk for each comorbidity while controlling for the others may help to better characterize these relationships.

Using multivariate analysis, we found that HS patients with comorbid thyroid disease had no significant differences in hospital outcome measures compared with HS patients without thyroid disease despite significant differences on univariate analysis (P<.05). Similarly, in a 2018 cross-sectional study of 430 HS patients and 20,780 controls in Denmark, the HS group had 10% lower thyroid-stimulating hormone levels vs the control group, but this did not significantly affect HS severity and thyroid function on multivariate analysis.⁶ In a 2020 cross-sectional analysis of 290 Greek HS patients, thyroid disease was associated with higher HS severity using Hurley classification (OR, 1.19 [95% CI, 1.03-1.51]) and International Hidradenitis Suppurativa Severity Score System 4 classification (OR, 1.29 [95% CI, 1.13-1.62]); however, this analysis was univariate and did not account for confounders.⁷ Taken together, our study and previous research suggest that thyroid disease is not an independent prognostic indicator for hospital outcome measures in HS patients when cofounders are considered and therefore may not warrant extra caution when treating hospitalized HS patients.

Nicotine dependence was an important potential confounder with regard to the effects of comorbid thyroid disease on outcomes of HS patients in our study. While we found that the prevalence of nicotine dependence was higher in HS patients vs matched controls, HS patients with comorbid thyroid disease had a lower prevalence of nicotine dependence than HS patients without thyroid disease. Furthermore, thyroid disease was associated with decreased odds of nicotine dependence in HS patients when adjusting for confounders. Previous studies have shown an association between cigarette smoking and HS. Smoking also may affect thyroid function via thiocyanate, sympathetic activation, or immunologic disturbances. Smoking may have both prothyroid and antithyroid effects.⁶ In a 2023 cross-sectional study of 108 HS patients and 52 age- and sex-matched controls in Germany, HS patients had higher thyroid antibody (TRAb) levels compared with controls (median TRAb level, 15.4 vs 14.2 [P=.026]), with even greater increases in TRAb in HS patients who were smokers or former smokers vs never smokers (median TRAb level, 1.18 vs 1.08 [P=.042]).²

There was a lower frequency of thyroid disease in our HS cohort compared with our matched controls cohort. While there are conflicting reports on the association between HS and thyroid disease in the literature, 2 recent meta-analyses of 5 and 6 case-control studies, respectively, found an association between HS and thyroid disease (OR, 1.36 [95% CI, 1.13-1.64] and 1.88 [95% CI, 1.25-2.81]).^1,8 Notably, these studies were either claims or survey based, included outpatients, or were unspecified. One potential explanation for the difference in our findings vs those of other studies could be underdiagnosis of thyroid disease in hospitalized HS patients. We found that HS patients were most frequently Medicaid or Medicare insured compared to controls, who most frequently were privately insured. Increased availability and ease of access to outpatient medical care through private health insurance may be a possible contributor to the higher frequency of diagnosed thyroid disease in control patients in our study; therefore, awareness of potential underdiagnosis of thyroid disease in hospitalized HS patients is recommended.

Limitations of our study included those inherent to the NIS database, including potential miscoding and lack of data on pharmacologic treatments. Outcome measures assessed were limited by inclusion of both primary and secondary diagnoses of HS and thyroid disease in our cohort and may have been affected by other conditions. As with any observational study, there was a possibility of unidentified confounders unaccounted for in our study.

In conclusion, in this national inpatient-matched cohort study, thyroid disease was associated with increased odds of obesity, DM, and AKI in HS inpatients but was not an independent risk factor for worse hospital outcome measures. Therefore, while increased surveillance of associated comorbidities is appropriate, thyroid disease may not be a cause for increased concern for dermatologists treating hospitalized HS patients. Prospective studies are necessary to better characterize these findings.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful recurrent abscesses. Several autoimmune and endocrine diseases are associated with HS, including inflammatory bowel disease and diabetes mellitus (DM).¹ Notably, the association between HS and thyroid disorders is poorly characterized,² and there are no known nationwide studies exploring this potential association in the hospital setting. In this cross-sectional matched cohort study, we aimed to characterize HS patients with comorbid thyroid disorders as well as to explore whether thyroid disease is associated with comorbidities and hospital outcome measures in these patients.

