Cutis

Introduced in 1982, isotretinoin is a retinoid derivative that has been widely used to treat various dermatologic conditions such as acne vulgaris, rosacea, hidradenitis suppurativa, and hair folliculitis. ¹ It remains one of the most effective drugs for the treatment of all forms of acne vulgaris, especially the nodulocystic type, and exerts its effects via different mechanisms that affect the major domains involved in the pathogenesis of acne. ² One month after treatment initiation, isotretinoin suppresses sebum production by decreasing the size and activity of sebaceous glands. In addition, it notably stabilizes keratinization of the skin and decreases the number of Propionibacterium acnes, which will minimize the inflammation associated with acne. ^3,4 Despite its beneficial effects, isotretinoin therapy has been associated with several complications. The most commonly reported adverse effects include fissured lips, dry skin, eczema, epistaxis, dry eyes, gastrointestinal tract upset, angular stomatitis, and back pain. Less frequent systemic adverse effects have been reported and relate mainly to teratogenicity, pancreatitis, drug-induced hepatotoxicity, leukopenia, and thrombocytopenia. ⁵

Isotretinoin use has been associated with alterations in hepatic and lipid profiles; elevations of serum liver enzymes and triglycerides (TGs) following isotretinoin treatment have been reported.⁴ Consequently, different protocols for laboratory monitoring during isotretinoin therapy have been established and utilized by various health care institutes.⁶ Despite the time and economic investment involved, certain protocols recommend repetition of liver function tests and several other laboratory parameters following a baseline test.⁷ The aim of this study was to determine the prevalence of laboratory changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, and TGs among patients with acne receiving isotretinoin therapy, as well as to link the initial and second laboratory readings of the aforementioned parameters following initiation of isotretinoin treatment.

Materials and Methods

This retrospective cohort design study obtained patient data, including laboratory test results, from the Electronic System for Integrated Health Information at King Khalid University Hospital (KKUH)(Riyadh, Saudi Arabia). All patients older than 16 years who presented with acne vulgaris to the dermatology department at KKUH; who received a course of isotretinoin for at least 4 weeks between 2011 and 2016; and who had available baseline readings of ALT, AST, cholesterol, and TGs, as well as 2 concurrent follow-up readings after isotretinoin treatment initiation, were included in this study. Patients with only 1 reading following treatment initiation and those receiving isotretinoin treatment for reasons other than acne were excluded. This study was approved by the institutional review board of the College of Medicine at King Saud University (Riyadh, Saudi Arabia)(E-18-3310).

Statistical Analysis
Data were entered into a Microsoft Excel document, and statistical analysis was performed using SPSS (version 22.0). Data were represented as numbers and percentages. Repeated measures analysis was performed using the Cochran Q test to compare proportions of abnormal laboratory values among 3 groups: baseline, first reading, and second reading. When test results were significant, a post hoc test was used to compare proportions between any 2 groups. Moreover, a Spearman rank correlation was performed to investigate the association between the daily isotretinoin dose and the laboratory parameters. Results with P<.05 were considered statistically significant.

Results

During the study period, treatment with oral isotretinoin was undertaken by 386 patients at KKUH. Several of these patients were excluded due to incomplete medical records. The age of the studied patients ranged from 17 to 60 years, with a median age of 24 years (interquartile range, 20−28 years). The daily administered dose ranged from 10 to 80 mg, with a median dose of 30 mg (interquartile range, 20−40 mg), as illustrated in the Table. Repeated-measures analysis of liver enzymes (AST and ALT), total cholesterol, and TGs is detailed in eTable 1. Eight (2.2%) of 371 patients showed abnormal baseline AST levels. The first follow-up measurements of AST revealed high levels in 7 (1.9%) patients. This figure doubled (14 [3.8%] patients) at the second follow-up, with no statistically significant differences (P>.05). Likewise, ALT showed abnormally high levels at baseline and at both the first and second follow-ups (47/371 [12.7%], 49/371 [13.2%], and 37/371 [10.0%], respectively) with no significant differences (P>.05). Furthermore, the proportions of high cholesterol levels at baseline and at both the first and second follow-ups (40/331 [12.1%], 72/331 [21.8%], and 62/331 [18.7%], respectively) showed a statistically significant difference (P=.001). The proportions of high cholesterol levels in both the first and second follow-ups were significantly higher than the baseline proportions (P=.001 and P=.002, respectively). However, the percentages of high cholesterol were reduced at the second reading relative to the first but with no significant differences. Regarding TGs, there was a statistically significant difference in the proportions of high levels over time (5/320 [1.6%], 12/320 [3.8%], and 14/320 [4.4%] at baseline and at the first and second readings, respectively). Moreover, pairwise comparison among the 3 readings revealed a significant difference between the second follow-up and the baseline levels (P=.048). eTable 2 demonstrates statistically significant positive weak associations between the daily administered isotretinoin dose and each of the cholesterol and TG levels, both at the first and second follow-up readings (P<.05).

Comment

Evaluation of the effects of isotretinoin on liver enzymes and lipids has suggested that oral isotretinoin may cause alterations in liver aminotransferases (AST and ALT) and lipid profiles to various degrees.⁸ Furthermore, there are controversies regarding the routine laboratory monitoring of these patients. Some studies have reported severe alterations in serum liver transaminase and lipid levels, and they support the need for careful monitoring when treating patients with isotretinoin. However, other studies have reported that adverse effects are minimal, with no need for costly laboratory monitoring.⁹

Our study explored the profile of changes in liver aminotransferases (AST and ALT), cholesterol, and TGs in patients with acne who had been treated with oral isotretinoin. The cholesterol levels showed a nonprogressive increase, with a prevalence rate of 21.8% and 18.7% at the first and second follow-ups, respectively. Likewise, the frequency of high TG levels was 3.8% and 4.4%, respectively, with significant differences from the baseline levels (P=.041). However, liver enzymes were less affected by isotretinoin therapy than lipid profiles. Both AST and ALT showed nonsignificant minimal elevations during follow-up of the patients.

Similar to our findings, Zane et al⁶ at the University of California, San Francisco, studied 13,772 patients with acne who underwent oral isotretinoin therapy between 1995 and 2002. They reported a cumulative incidence of new abnormalities in patients with normal values at baseline at a frequency of 44% for TG levels, 31% for total cholesterol levels, and 11% for transaminase levels. Moreover, they suggested that these abnormalities generally were transient and reversible.⁶ Another retrospective study in Brazil included 130 patients who were treated with isotretinoin for 3 months and reported that TG levels had increased beyond the normal range in 11% of patients, whereas 8.6% had elevated AST levels and 7.3% had elevated ALT levels.⁸ Comparable to our findings, Kizilyel et al¹⁰ concluded that isotretinoin appeared to have a greater effect on lipids than on liver enzymes, and they recommended its use with careful monitoring.

The transient effects of isotretinoin therapy on lipid profiles were highlighted in an earlier study. It has been reported that the changes in low-density lipoprotein and TGs returned to baseline levels 2 months following termination of treatment.¹¹ Although many studies have reported alterations in serum transaminase and lipid levels, other studies fail to report any such effects. Alcalay et al⁷ investigated 907 patients who completed a treatment course lasting 5 to 9 months. They reported that only 1.5% of patients had serum TG levels above 400 mg. Additionally, serum levels of liver enzymes were not elevated to a degree necessitating discontinuation of treatment. They concluded that isotretinoin is a safe therapeutic drug and suggested that there is no need for routine laboratory follow-up in young healthy patients apart from a pregnancy test for females.⁷ In addition, Brito et al¹² conducted a prospective clinical and laboratory evaluation of 150 patients being treated with oral isotretinoin prior to the start of therapy, 1 month after therapy initiation, and every 3 months thereafter until the completion of treatment. They found no statistically significant changes in liver transaminase, TG, or cholesterol levels.¹² In another study of 30 participants, Baxter et al¹³ also reported no significant changes in TG or cholesterol levels measured at baseline or during treatment with isotretinoin. Furthermore, a systematic review and meta-analysis has estimated the laboratory changes that occur during isotretinoin therapy of acne vulgaris.¹⁴ The evidence revealed in this study does not support monthly laboratory testing for use of standard doses of oral isotretinoin for the typical patient with acne.

Conclusion

In our study, liver enzymes were less affected than lipids in patients who were treated with isotretinoin. Additionally, laboratory alterations in lipid profiles were nonprogressive and nonsevere. Consequently, isotretinoin may be administered with minimal concern for changes in serum transaminase and lipid profile. However, physicians should exercise caution when administering isotretinoin in patients with a history of abnormal findings.

Introduced in 1982, isotretinoin is a retinoid derivative that has been widely used to treat various dermatologic conditions such as acne vulgaris, rosacea, hidradenitis suppurativa, and hair folliculitis. ¹ It remains one of the most effective drugs for the treatment of all forms of acne vulgaris, especially the nodulocystic type, and exerts its effects via different mechanisms that affect the major domains involved in the pathogenesis of acne. ² One month after treatment initiation, isotretinoin suppresses sebum production by decreasing the size and activity of sebaceous glands. In addition, it notably stabilizes keratinization of the skin and decreases the number of Propionibacterium acnes, which will minimize the inflammation associated with acne. ^3,4 Despite its beneficial effects, isotretinoin therapy has been associated with several complications. The most commonly reported adverse effects include fissured lips, dry skin, eczema, epistaxis, dry eyes, gastrointestinal tract upset, angular stomatitis, and back pain. Less frequent systemic adverse effects have been reported and relate mainly to teratogenicity, pancreatitis, drug-induced hepatotoxicity, leukopenia, and thrombocytopenia. ⁵

Isotretinoin use has been associated with alterations in hepatic and lipid profiles; elevations of serum liver enzymes and triglycerides (TGs) following isotretinoin treatment have been reported.⁴ Consequently, different protocols for laboratory monitoring during isotretinoin therapy have been established and utilized by various health care institutes.⁶ Despite the time and economic investment involved, certain protocols recommend repetition of liver function tests and several other laboratory parameters following a baseline test.⁷ The aim of this study was to determine the prevalence of laboratory changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, and TGs among patients with acne receiving isotretinoin therapy, as well as to link the initial and second laboratory readings of the aforementioned parameters following initiation of isotretinoin treatment.

Materials and Methods

This retrospective cohort design study obtained patient data, including laboratory test results, from the Electronic System for Integrated Health Information at King Khalid University Hospital (KKUH)(Riyadh, Saudi Arabia). All patients older than 16 years who presented with acne vulgaris to the dermatology department at KKUH; who received a course of isotretinoin for at least 4 weeks between 2011 and 2016; and who had available baseline readings of ALT, AST, cholesterol, and TGs, as well as 2 concurrent follow-up readings after isotretinoin treatment initiation, were included in this study. Patients with only 1 reading following treatment initiation and those receiving isotretinoin treatment for reasons other than acne were excluded. This study was approved by the institutional review board of the College of Medicine at King Saud University (Riyadh, Saudi Arabia)(E-18-3310).

Statistical Analysis
Data were entered into a Microsoft Excel document, and statistical analysis was performed using SPSS (version 22.0). Data were represented as numbers and percentages. Repeated measures analysis was performed using the Cochran Q test to compare proportions of abnormal laboratory values among 3 groups: baseline, first reading, and second reading. When test results were significant, a post hoc test was used to compare proportions between any 2 groups. Moreover, a Spearman rank correlation was performed to investigate the association between the daily isotretinoin dose and the laboratory parameters. Results with P<.05 were considered statistically significant.

Results

During the study period, treatment with oral isotretinoin was undertaken by 386 patients at KKUH. Several of these patients were excluded due to incomplete medical records. The age of the studied patients ranged from 17 to 60 years, with a median age of 24 years (interquartile range, 20−28 years). The daily administered dose ranged from 10 to 80 mg, with a median dose of 30 mg (interquartile range, 20−40 mg), as illustrated in the Table. Repeated-measures analysis of liver enzymes (AST and ALT), total cholesterol, and TGs is detailed in eTable 1. Eight (2.2%) of 371 patients showed abnormal baseline AST levels. The first follow-up measurements of AST revealed high levels in 7 (1.9%) patients. This figure doubled (14 [3.8%] patients) at the second follow-up, with no statistically significant differences (P>.05). Likewise, ALT showed abnormally high levels at baseline and at both the first and second follow-ups (47/371 [12.7%], 49/371 [13.2%], and 37/371 [10.0%], respectively) with no significant differences (P>.05). Furthermore, the proportions of high cholesterol levels at baseline and at both the first and second follow-ups (40/331 [12.1%], 72/331 [21.8%], and 62/331 [18.7%], respectively) showed a statistically significant difference (P=.001). The proportions of high cholesterol levels in both the first and second follow-ups were significantly higher than the baseline proportions (P=.001 and P=.002, respectively). However, the percentages of high cholesterol were reduced at the second reading relative to the first but with no significant differences. Regarding TGs, there was a statistically significant difference in the proportions of high levels over time (5/320 [1.6%], 12/320 [3.8%], and 14/320 [4.4%] at baseline and at the first and second readings, respectively). Moreover, pairwise comparison among the 3 readings revealed a significant difference between the second follow-up and the baseline levels (P=.048). eTable 2 demonstrates statistically significant positive weak associations between the daily administered isotretinoin dose and each of the cholesterol and TG levels, both at the first and second follow-up readings (P<.05).

Comment

Evaluation of the effects of isotretinoin on liver enzymes and lipids has suggested that oral isotretinoin may cause alterations in liver aminotransferases (AST and ALT) and lipid profiles to various degrees.⁸ Furthermore, there are controversies regarding the routine laboratory monitoring of these patients. Some studies have reported severe alterations in serum liver transaminase and lipid levels, and they support the need for careful monitoring when treating patients with isotretinoin. However, other studies have reported that adverse effects are minimal, with no need for costly laboratory monitoring.⁹

Our study explored the profile of changes in liver aminotransferases (AST and ALT), cholesterol, and TGs in patients with acne who had been treated with oral isotretinoin. The cholesterol levels showed a nonprogressive increase, with a prevalence rate of 21.8% and 18.7% at the first and second follow-ups, respectively. Likewise, the frequency of high TG levels was 3.8% and 4.4%, respectively, with significant differences from the baseline levels (P=.041). However, liver enzymes were less affected by isotretinoin therapy than lipid profiles. Both AST and ALT showed nonsignificant minimal elevations during follow-up of the patients.

Similar to our findings, Zane et al⁶ at the University of California, San Francisco, studied 13,772 patients with acne who underwent oral isotretinoin therapy between 1995 and 2002. They reported a cumulative incidence of new abnormalities in patients with normal values at baseline at a frequency of 44% for TG levels, 31% for total cholesterol levels, and 11% for transaminase levels. Moreover, they suggested that these abnormalities generally were transient and reversible.⁶ Another retrospective study in Brazil included 130 patients who were treated with isotretinoin for 3 months and reported that TG levels had increased beyond the normal range in 11% of patients, whereas 8.6% had elevated AST levels and 7.3% had elevated ALT levels.⁸ Comparable to our findings, Kizilyel et al¹⁰ concluded that isotretinoin appeared to have a greater effect on lipids than on liver enzymes, and they recommended its use with careful monitoring.