The 2019 National Inpatient Sample (NIS) was weighted in accordance with NIS-assigned weight variables and queried for HS, hypothyroidism, and hyperthyroidism cases using International Classification of Diseases, Tenth Revision, codes L73.2, E03, and E05, respectively. Propensity score matching based on age and sex was performed using a nearest-neighbor method in the MatchIt statistical R package. Patient demographics, comorbidities, and outcome variables were collected. Univariable analysis of HS patients with thyroid disease vs those without thyroid disease vs controls without HS were performed using X² and t-test functions in SPSS statistical software (IBM). A series of multivariate analyses were performed using SPSS logistic and linear regression models to examine the effect of thyroid disease on hospital outcome measures and comorbidities in HS patients, with statistical significance set at P=.05.

A total of 1720 HS patients with comorbid thyroid disease (hyperthyroidism/hypothyroidism), 23,785 HS patients without thyroid disease, and 25,497 age- and sex-matched controls were included in the analysis. On average, HS patients with comorbid thyroid disease were older than HS patients without thyroid disease and controls (49.36 years vs 42.17 years vs 42.66 years [P<.001]), more likely to be female (75.58% vs 58.67% vs 59.81% [P<.001]), more likely to be in the highest income quartile (17.52% vs 12.18% vs 8.14% [P<.001]), and more likely to be Medicare insured (39.07% vs 27.47% vs 18.02% [P<.001])(eTable).

On univariate analysis of hospital outcome measures, HS patients with comorbid thyroid disease had the highest frequency of extreme likelihood of dying compared with HS patients without thyroid disease and with controls (6.40% vs 5.38% vs 2.47% [P<.001]), the highest mean number of diagnoses (18.31 vs 14.14 vs 8.57 [P<.001]), and the longest mean length of hospital stay (6.03 days vs 5.94 days vs 3.73 days [P<.001]). On univariate analysis of comorbidities, HS patients with thyroid disease had the highest incidence of the following comorbidities compared with HS patients without thyroid disease and controls: hypertension (34.01% vs 28.55% vs 22.39% [P<.001]), DM (48.26% vs 35.63% vs 18.05% [P<.001]), obesity (46.80% vs 39.65% vs 11.70% [P<.001]), and acute kidney injury (AKI)(21.80% vs 13.10% vs 6.33% [P<.001])(eTable).

A multivariate analysis adjusting for multiple potential confounders including age, sex, race, median income quartile, disposition/discharge location, and primary payer was performed for hospital outcome measures and comorbidities. There were no significant differences in hospital outcome measures between HS patients with comorbid thyroid disease vs those without thyroid disease (P>.05)(Table 1). Thyroid disease was associated with increased odds of comorbid DM (odds ratio [OR], 1.242 [95% CI, 1.113-1.386]), obesity (OR, 1.173 [95% CI, 1.057-1.302]), and AKI (OR, 1.623 [95% CI, 1.423-1.851]) and decreased odds of comorbid nicotine dependence (OR, 0.609 [95% CI, 0.540-0.687]), skin and soft tissue infections (OR, 0.712 [95% CI, 0.637-0.797]), and sepsis (OR, 0.836 [95% CI, 0.717-0.973]) in HS patients (Table 2).

We found that HS patients with thyroid disease had increased odds of comorbid obesity, DM, and AKI compared with HS patients without thyroid disease when adjusting for potential confounders on multivariate analysis. A 2019 nationwide cross-sectional study of 18,224 patients with thyroid disease and 72,896 controls in Taiwan showed a higher prevalence of obesity (1.26% vs 0.57% [P<.0001]) and a higher hazard ratio (HR) of type 2 DM (HR, 1.23 [95% CI, 1.16-1.31]) in the thyroid disease group vs the controls.³ In a 2024 claims-based national cohort study of 4,152,830 patients with 2 or more consecutive thyroid-stimulating hormone measurements in the United States, patients with hypothyroidism and hyperthyroidism had a higher incidence risk for kidney dysfunction vs patients with euthyroidism (HRs, 1.37 [95% CI, 1.34–1.40] and 1.42 [95% CI, 1.39-1.45]).⁴ In addition, patients with and without DM and thyroid disease had increased risk for kidney disease compared to patients with and without DM and euthyroidism (hypothyroidism: HRs, 1.17 [95% CI, 1.13-1.22] and 1.52 [95% CI, 1.49-1.56]; hyperthyroidism: HRs, 1.34 [95% CI, 1.29-1.38] and 1.36 [95% CI, 1.33-1.39]). Furthermore, patients with and without obesity and thyroid disease had increased risk for kidney disease compared to patients with and without obesity and with euthyroidism (hypothyroidism: HRs, 1.40 [95% CI, 1.36-1.45] and 1.26 [95% CI, 1.21-1.32]; hyperthyroidism: HRs, 1.34 [95% CI, 1.30-1.39] and 1.35 [95% CI, 1.30-1.40]).⁴ However, these studies did not focus on HS patients.⁵

Hidradenitis suppurativa has a major comorbidity burden, including obesity, DM, and kidney disease.⁵ Our findings suggest a potential additive risk for these conditions in HS patients with comorbid thyroid disease; therefore, heightened surveillance for obesity, DM, and AKI in this population is encouraged. Prospective and retrospective studies in HS patients assessing the risk for each comorbidity while controlling for the others may help to better characterize these relationships.

Using multivariate analysis, we found that HS patients with comorbid thyroid disease had no significant differences in hospital outcome measures compared with HS patients without thyroid disease despite significant differences on univariate analysis (P<.05). Similarly, in a 2018 cross-sectional study of 430 HS patients and 20,780 controls in Denmark, the HS group had 10% lower thyroid-stimulating hormone levels vs the control group, but this did not significantly affect HS severity and thyroid function on multivariate analysis.⁶ In a 2020 cross-sectional analysis of 290 Greek HS patients, thyroid disease was associated with higher HS severity using Hurley classification (OR, 1.19 [95% CI, 1.03-1.51]) and International Hidradenitis Suppurativa Severity Score System 4 classification (OR, 1.29 [95% CI, 1.13-1.62]); however, this analysis was univariate and did not account for confounders.⁷ Taken together, our study and previous research suggest that thyroid disease is not an independent prognostic indicator for hospital outcome measures in HS patients when cofounders are considered and therefore may not warrant extra caution when treating hospitalized HS patients.

Nicotine dependence was an important potential confounder with regard to the effects of comorbid thyroid disease on outcomes of HS patients in our study. While we found that the prevalence of nicotine dependence was higher in HS patients vs matched controls, HS patients with comorbid thyroid disease had a lower prevalence of nicotine dependence than HS patients without thyroid disease. Furthermore, thyroid disease was associated with decreased odds of nicotine dependence in HS patients when adjusting for confounders. Previous studies have shown an association between cigarette smoking and HS. Smoking also may affect thyroid function via thiocyanate, sympathetic activation, or immunologic disturbances. Smoking may have both prothyroid and antithyroid effects.⁶ In a 2023 cross-sectional study of 108 HS patients and 52 age- and sex-matched controls in Germany, HS patients had higher thyroid antibody (TRAb) levels compared with controls (median TRAb level, 15.4 vs 14.2 [P=.026]), with even greater increases in TRAb in HS patients who were smokers or former smokers vs never smokers (median TRAb level, 1.18 vs 1.08 [P=.042]).²

There was a lower frequency of thyroid disease in our HS cohort compared with our matched controls cohort. While there are conflicting reports on the association between HS and thyroid disease in the literature, 2 recent meta-analyses of 5 and 6 case-control studies, respectively, found an association between HS and thyroid disease (OR, 1.36 [95% CI, 1.13-1.64] and 1.88 [95% CI, 1.25-2.81]).^1,8 Notably, these studies were either claims or survey based, included outpatients, or were unspecified. One potential explanation for the difference in our findings vs those of other studies could be underdiagnosis of thyroid disease in hospitalized HS patients. We found that HS patients were most frequently Medicaid or Medicare insured compared to controls, who most frequently were privately insured. Increased availability and ease of access to outpatient medical care through private health insurance may be a possible contributor to the higher frequency of diagnosed thyroid disease in control patients in our study; therefore, awareness of potential underdiagnosis of thyroid disease in hospitalized HS patients is recommended.

Limitations of our study included those inherent to the NIS database, including potential miscoding and lack of data on pharmacologic treatments. Outcome measures assessed were limited by inclusion of both primary and secondary diagnoses of HS and thyroid disease in our cohort and may have been affected by other conditions. As with any observational study, there was a possibility of unidentified confounders unaccounted for in our study.

In conclusion, in this national inpatient-matched cohort study, thyroid disease was associated with increased odds of obesity, DM, and AKI in HS inpatients but was not an independent risk factor for worse hospital outcome measures. Therefore, while increased surveillance of associated comorbidities is appropriate, thyroid disease may not be a cause for increased concern for dermatologists treating hospitalized HS patients. Prospective studies are necessary to better characterize these findings.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful recurrent abscesses. Several autoimmune and endocrine diseases are associated with HS, including inflammatory bowel disease and diabetes mellitus (DM).¹ Notably, the association between HS and thyroid disorders is poorly characterized,² and there are no known nationwide studies exploring this potential association in the hospital setting. In this cross-sectional matched cohort study, we aimed to characterize HS patients with comorbid thyroid disorders as well as to explore whether thyroid disease is associated with comorbidities and hospital outcome measures in these patients.