The transient effects of isotretinoin therapy on lipid profiles were highlighted in an earlier study. It has been reported that the changes in low-density lipoprotein and TGs returned to baseline levels 2 months following termination of treatment.¹¹ Although many studies have reported alterations in serum transaminase and lipid levels, other studies fail to report any such effects. Alcalay et al⁷ investigated 907 patients who completed a treatment course lasting 5 to 9 months. They reported that only 1.5% of patients had serum TG levels above 400 mg. Additionally, serum levels of liver enzymes were not elevated to a degree necessitating discontinuation of treatment. They concluded that isotretinoin is a safe therapeutic drug and suggested that there is no need for routine laboratory follow-up in young healthy patients apart from a pregnancy test for females.⁷ In addition, Brito et al¹² conducted a prospective clinical and laboratory evaluation of 150 patients being treated with oral isotretinoin prior to the start of therapy, 1 month after therapy initiation, and every 3 months thereafter until the completion of treatment. They found no statistically significant changes in liver transaminase, TG, or cholesterol levels.¹² In another study of 30 participants, Baxter et al¹³ also reported no significant changes in TG or cholesterol levels measured at baseline or during treatment with isotretinoin. Furthermore, a systematic review and meta-analysis has estimated the laboratory changes that occur during isotretinoin therapy of acne vulgaris.¹⁴ The evidence revealed in this study does not support monthly laboratory testing for use of standard doses of oral isotretinoin for the typical patient with acne.

Conclusion

In our study, liver enzymes were less affected than lipids in patients who were treated with isotretinoin. Additionally, laboratory alterations in lipid profiles were nonprogressive and nonsevere. Consequently, isotretinoin may be administered with minimal concern for changes in serum transaminase and lipid profile. However, physicians should exercise caution when administering isotretinoin in patients with a history of abnormal findings.

Introduced in 1982, isotretinoin is a retinoid derivative that has been widely used to treat various dermatologic conditions such as acne vulgaris, rosacea, hidradenitis suppurativa, and hair folliculitis. ¹ It remains one of the most effective drugs for the treatment of all forms of acne vulgaris, especially the nodulocystic type, and exerts its effects via different mechanisms that affect the major domains involved in the pathogenesis of acne. ² One month after treatment initiation, isotretinoin suppresses sebum production by decreasing the size and activity of sebaceous glands. In addition, it notably stabilizes keratinization of the skin and decreases the number of Propionibacterium acnes, which will minimize the inflammation associated with acne. ^3,4 Despite its beneficial effects, isotretinoin therapy has been associated with several complications. The most commonly reported adverse effects include fissured lips, dry skin, eczema, epistaxis, dry eyes, gastrointestinal tract upset, angular stomatitis, and back pain. Less frequent systemic adverse effects have been reported and relate mainly to teratogenicity, pancreatitis, drug-induced hepatotoxicity, leukopenia, and thrombocytopenia. ⁵

Isotretinoin use has been associated with alterations in hepatic and lipid profiles; elevations of serum liver enzymes and triglycerides (TGs) following isotretinoin treatment have been reported.⁴ Consequently, different protocols for laboratory monitoring during isotretinoin therapy have been established and utilized by various health care institutes.⁶ Despite the time and economic investment involved, certain protocols recommend repetition of liver function tests and several other laboratory parameters following a baseline test.⁷ The aim of this study was to determine the prevalence of laboratory changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, and TGs among patients with acne receiving isotretinoin therapy, as well as to link the initial and second laboratory readings of the aforementioned parameters following initiation of isotretinoin treatment.

Materials and Methods

This retrospective cohort design study obtained patient data, including laboratory test results, from the Electronic System for Integrated Health Information at King Khalid University Hospital (KKUH)(Riyadh, Saudi Arabia). All patients older than 16 years who presented with acne vulgaris to the dermatology department at KKUH; who received a course of isotretinoin for at least 4 weeks between 2011 and 2016; and who had available baseline readings of ALT, AST, cholesterol, and TGs, as well as 2 concurrent follow-up readings after isotretinoin treatment initiation, were included in this study. Patients with only 1 reading following treatment initiation and those receiving isotretinoin treatment for reasons other than acne were excluded. This study was approved by the institutional review board of the College of Medicine at King Saud University (Riyadh, Saudi Arabia)(E-18-3310).

Statistical Analysis
Data were entered into a Microsoft Excel document, and statistical analysis was performed using SPSS (version 22.0). Data were represented as numbers and percentages. Repeated measures analysis was performed using the Cochran Q test to compare proportions of abnormal laboratory values among 3 groups: baseline, first reading, and second reading. When test results were significant, a post hoc test was used to compare proportions between any 2 groups. Moreover, a Spearman rank correlation was performed to investigate the association between the daily isotretinoin dose and the laboratory parameters. Results with P<.05 were considered statistically significant.

Results

During the study period, treatment with oral isotretinoin was undertaken by 386 patients at KKUH. Several of these patients were excluded due to incomplete medical records. The age of the studied patients ranged from 17 to 60 years, with a median age of 24 years (interquartile range, 20−28 years). The daily administered dose ranged from 10 to 80 mg, with a median dose of 30 mg (interquartile range, 20−40 mg), as illustrated in the Table. Repeated-measures analysis of liver enzymes (AST and ALT), total cholesterol, and TGs is detailed in eTable 1. Eight (2.2%) of 371 patients showed abnormal baseline AST levels. The first follow-up measurements of AST revealed high levels in 7 (1.9%) patients. This figure doubled (14 [3.8%] patients) at the second follow-up, with no statistically significant differences (P>.05). Likewise, ALT showed abnormally high levels at baseline and at both the first and second follow-ups (47/371 [12.7%], 49/371 [13.2%], and 37/371 [10.0%], respectively) with no significant differences (P>.05). Furthermore, the proportions of high cholesterol levels at baseline and at both the first and second follow-ups (40/331 [12.1%], 72/331 [21.8%], and 62/331 [18.7%], respectively) showed a statistically significant difference (P=.001). The proportions of high cholesterol levels in both the first and second follow-ups were significantly higher than the baseline proportions (P=.001 and P=.002, respectively). However, the percentages of high cholesterol were reduced at the second reading relative to the first but with no significant differences. Regarding TGs, there was a statistically significant difference in the proportions of high levels over time (5/320 [1.6%], 12/320 [3.8%], and 14/320 [4.4%] at baseline and at the first and second readings, respectively). Moreover, pairwise comparison among the 3 readings revealed a significant difference between the second follow-up and the baseline levels (P=.048). eTable 2 demonstrates statistically significant positive weak associations between the daily administered isotretinoin dose and each of the cholesterol and TG levels, both at the first and second follow-up readings (P<.05).

Comment

Evaluation of the effects of isotretinoin on liver enzymes and lipids has suggested that oral isotretinoin may cause alterations in liver aminotransferases (AST and ALT) and lipid profiles to various degrees.⁸ Furthermore, there are controversies regarding the routine laboratory monitoring of these patients. Some studies have reported severe alterations in serum liver transaminase and lipid levels, and they support the need for careful monitoring when treating patients with isotretinoin. However, other studies have reported that adverse effects are minimal, with no need for costly laboratory monitoring.⁹

Our study explored the profile of changes in liver aminotransferases (AST and ALT), cholesterol, and TGs in patients with acne who had been treated with oral isotretinoin. The cholesterol levels showed a nonprogressive increase, with a prevalence rate of 21.8% and 18.7% at the first and second follow-ups, respectively. Likewise, the frequency of high TG levels was 3.8% and 4.4%, respectively, with significant differences from the baseline levels (P=.041). However, liver enzymes were less affected by isotretinoin therapy than lipid profiles. Both AST and ALT showed nonsignificant minimal elevations during follow-up of the patients.

Similar to our findings, Zane et al⁶ at the University of California, San Francisco, studied 13,772 patients with acne who underwent oral isotretinoin therapy between 1995 and 2002. They reported a cumulative incidence of new abnormalities in patients with normal values at baseline at a frequency of 44% for TG levels, 31% for total cholesterol levels, and 11% for transaminase levels. Moreover, they suggested that these abnormalities generally were transient and reversible.⁶ Another retrospective study in Brazil included 130 patients who were treated with isotretinoin for 3 months and reported that TG levels had increased beyond the normal range in 11% of patients, whereas 8.6% had elevated AST levels and 7.3% had elevated ALT levels.⁸ Comparable to our findings, Kizilyel et al¹⁰ concluded that isotretinoin appeared to have a greater effect on lipids than on liver enzymes, and they recommended its use with careful monitoring.

The transient effects of isotretinoin therapy on lipid profiles were highlighted in an earlier study. It has been reported that the changes in low-density lipoprotein and TGs returned to baseline levels 2 months following termination of treatment.¹¹ Although many studies have reported alterations in serum transaminase and lipid levels, other studies fail to report any such effects. Alcalay et al⁷ investigated 907 patients who completed a treatment course lasting 5 to 9 months. They reported that only 1.5% of patients had serum TG levels above 400 mg. Additionally, serum levels of liver enzymes were not elevated to a degree necessitating discontinuation of treatment. They concluded that isotretinoin is a safe therapeutic drug and suggested that there is no need for routine laboratory follow-up in young healthy patients apart from a pregnancy test for females.⁷ In addition, Brito et al¹² conducted a prospective clinical and laboratory evaluation of 150 patients being treated with oral isotretinoin prior to the start of therapy, 1 month after therapy initiation, and every 3 months thereafter until the completion of treatment. They found no statistically significant changes in liver transaminase, TG, or cholesterol levels.¹² In another study of 30 participants, Baxter et al¹³ also reported no significant changes in TG or cholesterol levels measured at baseline or during treatment with isotretinoin. Furthermore, a systematic review and meta-analysis has estimated the laboratory changes that occur during isotretinoin therapy of acne vulgaris.¹⁴ The evidence revealed in this study does not support monthly laboratory testing for use of standard doses of oral isotretinoin for the typical patient with acne.

Conclusion

In our study, liver enzymes were less affected than lipids in patients who were treated with isotretinoin. Additionally, laboratory alterations in lipid profiles were nonprogressive and nonsevere. Consequently, isotretinoin may be administered with minimal concern for changes in serum transaminase and lipid profile. However, physicians should exercise caution when administering isotretinoin in patients with a history of abnormal findings.

To the Editor:

Etanercept is an immune-modulating drug used for the treatment of a variety of diseases including psoriasis, rheumatoid arthritis, and ankylosing spondylitis. It is an anti–tumor necrosis factor (TNF) fusion protein consisting of an extracellular domain of the p75 TNF receptor and the Fc portion of human IgG.¹ Etanercept is well known for its immunosuppressive side effects. A handful of case reports have provided evidence of squamous cell cancers in the setting of etanercept therapy. The most comprehensive description was a case series by Brewer et al² describing 4 patients with squamous cell carcinoma (SCC) that developed 1 to 17 months after the initiation of etanercept therapy. We present a case of a patient diagnosed with psoriasis and concomitant porokeratosis who developed multiple SCCs and squamous proliferations after initiation of etanercept therapy.

A 66-year-old man was referred to our clinic for treatment of psoriasis, as noted on a biopsy of the right ankle diagnosed several years prior. He was being treated with etanercept 50 mg twice weekly. Other treatments included calcipotriene–betamethasone dipropionate, salicylic acid gel, intralesional triamcinolone, clobetasol, and urea 40%. Physical examination revealed multiple erythematous tender nodules with hyperkeratotic scale distributed on the right arm and leg (Figure 1) that were concerning for SCC. Biopsies from 6 lesions revealed multiple SCC/keratoacanthomas (KAs) with verrucous features (Figure 2). Primers for human papillomavirus (HPV) 6, 11, 16, 18, 31, 33, and 51 were all negative. At that time, etanercept was discontinued. The patient was referred for Mohs micrographic surgery and underwent excision of several SCC lesions including an approximately 7-cm SCC on the right ankle (Figure 1B). Positron emission tomography/computed tomography found hypermetabolic lymphadenopathy. A follow-up biopsy of the inguinal nodes identified no malignant cells. Given their multiplicity, the patient was initiated on a prolonged course of a retinoid with acitretin 35 mg daily. The clearance of the large 7-cm lesion with a single stage of Mohs micrographic surgery directed suspicion to a pseudoepitheliomatous or HPV-induced cause for the lesions. Rereview of the original 6 biopsies indicated 1 definitive SCC on the right wrist, 2 KAs, and 3 that were most consistent with verruca vulgaris. At 1-year follow-up, most of the hyperkeratotic lesions had resolved with continued acitretin. Baseline porokeratosis lesions that were abundantly present on the arms and legs resolved by 1-year follow-up (Figure 3A).

The link between classic porokeratosis and the development of squamous cell proliferations is well established. Ninomiya et al³ noted a possible mechanism of p53 overexpression in the epidermis of porokeratotic lesions that may make the lesions particularly susceptible to the development of immunosuppression-induced SCC. Etanercept is an immune-modulating drug with well-known immunosuppressive side effects including reactivation of HPV as well as the development of SCCs.

Our patient initially was diagnosed with psoriasis and etanercept was initiated. The presence of coexistent porokeratosis likely predisposed him to etanercept-induced squamous proliferations including 2 SCCs and verrucous lesions, with histologic features suggesting SCC/KA. Histopathology revealed a cornoid lamella in SCC (Figure 3B), suggesting development of malignancy within epithelial clones, as noted by Lee et al.⁴

Targeted systemic therapies may lead to the formation of SCCs. The association between epidermal growth factor receptor (EGFR) kinase inhibitors and SCC formation is well known. For instance, sorafenib—a multikinase inhibitor that is downstream in the EGFR pathway—has been noted to induce epidermal growths including KAs and SCCs.⁵ There has been no definitive causal relationship identified between the development of SCC and TNF-α inhibitors. It has been suggested that perhaps there is an unmasking effect, as subclinical SCC manifests after TNF-α inhibition that leads to SCC development. Discontinuation of etanercept and resolution of lesions highlights a potential role of TNF-α inhibition and tumorigenesis of SCCs, especially in the background of porokeratosis. Vigilance for development of immunosuppression-induced malignancy, especially squamous cell proliferations, has become exceedingly important with exponentially increasing use of biologic therapies in medicine.

To the Editor:

Etanercept is an immune-modulating drug used for the treatment of a variety of diseases including psoriasis, rheumatoid arthritis, and ankylosing spondylitis. It is an anti–tumor necrosis factor (TNF) fusion protein consisting of an extracellular domain of the p75 TNF receptor and the Fc portion of human IgG.¹ Etanercept is well known for its immunosuppressive side effects. A handful of case reports have provided evidence of squamous cell cancers in the setting of etanercept therapy. The most comprehensive description was a case series by Brewer et al² describing 4 patients with squamous cell carcinoma (SCC) that developed 1 to 17 months after the initiation of etanercept therapy. We present a case of a patient diagnosed with psoriasis and concomitant porokeratosis who developed multiple SCCs and squamous proliferations after initiation of etanercept therapy.

A 66-year-old man was referred to our clinic for treatment of psoriasis, as noted on a biopsy of the right ankle diagnosed several years prior. He was being treated with etanercept 50 mg twice weekly. Other treatments included calcipotriene–betamethasone dipropionate, salicylic acid gel, intralesional triamcinolone, clobetasol, and urea 40%. Physical examination revealed multiple erythematous tender nodules with hyperkeratotic scale distributed on the right arm and leg (Figure 1) that were concerning for SCC. Biopsies from 6 lesions revealed multiple SCC/keratoacanthomas (KAs) with verrucous features (Figure 2). Primers for human papillomavirus (HPV) 6, 11, 16, 18, 31, 33, and 51 were all negative. At that time, etanercept was discontinued. The patient was referred for Mohs micrographic surgery and underwent excision of several SCC lesions including an approximately 7-cm SCC on the right ankle (Figure 1B). Positron emission tomography/computed tomography found hypermetabolic lymphadenopathy. A follow-up biopsy of the inguinal nodes identified no malignant cells. Given their multiplicity, the patient was initiated on a prolonged course of a retinoid with acitretin 35 mg daily. The clearance of the large 7-cm lesion with a single stage of Mohs micrographic surgery directed suspicion to a pseudoepitheliomatous or HPV-induced cause for the lesions. Rereview of the original 6 biopsies indicated 1 definitive SCC on the right wrist, 2 KAs, and 3 that were most consistent with verruca vulgaris. At 1-year follow-up, most of the hyperkeratotic lesions had resolved with continued acitretin. Baseline porokeratosis lesions that were abundantly present on the arms and legs resolved by 1-year follow-up (Figure 3A).

The link between classic porokeratosis and the development of squamous cell proliferations is well established. Ninomiya et al³ noted a possible mechanism of p53 overexpression in the epidermis of porokeratotic lesions that may make the lesions particularly susceptible to the development of immunosuppression-induced SCC. Etanercept is an immune-modulating drug with well-known immunosuppressive side effects including reactivation of HPV as well as the development of SCCs.

Our patient initially was diagnosed with psoriasis and etanercept was initiated. The presence of coexistent porokeratosis likely predisposed him to etanercept-induced squamous proliferations including 2 SCCs and verrucous lesions, with histologic features suggesting SCC/KA. Histopathology revealed a cornoid lamella in SCC (Figure 3B), suggesting development of malignancy within epithelial clones, as noted by Lee et al.⁴

Targeted systemic therapies may lead to the formation of SCCs. The association between epidermal growth factor receptor (EGFR) kinase inhibitors and SCC formation is well known. For instance, sorafenib—a multikinase inhibitor that is downstream in the EGFR pathway—has been noted to induce epidermal growths including KAs and SCCs.⁵ There has been no definitive causal relationship identified between the development of SCC and TNF-α inhibitors. It has been suggested that perhaps there is an unmasking effect, as subclinical SCC manifests after TNF-α inhibition that leads to SCC development. Discontinuation of etanercept and resolution of lesions highlights a potential role of TNF-α inhibition and tumorigenesis of SCCs, especially in the background of porokeratosis. Vigilance for development of immunosuppression-induced malignancy, especially squamous cell proliferations, has become exceedingly important with exponentially increasing use of biologic therapies in medicine.

To the Editor:

Etanercept is an immune-modulating drug used for the treatment of a variety of diseases including psoriasis, rheumatoid arthritis, and ankylosing spondylitis. It is an anti–tumor necrosis factor (TNF) fusion protein consisting of an extracellular domain of the p75 TNF receptor and the Fc portion of human IgG.¹ Etanercept is well known for its immunosuppressive side effects. A handful of case reports have provided evidence of squamous cell cancers in the setting of etanercept therapy. The most comprehensive description was a case series by Brewer et al² describing 4 patients with squamous cell carcinoma (SCC) that developed 1 to 17 months after the initiation of etanercept therapy. We present a case of a patient diagnosed with psoriasis and concomitant porokeratosis who developed multiple SCCs and squamous proliferations after initiation of etanercept therapy.

A 66-year-old man was referred to our clinic for treatment of psoriasis, as noted on a biopsy of the right ankle diagnosed several years prior. He was being treated with etanercept 50 mg twice weekly. Other treatments included calcipotriene–betamethasone dipropionate, salicylic acid gel, intralesional triamcinolone, clobetasol, and urea 40%. Physical examination revealed multiple erythematous tender nodules with hyperkeratotic scale distributed on the right arm and leg (Figure 1) that were concerning for SCC. Biopsies from 6 lesions revealed multiple SCC/keratoacanthomas (KAs) with verrucous features (Figure 2). Primers for human papillomavirus (HPV) 6, 11, 16, 18, 31, 33, and 51 were all negative. At that time, etanercept was discontinued. The patient was referred for Mohs micrographic surgery and underwent excision of several SCC lesions including an approximately 7-cm SCC on the right ankle (Figure 1B). Positron emission tomography/computed tomography found hypermetabolic lymphadenopathy. A follow-up biopsy of the inguinal nodes identified no malignant cells. Given their multiplicity, the patient was initiated on a prolonged course of a retinoid with acitretin 35 mg daily. The clearance of the large 7-cm lesion with a single stage of Mohs micrographic surgery directed suspicion to a pseudoepitheliomatous or HPV-induced cause for the lesions. Rereview of the original 6 biopsies indicated 1 definitive SCC on the right wrist, 2 KAs, and 3 that were most consistent with verruca vulgaris. At 1-year follow-up, most of the hyperkeratotic lesions had resolved with continued acitretin. Baseline porokeratosis lesions that were abundantly present on the arms and legs resolved by 1-year follow-up (Figure 3A).

The link between classic porokeratosis and the development of squamous cell proliferations is well established. Ninomiya et al³ noted a possible mechanism of p53 overexpression in the epidermis of porokeratotic lesions that may make the lesions particularly susceptible to the development of immunosuppression-induced SCC. Etanercept is an immune-modulating drug with well-known immunosuppressive side effects including reactivation of HPV as well as the development of SCCs.

Our patient initially was diagnosed with psoriasis and etanercept was initiated. The presence of coexistent porokeratosis likely predisposed him to etanercept-induced squamous proliferations including 2 SCCs and verrucous lesions, with histologic features suggesting SCC/KA. Histopathology revealed a cornoid lamella in SCC (Figure 3B), suggesting development of malignancy within epithelial clones, as noted by Lee et al.⁴

Targeted systemic therapies may lead to the formation of SCCs. The association between epidermal growth factor receptor (EGFR) kinase inhibitors and SCC formation is well known. For instance, sorafenib—a multikinase inhibitor that is downstream in the EGFR pathway—has been noted to induce epidermal growths including KAs and SCCs.⁵ There has been no definitive causal relationship identified between the development of SCC and TNF-α inhibitors. It has been suggested that perhaps there is an unmasking effect, as subclinical SCC manifests after TNF-α inhibition that leads to SCC development. Discontinuation of etanercept and resolution of lesions highlights a potential role of TNF-α inhibition and tumorigenesis of SCCs, especially in the background of porokeratosis. Vigilance for development of immunosuppression-induced malignancy, especially squamous cell proliferations, has become exceedingly important with exponentially increasing use of biologic therapies in medicine.

To the Editor:

A 56-year-old man with a history of stage IV metastatic penile squamous cell carcinoma treated with penectomy and chemotherapy with 5-fluorouracil and cisplatin presented with several painful ulcerations in the groin, abdomen, and thighs. The lesions initially appeared in the groin and were treated as bacterial abscesses with antibiotics. Over the next few weeks, new lesions appeared on the abdomen and thighs. An additional cycle of chemotherapy led to a reduction in number; however, they again increased within a few weeks. Medications included enoxaparin followed by 3 weeks of warfarin use due to a right leg deep vein thrombosis.

Physical examination revealed multiple 1- to 4-cm, firm, ulcerated nodules on the bilateral inguinal folds, abdomen, and upper thighs, as well as areas of livedo racemosa and noninflammatory retiform purpura with central ulceration (Figures 1 and 2). This retiform purpura was both perilesional and in areas without ulcerations. Laboratory values included the following: sodium, 127 mmol/L (reference range, 136–145 mmol/L); prothrombin time, 16.1 seconds (reference range, 11–15 seconds); white blood cell count, 20.69×10⁹/L (reference range, 4.5–11.0×10⁹/L) with 87% neutrophils (reference range, 54%–62%); hemoglobin, 6.1 g/dL (reference range, 13.5–17.5 g/dL); hematocrit, 18.8% (reference range, 41%–53%); platelets, 474×10⁹/L (reference range, 150–400×10⁹/L); D-dimer, 0.77 mg/L (reference range, ≤0.50 mg/L); fibrinogen, 489 mg/dL (reference range, 150–400 mg/dL); prior urine culture positive for Pseudomonas aeruginosa. He was negative for hepatitis B and hepatitis C viruses as well as HIV, and the lesions were not clinically consistent with herpes simplex virus, as they were not scalloped or circinate. Punch biopsies were obtained from a nodule on the left leg and a purpuric patch on the right leg.

Ischemic cutaneous lesions less commonly occur in the setting of malignancy and can be the result of both direct and indirect systemic effects from the cancer. Malignancies are known to directly trigger vasculopathies in other organs, most commonly the lungs, through 2 primary mechanisms. First, in carcinomatous arteriopathy, metastatic cells promote fibrocellular intimal proliferation of small pulmonary arteries and arterioles leading to stenosis, thrombosis, and obliteration. This mechanism has been described in pulmonary thrombotic microangiopathy secondary to lung carcinoma.⁴ This pathophysiology likely is also what underlies paraneoplastic acral vascular syndromes, which culminate in digital ischemia. Hypothesized mechanisms for this ischemia also range from vasospasm to thromboembolism.⁵ Secondly, in vasculitis carcinomatosa, metastatic tumor cells damage or block vessel walls, resulting in end-organ ischemia. Vasculitis carcinomatosa is a well-known phenomenon in angiocentric and intravascular lymphoid malignancies (typically of B-T or natural killer/T-cell origin) but also has been reported in a case of gastric adenocarcinoma with arterial invasion.⁶ This process is different than carcinoma telangiectoides where malignant cells may be present in the vasculature on histopathology but not trigger thrombosis and ischemic skin necrosis.

Systemic coagulopathies such as disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia purpura, and catastrophic antiphospholipid antibody syndrome can occur in the setting of malignancies.⁷ Clinically, all may present with livedo racemosa, noninflammatory retiform purpura, and widespread skin necrosis. In adult patients, purpura fulminans most often is seen in the setting of sepsis and DIC, with accompanying evidence of microangiopathy.⁸ Catastrophic antiphospholipid antibody syndrome can be triggered by malignancy and is characterized by central nervous system, renal, pulmonary, and gastrointestinal complications. Skin involvement such as ulcers, livedo reticularis, and gangrene have been reported.⁹ Other causes of thrombotic vasculopathy include warfarin necrosis, heparin-induced thrombotic thrombocytopenia, calciphylaxis, and angioinvasive infections.⁸ Warfarin necrosis and heparin-induced thrombotic thrombocytopenia typically present days after initiating therapy with the respective medication. Calciphylaxis typically occurs in patients on dialysis, though it may occur in nonuremic patients including those with malignancy.⁸ Patients with malignancies on chemotherapy can become neutropenic and are at risk for ecthyma gangrenosum due to P aeruginosa and other gram-negative rods, Staphylococcus aureus, and angioinvasive fungi.¹⁰

Based on clinical, histopathological, and laboratory data, we favored a diagnosis of cutaneous carcinomatous arteriopathy. Vasculitis carcinomatosa was a possibility despite the lack of vasculotropism on histopathology, which may have been due to biopsy site selection. Systemic coagulopathies such as DIC, thrombotic thrombocytopenia purpura, and catastrophic antiphospholipid antibody syndrome were unlikely, as the ischemic skin lesions and livedo racemosa were limited to areas adjacent to cutaneous metastases, and the patient lacked other common multiorgan manifestations or laboratory findings. Although our patient was on warfarin, he was on a stable dose for weeks and histopathologic features of subcutaneous thrombosis were not seen. The biopsy also was not consistent with calciphylaxis. Ecthyma gangrenosum was unlikely given the lack of organisms on histopathology and negative skin and blood cultures. Although additional laboratory testing in this patient may have included cryoglobulins and cryofibrinogens, both entities were unlikely due to a lack of ischemic acral lesions.

In conclusion, we present a case of localized thrombotic vasculopathy that likely was secondary to cutaneous carcinomatous arteriopathy in the setting of cutaneous metastatic penile squamous cell carcinoma. The differential diagnosis of retiform purpura, livedo racemosa, and other signs of cutaneous ischemia in patients with metastatic cancer is broad and can be the result of both direct and indirect systemic effects from the cancer. Appropriate workup in these cases should include skin biopsies for histopathology and culture, medication review, and laboratory evaluation for systemic coagulopathies.

To the Editor:

A 56-year-old man with a history of stage IV metastatic penile squamous cell carcinoma treated with penectomy and chemotherapy with 5-fluorouracil and cisplatin presented with several painful ulcerations in the groin, abdomen, and thighs. The lesions initially appeared in the groin and were treated as bacterial abscesses with antibiotics. Over the next few weeks, new lesions appeared on the abdomen and thighs. An additional cycle of chemotherapy led to a reduction in number; however, they again increased within a few weeks. Medications included enoxaparin followed by 3 weeks of warfarin use due to a right leg deep vein thrombosis.

Physical examination revealed multiple 1- to 4-cm, firm, ulcerated nodules on the bilateral inguinal folds, abdomen, and upper thighs, as well as areas of livedo racemosa and noninflammatory retiform purpura with central ulceration (Figures 1 and 2). This retiform purpura was both perilesional and in areas without ulcerations. Laboratory values included the following: sodium, 127 mmol/L (reference range, 136–145 mmol/L); prothrombin time, 16.1 seconds (reference range, 11–15 seconds); white blood cell count, 20.69×10⁹/L (reference range, 4.5–11.0×10⁹/L) with 87% neutrophils (reference range, 54%–62%); hemoglobin, 6.1 g/dL (reference range, 13.5–17.5 g/dL); hematocrit, 18.8% (reference range, 41%–53%); platelets, 474×10⁹/L (reference range, 150–400×10⁹/L); D-dimer, 0.77 mg/L (reference range, ≤0.50 mg/L); fibrinogen, 489 mg/dL (reference range, 150–400 mg/dL); prior urine culture positive for Pseudomonas aeruginosa. He was negative for hepatitis B and hepatitis C viruses as well as HIV, and the lesions were not clinically consistent with herpes simplex virus, as they were not scalloped or circinate. Punch biopsies were obtained from a nodule on the left leg and a purpuric patch on the right leg.

Ischemic cutaneous lesions less commonly occur in the setting of malignancy and can be the result of both direct and indirect systemic effects from the cancer. Malignancies are known to directly trigger vasculopathies in other organs, most commonly the lungs, through 2 primary mechanisms. First, in carcinomatous arteriopathy, metastatic cells promote fibrocellular intimal proliferation of small pulmonary arteries and arterioles leading to stenosis, thrombosis, and obliteration. This mechanism has been described in pulmonary thrombotic microangiopathy secondary to lung carcinoma.⁴ This pathophysiology likely is also what underlies paraneoplastic acral vascular syndromes, which culminate in digital ischemia. Hypothesized mechanisms for this ischemia also range from vasospasm to thromboembolism.⁵ Secondly, in vasculitis carcinomatosa, metastatic tumor cells damage or block vessel walls, resulting in end-organ ischemia. Vasculitis carcinomatosa is a well-known phenomenon in angiocentric and intravascular lymphoid malignancies (typically of B-T or natural killer/T-cell origin) but also has been reported in a case of gastric adenocarcinoma with arterial invasion.⁶ This process is different than carcinoma telangiectoides where malignant cells may be present in the vasculature on histopathology but not trigger thrombosis and ischemic skin necrosis.

Systemic coagulopathies such as disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia purpura, and catastrophic antiphospholipid antibody syndrome can occur in the setting of malignancies.⁷ Clinically, all may present with livedo racemosa, noninflammatory retiform purpura, and widespread skin necrosis. In adult patients, purpura fulminans most often is seen in the setting of sepsis and DIC, with accompanying evidence of microangiopathy.⁸ Catastrophic antiphospholipid antibody syndrome can be triggered by malignancy and is characterized by central nervous system, renal, pulmonary, and gastrointestinal complications. Skin involvement such as ulcers, livedo reticularis, and gangrene have been reported.⁹ Other causes of thrombotic vasculopathy include warfarin necrosis, heparin-induced thrombotic thrombocytopenia, calciphylaxis, and angioinvasive infections.⁸ Warfarin necrosis and heparin-induced thrombotic thrombocytopenia typically present days after initiating therapy with the respective medication. Calciphylaxis typically occurs in patients on dialysis, though it may occur in nonuremic patients including those with malignancy.⁸ Patients with malignancies on chemotherapy can become neutropenic and are at risk for ecthyma gangrenosum due to P aeruginosa and other gram-negative rods, Staphylococcus aureus, and angioinvasive fungi.¹⁰

Based on clinical, histopathological, and laboratory data, we favored a diagnosis of cutaneous carcinomatous arteriopathy. Vasculitis carcinomatosa was a possibility despite the lack of vasculotropism on histopathology, which may have been due to biopsy site selection. Systemic coagulopathies such as DIC, thrombotic thrombocytopenia purpura, and catastrophic antiphospholipid antibody syndrome were unlikely, as the ischemic skin lesions and livedo racemosa were limited to areas adjacent to cutaneous metastases, and the patient lacked other common multiorgan manifestations or laboratory findings. Although our patient was on warfarin, he was on a stable dose for weeks and histopathologic features of subcutaneous thrombosis were not seen. The biopsy also was not consistent with calciphylaxis. Ecthyma gangrenosum was unlikely given the lack of organisms on histopathology and negative skin and blood cultures. Although additional laboratory testing in this patient may have included cryoglobulins and cryofibrinogens, both entities were unlikely due to a lack of ischemic acral lesions.