The 2019 National Inpatient Sample (NIS) was weighted in accordance with NIS-assigned weight variables and queried for HS, hypothyroidism, and hyperthyroidism cases using International Classification of Diseases, Tenth Revision, codes L73.2, E03, and E05, respectively. Propensity score matching based on age and sex was performed using a nearest-neighbor method in the MatchIt statistical R package. Patient demographics, comorbidities, and outcome variables were collected. Univariable analysis of HS patients with thyroid disease vs those without thyroid disease vs controls without HS were performed using X² and t-test functions in SPSS statistical software (IBM). A series of multivariate analyses were performed using SPSS logistic and linear regression models to examine the effect of thyroid disease on hospital outcome measures and comorbidities in HS patients, with statistical significance set at P=.05.

A total of 1720 HS patients with comorbid thyroid disease (hyperthyroidism/hypothyroidism), 23,785 HS patients without thyroid disease, and 25,497 age- and sex-matched controls were included in the analysis. On average, HS patients with comorbid thyroid disease were older than HS patients without thyroid disease and controls (49.36 years vs 42.17 years vs 42.66 years [P<.001]), more likely to be female (75.58% vs 58.67% vs 59.81% [P<.001]), more likely to be in the highest income quartile (17.52% vs 12.18% vs 8.14% [P<.001]), and more likely to be Medicare insured (39.07% vs 27.47% vs 18.02% [P<.001])(eTable).

On univariate analysis of hospital outcome measures, HS patients with comorbid thyroid disease had the highest frequency of extreme likelihood of dying compared with HS patients without thyroid disease and with controls (6.40% vs 5.38% vs 2.47% [P<.001]), the highest mean number of diagnoses (18.31 vs 14.14 vs 8.57 [P<.001]), and the longest mean length of hospital stay (6.03 days vs 5.94 days vs 3.73 days [P<.001]). On univariate analysis of comorbidities, HS patients with thyroid disease had the highest incidence of the following comorbidities compared with HS patients without thyroid disease and controls: hypertension (34.01% vs 28.55% vs 22.39% [P<.001]), DM (48.26% vs 35.63% vs 18.05% [P<.001]), obesity (46.80% vs 39.65% vs 11.70% [P<.001]), and acute kidney injury (AKI)(21.80% vs 13.10% vs 6.33% [P<.001])(eTable).

A multivariate analysis adjusting for multiple potential confounders including age, sex, race, median income quartile, disposition/discharge location, and primary payer was performed for hospital outcome measures and comorbidities. There were no significant differences in hospital outcome measures between HS patients with comorbid thyroid disease vs those without thyroid disease (P>.05)(Table 1). Thyroid disease was associated with increased odds of comorbid DM (odds ratio [OR], 1.242 [95% CI, 1.113-1.386]), obesity (OR, 1.173 [95% CI, 1.057-1.302]), and AKI (OR, 1.623 [95% CI, 1.423-1.851]) and decreased odds of comorbid nicotine dependence (OR, 0.609 [95% CI, 0.540-0.687]), skin and soft tissue infections (OR, 0.712 [95% CI, 0.637-0.797]), and sepsis (OR, 0.836 [95% CI, 0.717-0.973]) in HS patients (Table 2).

We found that HS patients with thyroid disease had increased odds of comorbid obesity, DM, and AKI compared with HS patients without thyroid disease when adjusting for potential confounders on multivariate analysis. A 2019 nationwide cross-sectional study of 18,224 patients with thyroid disease and 72,896 controls in Taiwan showed a higher prevalence of obesity (1.26% vs 0.57% [P<.0001]) and a higher hazard ratio (HR) of type 2 DM (HR, 1.23 [95% CI, 1.16-1.31]) in the thyroid disease group vs the controls.³ In a 2024 claims-based national cohort study of 4,152,830 patients with 2 or more consecutive thyroid-stimulating hormone measurements in the United States, patients with hypothyroidism and hyperthyroidism had a higher incidence risk for kidney dysfunction vs patients with euthyroidism (HRs, 1.37 [95% CI, 1.34–1.40] and 1.42 [95% CI, 1.39-1.45]).⁴ In addition, patients with and without DM and thyroid disease had increased risk for kidney disease compared to patients with and without DM and euthyroidism (hypothyroidism: HRs, 1.17 [95% CI, 1.13-1.22] and 1.52 [95% CI, 1.49-1.56]; hyperthyroidism: HRs, 1.34 [95% CI, 1.29-1.38] and 1.36 [95% CI, 1.33-1.39]). Furthermore, patients with and without obesity and thyroid disease had increased risk for kidney disease compared to patients with and without obesity and with euthyroidism (hypothyroidism: HRs, 1.40 [95% CI, 1.36-1.45] and 1.26 [95% CI, 1.21-1.32]; hyperthyroidism: HRs, 1.34 [95% CI, 1.30-1.39] and 1.35 [95% CI, 1.30-1.40]).⁴ However, these studies did not focus on HS patients.⁵