In conclusion, we present a case of localized thrombotic vasculopathy that likely was secondary to cutaneous carcinomatous arteriopathy in the setting of cutaneous metastatic penile squamous cell carcinoma. The differential diagnosis of retiform purpura, livedo racemosa, and other signs of cutaneous ischemia in patients with metastatic cancer is broad and can be the result of both direct and indirect systemic effects from the cancer. Appropriate workup in these cases should include skin biopsies for histopathology and culture, medication review, and laboratory evaluation for systemic coagulopathies.

To the Editor:

A 56-year-old man with a history of stage IV metastatic penile squamous cell carcinoma treated with penectomy and chemotherapy with 5-fluorouracil and cisplatin presented with several painful ulcerations in the groin, abdomen, and thighs. The lesions initially appeared in the groin and were treated as bacterial abscesses with antibiotics. Over the next few weeks, new lesions appeared on the abdomen and thighs. An additional cycle of chemotherapy led to a reduction in number; however, they again increased within a few weeks. Medications included enoxaparin followed by 3 weeks of warfarin use due to a right leg deep vein thrombosis.

Physical examination revealed multiple 1- to 4-cm, firm, ulcerated nodules on the bilateral inguinal folds, abdomen, and upper thighs, as well as areas of livedo racemosa and noninflammatory retiform purpura with central ulceration (Figures 1 and 2). This retiform purpura was both perilesional and in areas without ulcerations. Laboratory values included the following: sodium, 127 mmol/L (reference range, 136–145 mmol/L); prothrombin time, 16.1 seconds (reference range, 11–15 seconds); white blood cell count, 20.69×10⁹/L (reference range, 4.5–11.0×10⁹/L) with 87% neutrophils (reference range, 54%–62%); hemoglobin, 6.1 g/dL (reference range, 13.5–17.5 g/dL); hematocrit, 18.8% (reference range, 41%–53%); platelets, 474×10⁹/L (reference range, 150–400×10⁹/L); D-dimer, 0.77 mg/L (reference range, ≤0.50 mg/L); fibrinogen, 489 mg/dL (reference range, 150–400 mg/dL); prior urine culture positive for Pseudomonas aeruginosa. He was negative for hepatitis B and hepatitis C viruses as well as HIV, and the lesions were not clinically consistent with herpes simplex virus, as they were not scalloped or circinate. Punch biopsies were obtained from a nodule on the left leg and a purpuric patch on the right leg.

Ischemic cutaneous lesions less commonly occur in the setting of malignancy and can be the result of both direct and indirect systemic effects from the cancer. Malignancies are known to directly trigger vasculopathies in other organs, most commonly the lungs, through 2 primary mechanisms. First, in carcinomatous arteriopathy, metastatic cells promote fibrocellular intimal proliferation of small pulmonary arteries and arterioles leading to stenosis, thrombosis, and obliteration. This mechanism has been described in pulmonary thrombotic microangiopathy secondary to lung carcinoma.⁴ This pathophysiology likely is also what underlies paraneoplastic acral vascular syndromes, which culminate in digital ischemia. Hypothesized mechanisms for this ischemia also range from vasospasm to thromboembolism.⁵ Secondly, in vasculitis carcinomatosa, metastatic tumor cells damage or block vessel walls, resulting in end-organ ischemia. Vasculitis carcinomatosa is a well-known phenomenon in angiocentric and intravascular lymphoid malignancies (typically of B-T or natural killer/T-cell origin) but also has been reported in a case of gastric adenocarcinoma with arterial invasion.⁶ This process is different than carcinoma telangiectoides where malignant cells may be present in the vasculature on histopathology but not trigger thrombosis and ischemic skin necrosis.

Systemic coagulopathies such as disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia purpura, and catastrophic antiphospholipid antibody syndrome can occur in the setting of malignancies.⁷ Clinically, all may present with livedo racemosa, noninflammatory retiform purpura, and widespread skin necrosis. In adult patients, purpura fulminans most often is seen in the setting of sepsis and DIC, with accompanying evidence of microangiopathy.⁸ Catastrophic antiphospholipid antibody syndrome can be triggered by malignancy and is characterized by central nervous system, renal, pulmonary, and gastrointestinal complications. Skin involvement such as ulcers, livedo reticularis, and gangrene have been reported.⁹ Other causes of thrombotic vasculopathy include warfarin necrosis, heparin-induced thrombotic thrombocytopenia, calciphylaxis, and angioinvasive infections.⁸ Warfarin necrosis and heparin-induced thrombotic thrombocytopenia typically present days after initiating therapy with the respective medication. Calciphylaxis typically occurs in patients on dialysis, though it may occur in nonuremic patients including those with malignancy.⁸ Patients with malignancies on chemotherapy can become neutropenic and are at risk for ecthyma gangrenosum due to P aeruginosa and other gram-negative rods, Staphylococcus aureus, and angioinvasive fungi.¹⁰

Based on clinical, histopathological, and laboratory data, we favored a diagnosis of cutaneous carcinomatous arteriopathy. Vasculitis carcinomatosa was a possibility despite the lack of vasculotropism on histopathology, which may have been due to biopsy site selection. Systemic coagulopathies such as DIC, thrombotic thrombocytopenia purpura, and catastrophic antiphospholipid antibody syndrome were unlikely, as the ischemic skin lesions and livedo racemosa were limited to areas adjacent to cutaneous metastases, and the patient lacked other common multiorgan manifestations or laboratory findings. Although our patient was on warfarin, he was on a stable dose for weeks and histopathologic features of subcutaneous thrombosis were not seen. The biopsy also was not consistent with calciphylaxis. Ecthyma gangrenosum was unlikely given the lack of organisms on histopathology and negative skin and blood cultures. Although additional laboratory testing in this patient may have included cryoglobulins and cryofibrinogens, both entities were unlikely due to a lack of ischemic acral lesions.

In conclusion, we present a case of localized thrombotic vasculopathy that likely was secondary to cutaneous carcinomatous arteriopathy in the setting of cutaneous metastatic penile squamous cell carcinoma. The differential diagnosis of retiform purpura, livedo racemosa, and other signs of cutaneous ischemia in patients with metastatic cancer is broad and can be the result of both direct and indirect systemic effects from the cancer. Appropriate workup in these cases should include skin biopsies for histopathology and culture, medication review, and laboratory evaluation for systemic coagulopathies.

Intraosseous (IO) access can afford a lifesaving means of vascular access in emergency settings, as it allows for the administration of large volumes of fluids, blood products, and medications at high flow rates directly into the highly vascularized osseous medullary cavity.¹ Fortunately, the complication rate with this resuscitative effort is low, with many reports demonstrating complication rates of less than 1%.² The most commonly reported complications include fluid extravasation, osteomyelitis, traumatic bone fracture, and epiphyseal plate damage.^1-3 Although compartment syndrome and skin necrosis have been reported,^4,5 there is no comprehensive list of sequelae resulting from fluid extravasation in the literature, and there are no known studies examining the incidence and types of cutaneous complications. In this study, we sought to evaluate the dermatologic impacts of this procedure.

Methods

We performed a retrospective chart review approved by the institutional review board at a large metropolitan level I trauma center in the Midwestern United States spanning 18 consecutive months to identify all patients who underwent IO line placement, either en route to or upon arrival at the trauma center. The electronic medical records of 113 patients (age range, 10 days–94 years) were identified using either an automated natural language look-up program with keywords including intraosseous access and IO or a Current Procedural Terminology code 36680. Data including patient age, reason for IO insertion, anatomic location of the IO, and complications secondary to IO line placement were recorded.

Results

We identified an overall complication rate of 2.7% (3/113), with only 1 patient showing isolated cutaneous complications from IO line placement. The complications in the first 2 patients included compartment syndrome following IO line placement in the right tibia and needle breakage during IO line placement. The third patient, a 30-year-old heart transplant recipient, developed tense bullae on the left leg 5 days after a resuscitative effort required IO access through the bilateral tibiae. The patient had received vasopressors as well as 750 mL of normal saline through these access points. Two days after resuscitation, she developed an enlarging ecchymosis around the left IO access point. On day 5, cutaneous findings included 2 large firm bullae on a purpuric base overlying the left proximal tibia and patella (Figure 1). After an ultrasound revealed no connection to the underlying joint space, the bullae were incised and drained for patient comfort, as she reported pain and undue pressure at the knee joint on initial dermatologic consultation. These symptoms abated after the procedure. Cultures of bullous fluid were negative for infection. Histopathologic examination revealed a subepidermal split with underlying minimal mixed inflammation, favoring the diagnosis of traumatic bullae.

At a scheduled 7-month dermatology follow-up, the wound bed appeared to be healing well with surrounding scarring with no residual bleeding or drainage (Figure 2) despite the patient reporting a protracted course of wound healing requiring debridement due to eschar formation and multiple follow-up appointments with the wound care service.

Comment

The most commonly reported complications with IO line placement result from fluid infiltration of the subcutaneous tissue secondary to catheter misplacement.^1,3 Extravasated fluid may lead to tissue damage, compartment syndrome, and even tissue necrosis in some cases.^1,4,5 Localized cellulitis and the formation of subcutaneous abscesses also have been reported, albeit rarely.^3,5

In our retrospective cohort review, we identified an additional potential complication of IO line placement that has not been widely reported—development of large traumatic bullae. It is most likely that this patient’s IO catheter became dislodged, resulting in extravasation of fluids into the dermal and subcutaneous tissues.

Our findings support the previously noted complication rate of less than 1% following IO line placement, with an overall complication rate of 2.7% that included only 1 patient with a cutaneous complication.² Given this low incidence, providers may not be used to recognizing such complications, leading to delayed or incorrect diagnosis of these entities. While there are certain conditions in which IO insertion is contraindicated, including severe bone diseases (eg, osteogenesis imperfecta, osteomyelitis), overlying cellulitis, and bone fracture, these conditions are rare and can be avoided in most cases by use of an alternative site for needle insertion.² Due to the widespread utility of this tool and its few contraindications, its use in hospitalized patients is rapidly increasing, necessitating a need for quick recognition of potential complications.

From previous data on the incidence of traumatic blisters with underlying bone fractures, there are several identifiable risk factors that could be extended to patients at high risk for developing cutaneous IO complications secondary to the trauma associated with needle insertion,⁶ including wound-healing impairments in patients with fragile lymphatics, peripheral vascular disease, diabetes, or collagen vascular diseases (eg, lupus, rheumatoid arthritis, Sjögren syndrome). Patients with these conditions should be closely monitored for the development of bullae.⁶ While the patient we highlighted in our study did not have a history of such conditions, her history of cardiac disease, recent resuscitation attempts, and immunosuppression certainly could have contributed to suboptimal tissue agility and repair after IO line placement.

Conclusion

Intraosseous access is a safe, effective, and reliable option for vascular access in both pediatric and adult populations that is widely used in both prehospital (ie, paramedic administered) and hospital settings, including intensive care units, emergency departments, and any acute situation where rapid vascular access is necessary. This retrospective chart review examining the incidence and types of cutaneous complications associated with IO line placement at a level I trauma center revealed a total complication rate similar to those reported in previous studies and also highlighted a unique postprocedural cutaneous finding of traumatic bullae. Although no unified management recommendations currently exist, providers should consider this complication in the differential for hospitalized patients with large, atypical, asymmetric bullae in the absence of an alternative explanation for such skin findings.

Intraosseous (IO) access can afford a lifesaving means of vascular access in emergency settings, as it allows for the administration of large volumes of fluids, blood products, and medications at high flow rates directly into the highly vascularized osseous medullary cavity.¹ Fortunately, the complication rate with this resuscitative effort is low, with many reports demonstrating complication rates of less than 1%.² The most commonly reported complications include fluid extravasation, osteomyelitis, traumatic bone fracture, and epiphyseal plate damage.^1-3 Although compartment syndrome and skin necrosis have been reported,^4,5 there is no comprehensive list of sequelae resulting from fluid extravasation in the literature, and there are no known studies examining the incidence and types of cutaneous complications. In this study, we sought to evaluate the dermatologic impacts of this procedure.

Methods

We performed a retrospective chart review approved by the institutional review board at a large metropolitan level I trauma center in the Midwestern United States spanning 18 consecutive months to identify all patients who underwent IO line placement, either en route to or upon arrival at the trauma center. The electronic medical records of 113 patients (age range, 10 days–94 years) were identified using either an automated natural language look-up program with keywords including intraosseous access and IO or a Current Procedural Terminology code 36680. Data including patient age, reason for IO insertion, anatomic location of the IO, and complications secondary to IO line placement were recorded.

Results

We identified an overall complication rate of 2.7% (3/113), with only 1 patient showing isolated cutaneous complications from IO line placement. The complications in the first 2 patients included compartment syndrome following IO line placement in the right tibia and needle breakage during IO line placement. The third patient, a 30-year-old heart transplant recipient, developed tense bullae on the left leg 5 days after a resuscitative effort required IO access through the bilateral tibiae. The patient had received vasopressors as well as 750 mL of normal saline through these access points. Two days after resuscitation, she developed an enlarging ecchymosis around the left IO access point. On day 5, cutaneous findings included 2 large firm bullae on a purpuric base overlying the left proximal tibia and patella (Figure 1). After an ultrasound revealed no connection to the underlying joint space, the bullae were incised and drained for patient comfort, as she reported pain and undue pressure at the knee joint on initial dermatologic consultation. These symptoms abated after the procedure. Cultures of bullous fluid were negative for infection. Histopathologic examination revealed a subepidermal split with underlying minimal mixed inflammation, favoring the diagnosis of traumatic bullae.

At a scheduled 7-month dermatology follow-up, the wound bed appeared to be healing well with surrounding scarring with no residual bleeding or drainage (Figure 2) despite the patient reporting a protracted course of wound healing requiring debridement due to eschar formation and multiple follow-up appointments with the wound care service.

Comment

The most commonly reported complications with IO line placement result from fluid infiltration of the subcutaneous tissue secondary to catheter misplacement.^1,3 Extravasated fluid may lead to tissue damage, compartment syndrome, and even tissue necrosis in some cases.^1,4,5 Localized cellulitis and the formation of subcutaneous abscesses also have been reported, albeit rarely.^3,5

In our retrospective cohort review, we identified an additional potential complication of IO line placement that has not been widely reported—development of large traumatic bullae. It is most likely that this patient’s IO catheter became dislodged, resulting in extravasation of fluids into the dermal and subcutaneous tissues.

Our findings support the previously noted complication rate of less than 1% following IO line placement, with an overall complication rate of 2.7% that included only 1 patient with a cutaneous complication.² Given this low incidence, providers may not be used to recognizing such complications, leading to delayed or incorrect diagnosis of these entities. While there are certain conditions in which IO insertion is contraindicated, including severe bone diseases (eg, osteogenesis imperfecta, osteomyelitis), overlying cellulitis, and bone fracture, these conditions are rare and can be avoided in most cases by use of an alternative site for needle insertion.² Due to the widespread utility of this tool and its few contraindications, its use in hospitalized patients is rapidly increasing, necessitating a need for quick recognition of potential complications.

From previous data on the incidence of traumatic blisters with underlying bone fractures, there are several identifiable risk factors that could be extended to patients at high risk for developing cutaneous IO complications secondary to the trauma associated with needle insertion,⁶ including wound-healing impairments in patients with fragile lymphatics, peripheral vascular disease, diabetes, or collagen vascular diseases (eg, lupus, rheumatoid arthritis, Sjögren syndrome). Patients with these conditions should be closely monitored for the development of bullae.⁶ While the patient we highlighted in our study did not have a history of such conditions, her history of cardiac disease, recent resuscitation attempts, and immunosuppression certainly could have contributed to suboptimal tissue agility and repair after IO line placement.

Conclusion

Intraosseous access is a safe, effective, and reliable option for vascular access in both pediatric and adult populations that is widely used in both prehospital (ie, paramedic administered) and hospital settings, including intensive care units, emergency departments, and any acute situation where rapid vascular access is necessary. This retrospective chart review examining the incidence and types of cutaneous complications associated with IO line placement at a level I trauma center revealed a total complication rate similar to those reported in previous studies and also highlighted a unique postprocedural cutaneous finding of traumatic bullae. Although no unified management recommendations currently exist, providers should consider this complication in the differential for hospitalized patients with large, atypical, asymmetric bullae in the absence of an alternative explanation for such skin findings.

Intraosseous (IO) access can afford a lifesaving means of vascular access in emergency settings, as it allows for the administration of large volumes of fluids, blood products, and medications at high flow rates directly into the highly vascularized osseous medullary cavity.¹ Fortunately, the complication rate with this resuscitative effort is low, with many reports demonstrating complication rates of less than 1%.² The most commonly reported complications include fluid extravasation, osteomyelitis, traumatic bone fracture, and epiphyseal plate damage.^1-3 Although compartment syndrome and skin necrosis have been reported,^4,5 there is no comprehensive list of sequelae resulting from fluid extravasation in the literature, and there are no known studies examining the incidence and types of cutaneous complications. In this study, we sought to evaluate the dermatologic impacts of this procedure.

Methods

We performed a retrospective chart review approved by the institutional review board at a large metropolitan level I trauma center in the Midwestern United States spanning 18 consecutive months to identify all patients who underwent IO line placement, either en route to or upon arrival at the trauma center. The electronic medical records of 113 patients (age range, 10 days–94 years) were identified using either an automated natural language look-up program with keywords including intraosseous access and IO or a Current Procedural Terminology code 36680. Data including patient age, reason for IO insertion, anatomic location of the IO, and complications secondary to IO line placement were recorded.

Results

We identified an overall complication rate of 2.7% (3/113), with only 1 patient showing isolated cutaneous complications from IO line placement. The complications in the first 2 patients included compartment syndrome following IO line placement in the right tibia and needle breakage during IO line placement. The third patient, a 30-year-old heart transplant recipient, developed tense bullae on the left leg 5 days after a resuscitative effort required IO access through the bilateral tibiae. The patient had received vasopressors as well as 750 mL of normal saline through these access points. Two days after resuscitation, she developed an enlarging ecchymosis around the left IO access point. On day 5, cutaneous findings included 2 large firm bullae on a purpuric base overlying the left proximal tibia and patella (Figure 1). After an ultrasound revealed no connection to the underlying joint space, the bullae were incised and drained for patient comfort, as she reported pain and undue pressure at the knee joint on initial dermatologic consultation. These symptoms abated after the procedure. Cultures of bullous fluid were negative for infection. Histopathologic examination revealed a subepidermal split with underlying minimal mixed inflammation, favoring the diagnosis of traumatic bullae.

At a scheduled 7-month dermatology follow-up, the wound bed appeared to be healing well with surrounding scarring with no residual bleeding or drainage (Figure 2) despite the patient reporting a protracted course of wound healing requiring debridement due to eschar formation and multiple follow-up appointments with the wound care service.

Comment

The most commonly reported complications with IO line placement result from fluid infiltration of the subcutaneous tissue secondary to catheter misplacement.^1,3 Extravasated fluid may lead to tissue damage, compartment syndrome, and even tissue necrosis in some cases.^1,4,5 Localized cellulitis and the formation of subcutaneous abscesses also have been reported, albeit rarely.^3,5

In our retrospective cohort review, we identified an additional potential complication of IO line placement that has not been widely reported—development of large traumatic bullae. It is most likely that this patient’s IO catheter became dislodged, resulting in extravasation of fluids into the dermal and subcutaneous tissues.

Our findings support the previously noted complication rate of less than 1% following IO line placement, with an overall complication rate of 2.7% that included only 1 patient with a cutaneous complication.² Given this low incidence, providers may not be used to recognizing such complications, leading to delayed or incorrect diagnosis of these entities. While there are certain conditions in which IO insertion is contraindicated, including severe bone diseases (eg, osteogenesis imperfecta, osteomyelitis), overlying cellulitis, and bone fracture, these conditions are rare and can be avoided in most cases by use of an alternative site for needle insertion.² Due to the widespread utility of this tool and its few contraindications, its use in hospitalized patients is rapidly increasing, necessitating a need for quick recognition of potential complications.

From previous data on the incidence of traumatic blisters with underlying bone fractures, there are several identifiable risk factors that could be extended to patients at high risk for developing cutaneous IO complications secondary to the trauma associated with needle insertion,⁶ including wound-healing impairments in patients with fragile lymphatics, peripheral vascular disease, diabetes, or collagen vascular diseases (eg, lupus, rheumatoid arthritis, Sjögren syndrome). Patients with these conditions should be closely monitored for the development of bullae.⁶ While the patient we highlighted in our study did not have a history of such conditions, her history of cardiac disease, recent resuscitation attempts, and immunosuppression certainly could have contributed to suboptimal tissue agility and repair after IO line placement.

Conclusion

Intraosseous access is a safe, effective, and reliable option for vascular access in both pediatric and adult populations that is widely used in both prehospital (ie, paramedic administered) and hospital settings, including intensive care units, emergency departments, and any acute situation where rapid vascular access is necessary. This retrospective chart review examining the incidence and types of cutaneous complications associated with IO line placement at a level I trauma center revealed a total complication rate similar to those reported in previous studies and also highlighted a unique postprocedural cutaneous finding of traumatic bullae. Although no unified management recommendations currently exist, providers should consider this complication in the differential for hospitalized patients with large, atypical, asymmetric bullae in the absence of an alternative explanation for such skin findings.

The Diagnosis: Dowling-Degos Disease

Histopathology demonstrated elongation of the epidermal rete ridges with increased basal pigmentation, suprapapillary epithelial thinning, dermal melanophages, and a mild lymphocytic infiltrate (Figure). Given the clinical and histologic findings, a diagnosis of Dowling-Degos disease (DDD) was made. The patient was counseled on the increased risk for her children developing DDD. Treatment with the erbium:YAG (Er:YAG) laser subsequently was initiated.

Dowling-Degos disease (also known as reticulate pigmented anomaly of the flexures) is an uncommon autosomal-dominant condition characterized by reticular hyperpigmentation involving the flexural and intertriginous sites. Classic DDD commonly is caused by lossof-function mutations in the keratin 5 gene, KRT5¹; however, DDD also may result from loss-of-function mutations in the protein O-fucosyltransferase 1, POFUT1, and protein O-glucosyltransferase 1, POGLUT1, genes.²

Rare cases of DDD associated with hidradenitis suppurativa are caused by mutations in the presenilin enhancer protein 2 gene, PSENEN.³

Of note, a missense mutation in KRT5 is implicated in epidermolysis bullosa simplex with mottled pigmentation. Onset of DDD typically occurs during the third to fourth decades of life. Reticulated hyperpigmented macules initially occur in the axillae and groin and progressively increase over time to involve the neck, inframammary folds, trunk, and flexural surfaces of the arms and thighs. Patients additionally may present with pitted perioral scars, comedolike lesions on the back and neck, epidermoid cysts, and hidradenitis suppurativa. Keratoacanthoma and squamous cell carcinoma rarely have been reported in association with classic DDD.^4,5

Dowling-Degos disease usually is asymptomatic, though pruritus seldom may occur in the affected flexural areas. Histologically, the epidermal rete ridges are elongated in a filiform or antlerlike pattern with increased pigmentation of the basal layer and thinning of the suprapapillary epithelium. Dermal melanosis and a mild perivascular lymphohistiocytic infiltrate also are present with no increase in the number of melanocytes.^6,7 Galli-Galli disease is a variant of DDD that shares similar clinical and histologic features of DDD but is distinguished from DDD by suprabasilar nondyskeratotic acantholysis on histology.⁸

Regarding other differential diagnoses for our patient, acanthosis nigricans may be distinguished clinically by the presence of velvety and/or verrucous plaques, commonly in the neck folds and axillae. Histologically, acanthosis nigricans is distinct from DDD and involves hyperkeratosis, acanthosis, and epidermal papillomatosis. Our patient had no history of diabetes mellitus or insulin resistance. Granular parakeratosis presents with hyperpigmented hyperkeratotic papules and plaques classically confined to the axillary region; however, the involvement of other intertriginous areas may occur. Histologically, granular parakeratosis demonstrates compact parakeratosis with small bluish keratohyalin granules within the stratum corneum. Confluent and reticulated papillomatosis presents with red-brown keratotic papules that initially appear in the intermammary region and spread laterally forming a reticulated pattern. Histology is similar to acanthosis nigricans and demonstrates hyperkeratosis, acanthosis, and papillomatosis. Inverse psoriasis presents with symmetric and sharply demarcated, erythematous, nonscaly plaques in the intertriginous areas. The plaques of inverse psoriasis may be pruritic and/or sore and occasionally may become macerated. Inverse psoriasis shares similar histologic findings compared to classic plaque psoriasis but may have less confluent parakeratosis.

Treatment of DDD essentially is reserved for cosmetic reasons. Topical hydroquinone, tretinoin, and corticosteroids have been used with limited to no success.^5,9 Beneficial results after treatment with the Er:YAG laser have been reported.¹⁰

The Diagnosis: Dowling-Degos Disease

Histopathology demonstrated elongation of the epidermal rete ridges with increased basal pigmentation, suprapapillary epithelial thinning, dermal melanophages, and a mild lymphocytic infiltrate (Figure). Given the clinical and histologic findings, a diagnosis of Dowling-Degos disease (DDD) was made. The patient was counseled on the increased risk for her children developing DDD. Treatment with the erbium:YAG (Er:YAG) laser subsequently was initiated.

Dowling-Degos disease (also known as reticulate pigmented anomaly of the flexures) is an uncommon autosomal-dominant condition characterized by reticular hyperpigmentation involving the flexural and intertriginous sites. Classic DDD commonly is caused by lossof-function mutations in the keratin 5 gene, KRT5¹; however, DDD also may result from loss-of-function mutations in the protein O-fucosyltransferase 1, POFUT1, and protein O-glucosyltransferase 1, POGLUT1, genes.²

Rare cases of DDD associated with hidradenitis suppurativa are caused by mutations in the presenilin enhancer protein 2 gene, PSENEN.³

Of note, a missense mutation in KRT5 is implicated in epidermolysis bullosa simplex with mottled pigmentation. Onset of DDD typically occurs during the third to fourth decades of life. Reticulated hyperpigmented macules initially occur in the axillae and groin and progressively increase over time to involve the neck, inframammary folds, trunk, and flexural surfaces of the arms and thighs. Patients additionally may present with pitted perioral scars, comedolike lesions on the back and neck, epidermoid cysts, and hidradenitis suppurativa. Keratoacanthoma and squamous cell carcinoma rarely have been reported in association with classic DDD.^4,5

Dowling-Degos disease usually is asymptomatic, though pruritus seldom may occur in the affected flexural areas. Histologically, the epidermal rete ridges are elongated in a filiform or antlerlike pattern with increased pigmentation of the basal layer and thinning of the suprapapillary epithelium. Dermal melanosis and a mild perivascular lymphohistiocytic infiltrate also are present with no increase in the number of melanocytes.^6,7 Galli-Galli disease is a variant of DDD that shares similar clinical and histologic features of DDD but is distinguished from DDD by suprabasilar nondyskeratotic acantholysis on histology.⁸

Regarding other differential diagnoses for our patient, acanthosis nigricans may be distinguished clinically by the presence of velvety and/or verrucous plaques, commonly in the neck folds and axillae. Histologically, acanthosis nigricans is distinct from DDD and involves hyperkeratosis, acanthosis, and epidermal papillomatosis. Our patient had no history of diabetes mellitus or insulin resistance. Granular parakeratosis presents with hyperpigmented hyperkeratotic papules and plaques classically confined to the axillary region; however, the involvement of other intertriginous areas may occur. Histologically, granular parakeratosis demonstrates compact parakeratosis with small bluish keratohyalin granules within the stratum corneum. Confluent and reticulated papillomatosis presents with red-brown keratotic papules that initially appear in the intermammary region and spread laterally forming a reticulated pattern. Histology is similar to acanthosis nigricans and demonstrates hyperkeratosis, acanthosis, and papillomatosis. Inverse psoriasis presents with symmetric and sharply demarcated, erythematous, nonscaly plaques in the intertriginous areas. The plaques of inverse psoriasis may be pruritic and/or sore and occasionally may become macerated. Inverse psoriasis shares similar histologic findings compared to classic plaque psoriasis but may have less confluent parakeratosis.

Treatment of DDD essentially is reserved for cosmetic reasons. Topical hydroquinone, tretinoin, and corticosteroids have been used with limited to no success.^5,9 Beneficial results after treatment with the Er:YAG laser have been reported.¹⁰

The Diagnosis: Dowling-Degos Disease

Histopathology demonstrated elongation of the epidermal rete ridges with increased basal pigmentation, suprapapillary epithelial thinning, dermal melanophages, and a mild lymphocytic infiltrate (Figure). Given the clinical and histologic findings, a diagnosis of Dowling-Degos disease (DDD) was made. The patient was counseled on the increased risk for her children developing DDD. Treatment with the erbium:YAG (Er:YAG) laser subsequently was initiated.

Dowling-Degos disease (also known as reticulate pigmented anomaly of the flexures) is an uncommon autosomal-dominant condition characterized by reticular hyperpigmentation involving the flexural and intertriginous sites. Classic DDD commonly is caused by lossof-function mutations in the keratin 5 gene, KRT5¹; however, DDD also may result from loss-of-function mutations in the protein O-fucosyltransferase 1, POFUT1, and protein O-glucosyltransferase 1, POGLUT1, genes.²

Rare cases of DDD associated with hidradenitis suppurativa are caused by mutations in the presenilin enhancer protein 2 gene, PSENEN.³

Of note, a missense mutation in KRT5 is implicated in epidermolysis bullosa simplex with mottled pigmentation. Onset of DDD typically occurs during the third to fourth decades of life. Reticulated hyperpigmented macules initially occur in the axillae and groin and progressively increase over time to involve the neck, inframammary folds, trunk, and flexural surfaces of the arms and thighs. Patients additionally may present with pitted perioral scars, comedolike lesions on the back and neck, epidermoid cysts, and hidradenitis suppurativa. Keratoacanthoma and squamous cell carcinoma rarely have been reported in association with classic DDD.^4,5

Dowling-Degos disease usually is asymptomatic, though pruritus seldom may occur in the affected flexural areas. Histologically, the epidermal rete ridges are elongated in a filiform or antlerlike pattern with increased pigmentation of the basal layer and thinning of the suprapapillary epithelium. Dermal melanosis and a mild perivascular lymphohistiocytic infiltrate also are present with no increase in the number of melanocytes.^6,7 Galli-Galli disease is a variant of DDD that shares similar clinical and histologic features of DDD but is distinguished from DDD by suprabasilar nondyskeratotic acantholysis on histology.⁸

Regarding other differential diagnoses for our patient, acanthosis nigricans may be distinguished clinically by the presence of velvety and/or verrucous plaques, commonly in the neck folds and axillae. Histologically, acanthosis nigricans is distinct from DDD and involves hyperkeratosis, acanthosis, and epidermal papillomatosis. Our patient had no history of diabetes mellitus or insulin resistance. Granular parakeratosis presents with hyperpigmented hyperkeratotic papules and plaques classically confined to the axillary region; however, the involvement of other intertriginous areas may occur. Histologically, granular parakeratosis demonstrates compact parakeratosis with small bluish keratohyalin granules within the stratum corneum. Confluent and reticulated papillomatosis presents with red-brown keratotic papules that initially appear in the intermammary region and spread laterally forming a reticulated pattern. Histology is similar to acanthosis nigricans and demonstrates hyperkeratosis, acanthosis, and papillomatosis. Inverse psoriasis presents with symmetric and sharply demarcated, erythematous, nonscaly plaques in the intertriginous areas. The plaques of inverse psoriasis may be pruritic and/or sore and occasionally may become macerated. Inverse psoriasis shares similar histologic findings compared to classic plaque psoriasis but may have less confluent parakeratosis.