Hidradenitis suppurativa has a major comorbidity burden, including obesity, DM, and kidney disease.⁵ Our findings suggest a potential additive risk for these conditions in HS patients with comorbid thyroid disease; therefore, heightened surveillance for obesity, DM, and AKI in this population is encouraged. Prospective and retrospective studies in HS patients assessing the risk for each comorbidity while controlling for the others may help to better characterize these relationships.

Using multivariate analysis, we found that HS patients with comorbid thyroid disease had no significant differences in hospital outcome measures compared with HS patients without thyroid disease despite significant differences on univariate analysis (P<.05). Similarly, in a 2018 cross-sectional study of 430 HS patients and 20,780 controls in Denmark, the HS group had 10% lower thyroid-stimulating hormone levels vs the control group, but this did not significantly affect HS severity and thyroid function on multivariate analysis.⁶ In a 2020 cross-sectional analysis of 290 Greek HS patients, thyroid disease was associated with higher HS severity using Hurley classification (OR, 1.19 [95% CI, 1.03-1.51]) and International Hidradenitis Suppurativa Severity Score System 4 classification (OR, 1.29 [95% CI, 1.13-1.62]); however, this analysis was univariate and did not account for confounders.⁷ Taken together, our study and previous research suggest that thyroid disease is not an independent prognostic indicator for hospital outcome measures in HS patients when cofounders are considered and therefore may not warrant extra caution when treating hospitalized HS patients.

Nicotine dependence was an important potential confounder with regard to the effects of comorbid thyroid disease on outcomes of HS patients in our study. While we found that the prevalence of nicotine dependence was higher in HS patients vs matched controls, HS patients with comorbid thyroid disease had a lower prevalence of nicotine dependence than HS patients without thyroid disease. Furthermore, thyroid disease was associated with decreased odds of nicotine dependence in HS patients when adjusting for confounders. Previous studies have shown an association between cigarette smoking and HS. Smoking also may affect thyroid function via thiocyanate, sympathetic activation, or immunologic disturbances. Smoking may have both prothyroid and antithyroid effects.⁶ In a 2023 cross-sectional study of 108 HS patients and 52 age- and sex-matched controls in Germany, HS patients had higher thyroid antibody (TRAb) levels compared with controls (median TRAb level, 15.4 vs 14.2 [P=.026]), with even greater increases in TRAb in HS patients who were smokers or former smokers vs never smokers (median TRAb level, 1.18 vs 1.08 [P=.042]).²

There was a lower frequency of thyroid disease in our HS cohort compared with our matched controls cohort. While there are conflicting reports on the association between HS and thyroid disease in the literature, 2 recent meta-analyses of 5 and 6 case-control studies, respectively, found an association between HS and thyroid disease (OR, 1.36 [95% CI, 1.13-1.64] and 1.88 [95% CI, 1.25-2.81]).^1,8 Notably, these studies were either claims or survey based, included outpatients, or were unspecified. One potential explanation for the difference in our findings vs those of other studies could be underdiagnosis of thyroid disease in hospitalized HS patients. We found that HS patients were most frequently Medicaid or Medicare insured compared to controls, who most frequently were privately insured. Increased availability and ease of access to outpatient medical care through private health insurance may be a possible contributor to the higher frequency of diagnosed thyroid disease in control patients in our study; therefore, awareness of potential underdiagnosis of thyroid disease in hospitalized HS patients is recommended.

Limitations of our study included those inherent to the NIS database, including potential miscoding and lack of data on pharmacologic treatments. Outcome measures assessed were limited by inclusion of both primary and secondary diagnoses of HS and thyroid disease in our cohort and may have been affected by other conditions. As with any observational study, there was a possibility of unidentified confounders unaccounted for in our study.

In conclusion, in this national inpatient-matched cohort study, thyroid disease was associated with increased odds of obesity, DM, and AKI in HS inpatients but was not an independent risk factor for worse hospital outcome measures. Therefore, while increased surveillance of associated comorbidities is appropriate, thyroid disease may not be a cause for increased concern for dermatologists treating hospitalized HS patients. Prospective studies are necessary to better characterize these findings.

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.