Treatment of DDD essentially is reserved for cosmetic reasons. Topical hydroquinone, tretinoin, and corticosteroids have been used with limited to no success.^5,9 Beneficial results after treatment with the Er:YAG laser have been reported.¹⁰

Regarded as dermatologic emergencies, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a spectrum of blistering skin diseases that have a high mortality rate. Because of a misguided immune response to medications or infections, CD8⁺ T lymphocytes release proinflammatory cytokines, giving rise to the extensive epidermal destruction seen in SJS and TEN. The exact pathogenesis of SJS and TEN is still poorly defined, but studies have proposed that T cells mediate keratinocyte (KC) apoptosis through perforin and granzyme release and activation of the Fas/Fas ligand (FasL). Functioning as a transmembrane death receptor in the tumor necrosis factor (TNF) superfamily, Fas (CD95) activates Fas-associated death domain protein, caspases, and nucleases, resulting in organized cell destruction. Likewise, perforin and granzymes also have been shown to play a similar role in apoptosis via activation of caspases.¹

Evidence for the role of TNF-α in SJS and TEN has been supported by findings of elevated levels of TNF-α within the blister fluid, serum, and KC cell surface. Additionally, TNF-α has been shown to upregulate inducible nitric oxide synthase in KCs, causing an accumulation of nitric oxide and subsequent FasL-mediated cell death.^1-3 Notably, studies have demonstrated a relative lack of lymphocytes in the tissue of TEN patients despite the extensive destruction that is observed, thus emphasizing the importance of amplification and cell signaling via inflammatory mediators such as TNF-α.¹ In this proposed model, T cells release IFN-γ, causing KCs to release TNF-α that subsequently promotes the upregulation of the aforementioned FasL.¹ Tumor necrosis factor α also may promote increased MHC class I complex deposition on KC surfaces that may play a role in perforin and granzyme-mediated apoptosis of KCs.¹

There is still debate on the standard of care for the treatment of SJS and TEN, attributed to the absence of randomized controlled trials and the rarity of the disease as well as the numerous conflicting studies evaluating potential treatments.^1,4 Despite conflicting data to support their use, supportive care and intravenous immunoglobulin (IVIG) continue to be common treatments for SJS and TEN in hospitals worldwide. Elucidation of the role of TNF-α has prompted the use of infliximab and etanercept. In a case series of Italian patients with TEN (average SCORTEN, 3.6) treated with the TNF-α antagonist etanercept, no mortality was observed, which was well below the calculated expected mortality of 46.9%.² Our retrospective study compared the use of a TNF antagonist to other therapies in the treatment of SJS/TEN. Our data suggest that etanercept is a lifesaving and disease-modifying therapy.

Methods

Twenty-two patients with SJS/TEN were included in this analysis. This included all patients who carried a clinical diagnosis of SJS/TEN with a confirmatory biopsy at our 2 university centers—University of California, Los Angeles, and Keck-LA County-Norris Hospital at the University of Southern California, Los Angeles—from 2013 to 2016. The diagnosis was rendered when a clinical diagnosis of SJS/TEN was given by a dermatologist and a confirmatory biopsy was performed. Every patient given a diagnosis of SJS/TEN at either university system from 2015 onward received an injection of etanercept given the positive results reported by Paradisi et al.²

The 9 patients who presented from 2013 to 2014 to our 2 hospital systems and were given a diagnosis of SJS/TEN received either IVIG or supportive care alone and had an average body surface area (BSA) affected of 23%. The 13 patients who presented from 2015 to 2016 were treated with etanercept in the form of a 50-mg subcutaneous injection given once to the right upper arm. Of this group, 4 patients received dual therapy with both IVIG and etanercept. In the etanercept-treated group (etanercept alone and etanercept plus IVIG), the average BSA affected was 30%. At the time of preliminary diagnosis, all patient medications were evaluated for a possible temporal relationship to the onset of rash and were discontinued if felt to be causative. The causative agent and treatment course for each patient is summarized in Table 1.

Results

A total of 13 patients received etanercept. The mean SCORTEN was 2.2. The observed mortality was 0%, which was markedly lower than the predicted mortality of 24.3% (as determined by linear interpolation). Of this cohort, 9 patients received etanercept alone (mean SCORTEN of 2.1, predicted mortality of 22.9%), whereas 4 patients received a combination of etanercept and IVIG (mean SCORTEN of 2.3, predicted mortality of 27.2%).

The 4 patients who received both etanercept and IVIG received dual therapy for varying reasons. In patient 2 (Table 1), the perceived severity of this case ultimately led to the decision to start IVIG in addition to etanercept, resulting in rapid recovery and discharge after only 1 week of hospitalization. Intravenous immunoglobulin also was given in patient 3 (SCORTEN of 4) and patient 6 (SCORTEN of 2) for progression of disease despite administration of etanercept, with subsequent cessation of progression after the addition of the second agent (IVIG). Patient 12 might have done well on etanercept monotherapy but was administered IVIG as a precautionary measure because of hospital treatment algorithms.

Nine patients did not receive etanercept. Of this group, 5 received IVIG and 4 were managed with supportive care alone. The average SCORTEN for this group was 2.4, only slightly higher than the group that received etanercept (Table 2). The mortality rate in this group was 33%, which was higher than the predicted mortality of 28.1%.

Comment

There is no definitive gold standard treatment of SJS, SJS/TEN overlap, or TEN. However, generally agreed upon management includes immediate discontinuation of the offending medication and supportive therapy with aggressive electrolyte replacement and wound care. Management in a burn unit or intensive care unit is recommended in severe cases. Contention over the efficacy of various medications in the treatment of SJS and TEN continues and largely is due to the rarity of SJS and TEN; studies are small and almost all lack randomization. Therapies that have been used include high-dose steroids, IVIG, plasmapheresis, cyclophosphamide, cyclosporine A, and TNF inhibitors (eg, etanercept, infliximab).¹

Evidence for the use of anti–TNF-α antibodies has been limited thus far, with most of the literature focusing on infliximab and etanercept. Adalimumab, a fully humanized clonal antibody, has no reported cases in the dermatologic literature for use in patients with SJS/TEN. Two case reports of adalimumab paradoxically causing SJS have been documented. In both cases, adalimumab was stopped and patients responded to intravenous corticosteroids and infliximab.^7,8 Similarly, thalidomide has not proven to be a promising anti–TNF-α agent for the treatment of SJS/TEN. In the only attempted randomized controlled trial for SJS and TEN, thalidomide appeared to increase mortality, eventuating in this trial being terminated prior to the planned end date.⁹Infliximab and etanercept have several case reports and a few case series highlighting potentially efficacious application of TNF-α inhibitors for the treatment of SJS/TEN.^10-13 In 2002, Fischer et al¹⁰ reported the first case of TEN treated successfully with a single dose of infliximab 5 mg/kg. Kreft et al¹⁴ reported on etoricoxib-induced TEN that was treated with infliximab 5 mg/kg, which led to re-epithelialization within 5 weeks (notably a 5-week re-epithelialization time is not necessarily an improvement).

In 2005, Hunger et al³ demonstrated TNF-α’s release by KCs in the epidermis and by inflammatory cells in the dermis of a TEN patient. Twenty-four hours after the administration of infliximab 5 mg/kg in these patients, TNF-α was found to be below normal and epidermal detachment ceased.³ Wojtkietwicz et al¹³ demonstrated benefit following an infusion of infliximab 5 mg/kg in a patient whose disease continued to progress despite treatment with dexamethasone and 1.8 g/kg of IVIG.

Then 2 subsequent case series added further support for the efficacy of infliximab in the treatment of TEN. Patmanidis et al¹⁵ and Gaitanis et al¹⁶ reported similar results in 4 patients, each treated with infliximab 5 mg/kg immediately followed by initiation of high-dose IVIG (2 g/kg over 5 days). Zárate-Correa et al¹⁷ reported a 0% mortality rate and near-complete re-epithelialization after 5 to 14 days in 4 patients treated with a single 300-mg dose of infliximab.

However, the success of infliximab in the treatment of TEN has been countered by the pilot study by Paquet et al,¹⁸ which compared the efficacy of 150 mg/kg of N-acetylcysteine alone vs adding infliximab 5 mg/kg to treat 10 TEN patients. The study demonstrated no benefit at 48 hours in the group given infliximab, the time frame in which prior case reports touting infliximab’s benefit claimed the benefit was observed. Similarly, there was no effect on mortality for either treatment modality as assessed by illness auxiliary score.¹⁸

Evidence in support of the use of etanercept in the treatment of SJS/TEN is mounting, and some centers have begun to use it as the first-choice therapy for SJS/TEN. The first case was reported by Famularo et al,¹⁹ in which a patient with TEN was given 2 doses of etanercept 25 mg after failure to improve with prednisolone 1 mg/kg. The patient showed near-complete and rapid re-epithelization in 6 days before death due to disseminated intravascular coagulation 10 days after admission.¹⁹ Gubinelli et al²⁰ and Sadighha²¹ independently reported cases of TEN and TEN/acute generalized exanthematous pustulosis overlap treated with a total of 50 mg of etanercept, demonstrating rapid cessation of lesion progression. Didona et al²² found similar benefit using etanercept 50 mg to treat TEN secondary to rituximab after failure to improve with prednisone and cyclophosphamide. Treatment of TEN with etanercept in an HIV-positive patient also has been reported. Lee et al²³ described a patient who was administered 50-mg and 25-mg injections on days 3 and 5 of hospitalization, respectively, with re-epithelialization occurring by day 8. Finally, Owczarczyk-Saczonek et al²⁴ reported a case of SJS in a patient with a 4-year history of etanercept and sulfasalazine treatment of rheumatoid arthritis; sulfasalazine was stopped, but this patient was continued on etanercept until resolution of skin and mucosal symptoms. However, it is important to consider the possibility of publication bias among these cases selected for their positive outcomes.

Perhaps the most compelling literature regarding the use of etanercept for TEN was described in a case series by Paradisi et al.² This study included 10 patients with TEN, all of whom demonstrated complete re-epithelialization shortly after receiving etanercept 50 mg. Average SCORTEN was 3.6 with a range of 2 to 6. Eight patients in this study had severe comorbidities and all 10 patients survived, with a time to re-epithelialization ranging from 7 to 20 days.² Additionally, a randomized controlled trial showed that 38 etanercept-treated patients had improved mortality (P=.266) and re-epithelialization time (P=.01) compared to patients treated with intravenous methylprednisolone.²⁵Limitations to our study are similar to other reports of SJS/TEN and included the small number of cases and lack of randomization. Additionally, we do not have data available for all patients for time between onset of disease and treatment initiation. Because of these challenges, data presented in this case series is observational only. Additionally, the patients treated with etanercept alone had a slightly lower SCORTEN compared to the group that received IVIG or supportive care alone (2.1 and 2.4 respectively). However, the etanercept-only group actually had higher involvement of epidermal detachment (33%) compared to the non-etanercept group (23%).

Conclusion

Although treatment with etanercept lacks the support of a randomized controlled trial, similar to all other treatments currently used for SJS and TEN, preliminary reports highlight a benefit in disease progression and improvement in time to re-epithelialization. In particular, if etanercept 50 mg subcutaneously is given as monotherapy or is given early in the disease course (prior to other therapies being attempted and ideally within 6 hours of presentation), our data suggest an even greater trend toward improved mortality and decreased time to re-epithelialization. Additionally, our findings may suggest that in some patients, etanercept monotherapy is not an adequate intervention but the addition of IVIG may be helpful; however, the senior author (S.W.) notes anecdotally that in his experience with the patients treated at the University of California Los Angeles, the order of administration of combination therapies—etanercept followed by IVIG—was important in addition to the choice of therapy. These findings are promising enough to warrant a multicenter randomized controlled trial comparing the efficacy of etanercept to other more commonly used treatments for this spectrum of disease, including IVIG and/or cyclosporine. Based on the data presented in this case series, including the 13 patients who received etanercept and had a 0% mortality rate, etanercept may be viewed as a targeted therapeutic intervention for patients with SJS and TEN.

Regarded as dermatologic emergencies, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a spectrum of blistering skin diseases that have a high mortality rate. Because of a misguided immune response to medications or infections, CD8⁺ T lymphocytes release proinflammatory cytokines, giving rise to the extensive epidermal destruction seen in SJS and TEN. The exact pathogenesis of SJS and TEN is still poorly defined, but studies have proposed that T cells mediate keratinocyte (KC) apoptosis through perforin and granzyme release and activation of the Fas/Fas ligand (FasL). Functioning as a transmembrane death receptor in the tumor necrosis factor (TNF) superfamily, Fas (CD95) activates Fas-associated death domain protein, caspases, and nucleases, resulting in organized cell destruction. Likewise, perforin and granzymes also have been shown to play a similar role in apoptosis via activation of caspases.¹

Evidence for the role of TNF-α in SJS and TEN has been supported by findings of elevated levels of TNF-α within the blister fluid, serum, and KC cell surface. Additionally, TNF-α has been shown to upregulate inducible nitric oxide synthase in KCs, causing an accumulation of nitric oxide and subsequent FasL-mediated cell death.^1-3 Notably, studies have demonstrated a relative lack of lymphocytes in the tissue of TEN patients despite the extensive destruction that is observed, thus emphasizing the importance of amplification and cell signaling via inflammatory mediators such as TNF-α.¹ In this proposed model, T cells release IFN-γ, causing KCs to release TNF-α that subsequently promotes the upregulation of the aforementioned FasL.¹ Tumor necrosis factor α also may promote increased MHC class I complex deposition on KC surfaces that may play a role in perforin and granzyme-mediated apoptosis of KCs.¹

There is still debate on the standard of care for the treatment of SJS and TEN, attributed to the absence of randomized controlled trials and the rarity of the disease as well as the numerous conflicting studies evaluating potential treatments.^1,4 Despite conflicting data to support their use, supportive care and intravenous immunoglobulin (IVIG) continue to be common treatments for SJS and TEN in hospitals worldwide. Elucidation of the role of TNF-α has prompted the use of infliximab and etanercept. In a case series of Italian patients with TEN (average SCORTEN, 3.6) treated with the TNF-α antagonist etanercept, no mortality was observed, which was well below the calculated expected mortality of 46.9%.² Our retrospective study compared the use of a TNF antagonist to other therapies in the treatment of SJS/TEN. Our data suggest that etanercept is a lifesaving and disease-modifying therapy.

Methods

Twenty-two patients with SJS/TEN were included in this analysis. This included all patients who carried a clinical diagnosis of SJS/TEN with a confirmatory biopsy at our 2 university centers—University of California, Los Angeles, and Keck-LA County-Norris Hospital at the University of Southern California, Los Angeles—from 2013 to 2016. The diagnosis was rendered when a clinical diagnosis of SJS/TEN was given by a dermatologist and a confirmatory biopsy was performed. Every patient given a diagnosis of SJS/TEN at either university system from 2015 onward received an injection of etanercept given the positive results reported by Paradisi et al.²

The 9 patients who presented from 2013 to 2014 to our 2 hospital systems and were given a diagnosis of SJS/TEN received either IVIG or supportive care alone and had an average body surface area (BSA) affected of 23%. The 13 patients who presented from 2015 to 2016 were treated with etanercept in the form of a 50-mg subcutaneous injection given once to the right upper arm. Of this group, 4 patients received dual therapy with both IVIG and etanercept. In the etanercept-treated group (etanercept alone and etanercept plus IVIG), the average BSA affected was 30%. At the time of preliminary diagnosis, all patient medications were evaluated for a possible temporal relationship to the onset of rash and were discontinued if felt to be causative. The causative agent and treatment course for each patient is summarized in Table 1.

Results

A total of 13 patients received etanercept. The mean SCORTEN was 2.2. The observed mortality was 0%, which was markedly lower than the predicted mortality of 24.3% (as determined by linear interpolation). Of this cohort, 9 patients received etanercept alone (mean SCORTEN of 2.1, predicted mortality of 22.9%), whereas 4 patients received a combination of etanercept and IVIG (mean SCORTEN of 2.3, predicted mortality of 27.2%).

The 4 patients who received both etanercept and IVIG received dual therapy for varying reasons. In patient 2 (Table 1), the perceived severity of this case ultimately led to the decision to start IVIG in addition to etanercept, resulting in rapid recovery and discharge after only 1 week of hospitalization. Intravenous immunoglobulin also was given in patient 3 (SCORTEN of 4) and patient 6 (SCORTEN of 2) for progression of disease despite administration of etanercept, with subsequent cessation of progression after the addition of the second agent (IVIG). Patient 12 might have done well on etanercept monotherapy but was administered IVIG as a precautionary measure because of hospital treatment algorithms.

Nine patients did not receive etanercept. Of this group, 5 received IVIG and 4 were managed with supportive care alone. The average SCORTEN for this group was 2.4, only slightly higher than the group that received etanercept (Table 2). The mortality rate in this group was 33%, which was higher than the predicted mortality of 28.1%.

Comment

There is no definitive gold standard treatment of SJS, SJS/TEN overlap, or TEN. However, generally agreed upon management includes immediate discontinuation of the offending medication and supportive therapy with aggressive electrolyte replacement and wound care. Management in a burn unit or intensive care unit is recommended in severe cases. Contention over the efficacy of various medications in the treatment of SJS and TEN continues and largely is due to the rarity of SJS and TEN; studies are small and almost all lack randomization. Therapies that have been used include high-dose steroids, IVIG, plasmapheresis, cyclophosphamide, cyclosporine A, and TNF inhibitors (eg, etanercept, infliximab).¹

Evidence for the use of anti–TNF-α antibodies has been limited thus far, with most of the literature focusing on infliximab and etanercept. Adalimumab, a fully humanized clonal antibody, has no reported cases in the dermatologic literature for use in patients with SJS/TEN. Two case reports of adalimumab paradoxically causing SJS have been documented. In both cases, adalimumab was stopped and patients responded to intravenous corticosteroids and infliximab.^7,8 Similarly, thalidomide has not proven to be a promising anti–TNF-α agent for the treatment of SJS/TEN. In the only attempted randomized controlled trial for SJS and TEN, thalidomide appeared to increase mortality, eventuating in this trial being terminated prior to the planned end date.⁹Infliximab and etanercept have several case reports and a few case series highlighting potentially efficacious application of TNF-α inhibitors for the treatment of SJS/TEN.^10-13 In 2002, Fischer et al¹⁰ reported the first case of TEN treated successfully with a single dose of infliximab 5 mg/kg. Kreft et al¹⁴ reported on etoricoxib-induced TEN that was treated with infliximab 5 mg/kg, which led to re-epithelialization within 5 weeks (notably a 5-week re-epithelialization time is not necessarily an improvement).

In 2005, Hunger et al³ demonstrated TNF-α’s release by KCs in the epidermis and by inflammatory cells in the dermis of a TEN patient. Twenty-four hours after the administration of infliximab 5 mg/kg in these patients, TNF-α was found to be below normal and epidermal detachment ceased.³ Wojtkietwicz et al¹³ demonstrated benefit following an infusion of infliximab 5 mg/kg in a patient whose disease continued to progress despite treatment with dexamethasone and 1.8 g/kg of IVIG.

Then 2 subsequent case series added further support for the efficacy of infliximab in the treatment of TEN. Patmanidis et al¹⁵ and Gaitanis et al¹⁶ reported similar results in 4 patients, each treated with infliximab 5 mg/kg immediately followed by initiation of high-dose IVIG (2 g/kg over 5 days). Zárate-Correa et al¹⁷ reported a 0% mortality rate and near-complete re-epithelialization after 5 to 14 days in 4 patients treated with a single 300-mg dose of infliximab.

However, the success of infliximab in the treatment of TEN has been countered by the pilot study by Paquet et al,¹⁸ which compared the efficacy of 150 mg/kg of N-acetylcysteine alone vs adding infliximab 5 mg/kg to treat 10 TEN patients. The study demonstrated no benefit at 48 hours in the group given infliximab, the time frame in which prior case reports touting infliximab’s benefit claimed the benefit was observed. Similarly, there was no effect on mortality for either treatment modality as assessed by illness auxiliary score.¹⁸

Evidence in support of the use of etanercept in the treatment of SJS/TEN is mounting, and some centers have begun to use it as the first-choice therapy for SJS/TEN. The first case was reported by Famularo et al,¹⁹ in which a patient with TEN was given 2 doses of etanercept 25 mg after failure to improve with prednisolone 1 mg/kg. The patient showed near-complete and rapid re-epithelization in 6 days before death due to disseminated intravascular coagulation 10 days after admission.¹⁹ Gubinelli et al²⁰ and Sadighha²¹ independently reported cases of TEN and TEN/acute generalized exanthematous pustulosis overlap treated with a total of 50 mg of etanercept, demonstrating rapid cessation of lesion progression. Didona et al²² found similar benefit using etanercept 50 mg to treat TEN secondary to rituximab after failure to improve with prednisone and cyclophosphamide. Treatment of TEN with etanercept in an HIV-positive patient also has been reported. Lee et al²³ described a patient who was administered 50-mg and 25-mg injections on days 3 and 5 of hospitalization, respectively, with re-epithelialization occurring by day 8. Finally, Owczarczyk-Saczonek et al²⁴ reported a case of SJS in a patient with a 4-year history of etanercept and sulfasalazine treatment of rheumatoid arthritis; sulfasalazine was stopped, but this patient was continued on etanercept until resolution of skin and mucosal symptoms. However, it is important to consider the possibility of publication bias among these cases selected for their positive outcomes.

Perhaps the most compelling literature regarding the use of etanercept for TEN was described in a case series by Paradisi et al.² This study included 10 patients with TEN, all of whom demonstrated complete re-epithelialization shortly after receiving etanercept 50 mg. Average SCORTEN was 3.6 with a range of 2 to 6. Eight patients in this study had severe comorbidities and all 10 patients survived, with a time to re-epithelialization ranging from 7 to 20 days.² Additionally, a randomized controlled trial showed that 38 etanercept-treated patients had improved mortality (P=.266) and re-epithelialization time (P=.01) compared to patients treated with intravenous methylprednisolone.²⁵Limitations to our study are similar to other reports of SJS/TEN and included the small number of cases and lack of randomization. Additionally, we do not have data available for all patients for time between onset of disease and treatment initiation. Because of these challenges, data presented in this case series is observational only. Additionally, the patients treated with etanercept alone had a slightly lower SCORTEN compared to the group that received IVIG or supportive care alone (2.1 and 2.4 respectively). However, the etanercept-only group actually had higher involvement of epidermal detachment (33%) compared to the non-etanercept group (23%).

Conclusion

Although treatment with etanercept lacks the support of a randomized controlled trial, similar to all other treatments currently used for SJS and TEN, preliminary reports highlight a benefit in disease progression and improvement in time to re-epithelialization. In particular, if etanercept 50 mg subcutaneously is given as monotherapy or is given early in the disease course (prior to other therapies being attempted and ideally within 6 hours of presentation), our data suggest an even greater trend toward improved mortality and decreased time to re-epithelialization. Additionally, our findings may suggest that in some patients, etanercept monotherapy is not an adequate intervention but the addition of IVIG may be helpful; however, the senior author (S.W.) notes anecdotally that in his experience with the patients treated at the University of California Los Angeles, the order of administration of combination therapies—etanercept followed by IVIG—was important in addition to the choice of therapy. These findings are promising enough to warrant a multicenter randomized controlled trial comparing the efficacy of etanercept to other more commonly used treatments for this spectrum of disease, including IVIG and/or cyclosporine. Based on the data presented in this case series, including the 13 patients who received etanercept and had a 0% mortality rate, etanercept may be viewed as a targeted therapeutic intervention for patients with SJS and TEN.

Regarded as dermatologic emergencies, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a spectrum of blistering skin diseases that have a high mortality rate. Because of a misguided immune response to medications or infections, CD8⁺ T lymphocytes release proinflammatory cytokines, giving rise to the extensive epidermal destruction seen in SJS and TEN. The exact pathogenesis of SJS and TEN is still poorly defined, but studies have proposed that T cells mediate keratinocyte (KC) apoptosis through perforin and granzyme release and activation of the Fas/Fas ligand (FasL). Functioning as a transmembrane death receptor in the tumor necrosis factor (TNF) superfamily, Fas (CD95) activates Fas-associated death domain protein, caspases, and nucleases, resulting in organized cell destruction. Likewise, perforin and granzymes also have been shown to play a similar role in apoptosis via activation of caspases.¹

Evidence for the role of TNF-α in SJS and TEN has been supported by findings of elevated levels of TNF-α within the blister fluid, serum, and KC cell surface. Additionally, TNF-α has been shown to upregulate inducible nitric oxide synthase in KCs, causing an accumulation of nitric oxide and subsequent FasL-mediated cell death.^1-3 Notably, studies have demonstrated a relative lack of lymphocytes in the tissue of TEN patients despite the extensive destruction that is observed, thus emphasizing the importance of amplification and cell signaling via inflammatory mediators such as TNF-α.¹ In this proposed model, T cells release IFN-γ, causing KCs to release TNF-α that subsequently promotes the upregulation of the aforementioned FasL.¹ Tumor necrosis factor α also may promote increased MHC class I complex deposition on KC surfaces that may play a role in perforin and granzyme-mediated apoptosis of KCs.¹

There is still debate on the standard of care for the treatment of SJS and TEN, attributed to the absence of randomized controlled trials and the rarity of the disease as well as the numerous conflicting studies evaluating potential treatments.^1,4 Despite conflicting data to support their use, supportive care and intravenous immunoglobulin (IVIG) continue to be common treatments for SJS and TEN in hospitals worldwide. Elucidation of the role of TNF-α has prompted the use of infliximab and etanercept. In a case series of Italian patients with TEN (average SCORTEN, 3.6) treated with the TNF-α antagonist etanercept, no mortality was observed, which was well below the calculated expected mortality of 46.9%.² Our retrospective study compared the use of a TNF antagonist to other therapies in the treatment of SJS/TEN. Our data suggest that etanercept is a lifesaving and disease-modifying therapy.

Methods

Twenty-two patients with SJS/TEN were included in this analysis. This included all patients who carried a clinical diagnosis of SJS/TEN with a confirmatory biopsy at our 2 university centers—University of California, Los Angeles, and Keck-LA County-Norris Hospital at the University of Southern California, Los Angeles—from 2013 to 2016. The diagnosis was rendered when a clinical diagnosis of SJS/TEN was given by a dermatologist and a confirmatory biopsy was performed. Every patient given a diagnosis of SJS/TEN at either university system from 2015 onward received an injection of etanercept given the positive results reported by Paradisi et al.²

The 9 patients who presented from 2013 to 2014 to our 2 hospital systems and were given a diagnosis of SJS/TEN received either IVIG or supportive care alone and had an average body surface area (BSA) affected of 23%. The 13 patients who presented from 2015 to 2016 were treated with etanercept in the form of a 50-mg subcutaneous injection given once to the right upper arm. Of this group, 4 patients received dual therapy with both IVIG and etanercept. In the etanercept-treated group (etanercept alone and etanercept plus IVIG), the average BSA affected was 30%. At the time of preliminary diagnosis, all patient medications were evaluated for a possible temporal relationship to the onset of rash and were discontinued if felt to be causative. The causative agent and treatment course for each patient is summarized in Table 1.

Results

A total of 13 patients received etanercept. The mean SCORTEN was 2.2. The observed mortality was 0%, which was markedly lower than the predicted mortality of 24.3% (as determined by linear interpolation). Of this cohort, 9 patients received etanercept alone (mean SCORTEN of 2.1, predicted mortality of 22.9%), whereas 4 patients received a combination of etanercept and IVIG (mean SCORTEN of 2.3, predicted mortality of 27.2%).

The 4 patients who received both etanercept and IVIG received dual therapy for varying reasons. In patient 2 (Table 1), the perceived severity of this case ultimately led to the decision to start IVIG in addition to etanercept, resulting in rapid recovery and discharge after only 1 week of hospitalization. Intravenous immunoglobulin also was given in patient 3 (SCORTEN of 4) and patient 6 (SCORTEN of 2) for progression of disease despite administration of etanercept, with subsequent cessation of progression after the addition of the second agent (IVIG). Patient 12 might have done well on etanercept monotherapy but was administered IVIG as a precautionary measure because of hospital treatment algorithms.

Nine patients did not receive etanercept. Of this group, 5 received IVIG and 4 were managed with supportive care alone. The average SCORTEN for this group was 2.4, only slightly higher than the group that received etanercept (Table 2). The mortality rate in this group was 33%, which was higher than the predicted mortality of 28.1%.

Comment

There is no definitive gold standard treatment of SJS, SJS/TEN overlap, or TEN. However, generally agreed upon management includes immediate discontinuation of the offending medication and supportive therapy with aggressive electrolyte replacement and wound care. Management in a burn unit or intensive care unit is recommended in severe cases. Contention over the efficacy of various medications in the treatment of SJS and TEN continues and largely is due to the rarity of SJS and TEN; studies are small and almost all lack randomization. Therapies that have been used include high-dose steroids, IVIG, plasmapheresis, cyclophosphamide, cyclosporine A, and TNF inhibitors (eg, etanercept, infliximab).¹

Evidence for the use of anti–TNF-α antibodies has been limited thus far, with most of the literature focusing on infliximab and etanercept. Adalimumab, a fully humanized clonal antibody, has no reported cases in the dermatologic literature for use in patients with SJS/TEN. Two case reports of adalimumab paradoxically causing SJS have been documented. In both cases, adalimumab was stopped and patients responded to intravenous corticosteroids and infliximab.^7,8 Similarly, thalidomide has not proven to be a promising anti–TNF-α agent for the treatment of SJS/TEN. In the only attempted randomized controlled trial for SJS and TEN, thalidomide appeared to increase mortality, eventuating in this trial being terminated prior to the planned end date.⁹Infliximab and etanercept have several case reports and a few case series highlighting potentially efficacious application of TNF-α inhibitors for the treatment of SJS/TEN.^10-13 In 2002, Fischer et al¹⁰ reported the first case of TEN treated successfully with a single dose of infliximab 5 mg/kg. Kreft et al¹⁴ reported on etoricoxib-induced TEN that was treated with infliximab 5 mg/kg, which led to re-epithelialization within 5 weeks (notably a 5-week re-epithelialization time is not necessarily an improvement).

In 2005, Hunger et al³ demonstrated TNF-α’s release by KCs in the epidermis and by inflammatory cells in the dermis of a TEN patient. Twenty-four hours after the administration of infliximab 5 mg/kg in these patients, TNF-α was found to be below normal and epidermal detachment ceased.³ Wojtkietwicz et al¹³ demonstrated benefit following an infusion of infliximab 5 mg/kg in a patient whose disease continued to progress despite treatment with dexamethasone and 1.8 g/kg of IVIG.

Then 2 subsequent case series added further support for the efficacy of infliximab in the treatment of TEN. Patmanidis et al¹⁵ and Gaitanis et al¹⁶ reported similar results in 4 patients, each treated with infliximab 5 mg/kg immediately followed by initiation of high-dose IVIG (2 g/kg over 5 days). Zárate-Correa et al¹⁷ reported a 0% mortality rate and near-complete re-epithelialization after 5 to 14 days in 4 patients treated with a single 300-mg dose of infliximab.

However, the success of infliximab in the treatment of TEN has been countered by the pilot study by Paquet et al,¹⁸ which compared the efficacy of 150 mg/kg of N-acetylcysteine alone vs adding infliximab 5 mg/kg to treat 10 TEN patients. The study demonstrated no benefit at 48 hours in the group given infliximab, the time frame in which prior case reports touting infliximab’s benefit claimed the benefit was observed. Similarly, there was no effect on mortality for either treatment modality as assessed by illness auxiliary score.¹⁸

Evidence in support of the use of etanercept in the treatment of SJS/TEN is mounting, and some centers have begun to use it as the first-choice therapy for SJS/TEN. The first case was reported by Famularo et al,¹⁹ in which a patient with TEN was given 2 doses of etanercept 25 mg after failure to improve with prednisolone 1 mg/kg. The patient showed near-complete and rapid re-epithelization in 6 days before death due to disseminated intravascular coagulation 10 days after admission.¹⁹ Gubinelli et al²⁰ and Sadighha²¹ independently reported cases of TEN and TEN/acute generalized exanthematous pustulosis overlap treated with a total of 50 mg of etanercept, demonstrating rapid cessation of lesion progression. Didona et al²² found similar benefit using etanercept 50 mg to treat TEN secondary to rituximab after failure to improve with prednisone and cyclophosphamide. Treatment of TEN with etanercept in an HIV-positive patient also has been reported. Lee et al²³ described a patient who was administered 50-mg and 25-mg injections on days 3 and 5 of hospitalization, respectively, with re-epithelialization occurring by day 8. Finally, Owczarczyk-Saczonek et al²⁴ reported a case of SJS in a patient with a 4-year history of etanercept and sulfasalazine treatment of rheumatoid arthritis; sulfasalazine was stopped, but this patient was continued on etanercept until resolution of skin and mucosal symptoms. However, it is important to consider the possibility of publication bias among these cases selected for their positive outcomes.

Perhaps the most compelling literature regarding the use of etanercept for TEN was described in a case series by Paradisi et al.² This study included 10 patients with TEN, all of whom demonstrated complete re-epithelialization shortly after receiving etanercept 50 mg. Average SCORTEN was 3.6 with a range of 2 to 6. Eight patients in this study had severe comorbidities and all 10 patients survived, with a time to re-epithelialization ranging from 7 to 20 days.² Additionally, a randomized controlled trial showed that 38 etanercept-treated patients had improved mortality (P=.266) and re-epithelialization time (P=.01) compared to patients treated with intravenous methylprednisolone.²⁵Limitations to our study are similar to other reports of SJS/TEN and included the small number of cases and lack of randomization. Additionally, we do not have data available for all patients for time between onset of disease and treatment initiation. Because of these challenges, data presented in this case series is observational only. Additionally, the patients treated with etanercept alone had a slightly lower SCORTEN compared to the group that received IVIG or supportive care alone (2.1 and 2.4 respectively). However, the etanercept-only group actually had higher involvement of epidermal detachment (33%) compared to the non-etanercept group (23%).

Conclusion

Although treatment with etanercept lacks the support of a randomized controlled trial, similar to all other treatments currently used for SJS and TEN, preliminary reports highlight a benefit in disease progression and improvement in time to re-epithelialization. In particular, if etanercept 50 mg subcutaneously is given as monotherapy or is given early in the disease course (prior to other therapies being attempted and ideally within 6 hours of presentation), our data suggest an even greater trend toward improved mortality and decreased time to re-epithelialization. Additionally, our findings may suggest that in some patients, etanercept monotherapy is not an adequate intervention but the addition of IVIG may be helpful; however, the senior author (S.W.) notes anecdotally that in his experience with the patients treated at the University of California Los Angeles, the order of administration of combination therapies—etanercept followed by IVIG—was important in addition to the choice of therapy. These findings are promising enough to warrant a multicenter randomized controlled trial comparing the efficacy of etanercept to other more commonly used treatments for this spectrum of disease, including IVIG and/or cyclosporine. Based on the data presented in this case series, including the 13 patients who received etanercept and had a 0% mortality rate, etanercept may be viewed as a targeted therapeutic intervention for patients with SJS and TEN.

The Accreditation Council for Graduate Medical Education has established core competencies to serve as a foundation for the training received in a dermatology residency program.¹ Although programs are required to have the same concentrations—patient care, medical knowledge, practice-based learning and improvement, interpersonal and communication skills, professionalism, and systems-based practice—no specific guidelines are in place regarding how each of these competencies should be reached within a training period.² Instead, it remains the responsibility of each program to formulate an individualized curriculum to facilitate proficiency in the multiple areas encompassed by a residency.

In many dermatology residency programs, dermatopathology is a substantial component of educational objectives and the curriculum.¹ Residents may spend as much as 25% of their training on dermatopathology. However, there is great variability among programs in methods of teaching dermatopathology. When Hinshaw³ surveyed 52 of 109 dermatology residency programs, they identified differences in dermatopathology teaching that included, but was not limited to, utilization of problem-based learning (in 40.4% of programs), integration of journal reviews (53.8%), and computer-based learning (19.2%). In addition, differences were identified in the recommended primary textbook and the makeup of faculty who taught dermatopathology.³

Although residency programs vary in their methods of teaching this important component of dermatology, most use a multiheaded microscope in some capacity for didactics or sign-out. For most trainees, the dermatopathology laboratory is a new environment compared to the clinical space that medical students and residents become accustomed to throughout their education, thus creating a knowledge gap for trainees on proper dermatopathology etiquette and universal guidelines.

With medical students, residents, and fellows in mind, we have prepared a basic “dermatopathology etiquette” reference for trainees. Just as there are universal rules in the operating room for surgery (eg, sterile technique), we want to establish a code of conduct at the microscope. We hope that these 10 tips will, first, be useful to those who are unsure how to approach their first experience with dermatopathology and, second, serve as a guideline to aid development of appropriate communication skills and functioning within this novel setting. This list also can serve as a resource for dermatopathology attendings to provide to rotating residents and students.

1. New to pathology? It’s okay to ask. Do not hesitate to ask upper-year residents, fellows, and attendings for instructions on such matters as how to adjust your eyepiece to get the best resolution. 

2. If a slide drops on the floor, do not move! Your first instinct might be to move your chair to look for the dropped slide, but you might roll over it and break it.

3. When the attending is looking through the scope, you look through the scope. Dermatopathology is a visual exercise. Getting in your “optic mileage” is best done under the guidance of an experienced dermatopathologist.

4. Rules regarding food and drink at the microscope vary by pathologist. It’s best to ask what each attending prefers. Safe advice is to avoid foods that make noise, such as chewing gum and chips, and food that has a strong odor, such as microwaved leftovers.

5. Limit use of a laptop, cell phone, and smartwatch. If you think that using any of these is necessary, it generally is best to announce that you are looking up something related to the case and then share your findings (but not the most recent post on your Facebook News Feed).

6. If you notice that something needs correcting on the report, speak up! We are all human; we all make typos. Do not hesitate to mention this as soon as possible, especially before the case is signed out. You will likely be thanked by your attending because it is harder to rectify once the report has been signed out.

7. Small talk often is welcome during large excisions. This is a great time to ask what others are doing next weekend or what happened in clinic earlier that day, or just to tell a good (clean) joke that is making the rounds. Conversely, if the case is complex, it often is best to wait until it is completed before asking questions.

8. When participating in a roundtable diagnosis, you are welcome to directly state the diagnosis for bread-and-butter cases, such as basal cell carcinomas and seborrheic keratoses. It is appropriate to be more descriptive and methodical in more complex cases. When evaluating a rash, give the general inflammatory pattern first. For example, is it spongiotic? Psoriasiform? Interface? Or a mixed pattern?

9. Extra points for identifying special sites! These include mucosal, genital, and acral sites. You might even get bonus points if you can determine something about the patient (child or adult) based on the pathologic features, such as variation in collagen patterns.

10. Whenever you are in doubt, just describe what you see. You can use the traditional top-down approach or start with stating the most evident finding, then proceed to a top-down description. If it is a neoplasm, describe the overall architecture; then, what you see at a cellular level will get you some points as well.

We acknowledge that this list of 10 tips is not comprehensive and might vary by attending and each institution’s distinctive training format. We are hopeful, however, that these 10 points of etiquette can serve as a guideline.

The Accreditation Council for Graduate Medical Education has established core competencies to serve as a foundation for the training received in a dermatology residency program.¹ Although programs are required to have the same concentrations—patient care, medical knowledge, practice-based learning and improvement, interpersonal and communication skills, professionalism, and systems-based practice—no specific guidelines are in place regarding how each of these competencies should be reached within a training period.² Instead, it remains the responsibility of each program to formulate an individualized curriculum to facilitate proficiency in the multiple areas encompassed by a residency.

In many dermatology residency programs, dermatopathology is a substantial component of educational objectives and the curriculum.¹ Residents may spend as much as 25% of their training on dermatopathology. However, there is great variability among programs in methods of teaching dermatopathology. When Hinshaw³ surveyed 52 of 109 dermatology residency programs, they identified differences in dermatopathology teaching that included, but was not limited to, utilization of problem-based learning (in 40.4% of programs), integration of journal reviews (53.8%), and computer-based learning (19.2%). In addition, differences were identified in the recommended primary textbook and the makeup of faculty who taught dermatopathology.³

Although residency programs vary in their methods of teaching this important component of dermatology, most use a multiheaded microscope in some capacity for didactics or sign-out. For most trainees, the dermatopathology laboratory is a new environment compared to the clinical space that medical students and residents become accustomed to throughout their education, thus creating a knowledge gap for trainees on proper dermatopathology etiquette and universal guidelines.

With medical students, residents, and fellows in mind, we have prepared a basic “dermatopathology etiquette” reference for trainees. Just as there are universal rules in the operating room for surgery (eg, sterile technique), we want to establish a code of conduct at the microscope. We hope that these 10 tips will, first, be useful to those who are unsure how to approach their first experience with dermatopathology and, second, serve as a guideline to aid development of appropriate communication skills and functioning within this novel setting. This list also can serve as a resource for dermatopathology attendings to provide to rotating residents and students.

1. New to pathology? It’s okay to ask. Do not hesitate to ask upper-year residents, fellows, and attendings for instructions on such matters as how to adjust your eyepiece to get the best resolution. 

2. If a slide drops on the floor, do not move! Your first instinct might be to move your chair to look for the dropped slide, but you might roll over it and break it.

3. When the attending is looking through the scope, you look through the scope. Dermatopathology is a visual exercise. Getting in your “optic mileage” is best done under the guidance of an experienced dermatopathologist.

4. Rules regarding food and drink at the microscope vary by pathologist. It’s best to ask what each attending prefers. Safe advice is to avoid foods that make noise, such as chewing gum and chips, and food that has a strong odor, such as microwaved leftovers.

5. Limit use of a laptop, cell phone, and smartwatch. If you think that using any of these is necessary, it generally is best to announce that you are looking up something related to the case and then share your findings (but not the most recent post on your Facebook News Feed).

6. If you notice that something needs correcting on the report, speak up! We are all human; we all make typos. Do not hesitate to mention this as soon as possible, especially before the case is signed out. You will likely be thanked by your attending because it is harder to rectify once the report has been signed out.

7. Small talk often is welcome during large excisions. This is a great time to ask what others are doing next weekend or what happened in clinic earlier that day, or just to tell a good (clean) joke that is making the rounds. Conversely, if the case is complex, it often is best to wait until it is completed before asking questions.

8. When participating in a roundtable diagnosis, you are welcome to directly state the diagnosis for bread-and-butter cases, such as basal cell carcinomas and seborrheic keratoses. It is appropriate to be more descriptive and methodical in more complex cases. When evaluating a rash, give the general inflammatory pattern first. For example, is it spongiotic? Psoriasiform? Interface? Or a mixed pattern?

9. Extra points for identifying special sites! These include mucosal, genital, and acral sites. You might even get bonus points if you can determine something about the patient (child or adult) based on the pathologic features, such as variation in collagen patterns.

10. Whenever you are in doubt, just describe what you see. You can use the traditional top-down approach or start with stating the most evident finding, then proceed to a top-down description. If it is a neoplasm, describe the overall architecture; then, what you see at a cellular level will get you some points as well.

We acknowledge that this list of 10 tips is not comprehensive and might vary by attending and each institution’s distinctive training format. We are hopeful, however, that these 10 points of etiquette can serve as a guideline.

The Accreditation Council for Graduate Medical Education has established core competencies to serve as a foundation for the training received in a dermatology residency program.¹ Although programs are required to have the same concentrations—patient care, medical knowledge, practice-based learning and improvement, interpersonal and communication skills, professionalism, and systems-based practice—no specific guidelines are in place regarding how each of these competencies should be reached within a training period.² Instead, it remains the responsibility of each program to formulate an individualized curriculum to facilitate proficiency in the multiple areas encompassed by a residency.

In many dermatology residency programs, dermatopathology is a substantial component of educational objectives and the curriculum.¹ Residents may spend as much as 25% of their training on dermatopathology. However, there is great variability among programs in methods of teaching dermatopathology. When Hinshaw³ surveyed 52 of 109 dermatology residency programs, they identified differences in dermatopathology teaching that included, but was not limited to, utilization of problem-based learning (in 40.4% of programs), integration of journal reviews (53.8%), and computer-based learning (19.2%). In addition, differences were identified in the recommended primary textbook and the makeup of faculty who taught dermatopathology.³

Although residency programs vary in their methods of teaching this important component of dermatology, most use a multiheaded microscope in some capacity for didactics or sign-out. For most trainees, the dermatopathology laboratory is a new environment compared to the clinical space that medical students and residents become accustomed to throughout their education, thus creating a knowledge gap for trainees on proper dermatopathology etiquette and universal guidelines.

With medical students, residents, and fellows in mind, we have prepared a basic “dermatopathology etiquette” reference for trainees. Just as there are universal rules in the operating room for surgery (eg, sterile technique), we want to establish a code of conduct at the microscope. We hope that these 10 tips will, first, be useful to those who are unsure how to approach their first experience with dermatopathology and, second, serve as a guideline to aid development of appropriate communication skills and functioning within this novel setting. This list also can serve as a resource for dermatopathology attendings to provide to rotating residents and students.

1. New to pathology? It’s okay to ask. Do not hesitate to ask upper-year residents, fellows, and attendings for instructions on such matters as how to adjust your eyepiece to get the best resolution. 

2. If a slide drops on the floor, do not move! Your first instinct might be to move your chair to look for the dropped slide, but you might roll over it and break it.

3. When the attending is looking through the scope, you look through the scope. Dermatopathology is a visual exercise. Getting in your “optic mileage” is best done under the guidance of an experienced dermatopathologist.

4. Rules regarding food and drink at the microscope vary by pathologist. It’s best to ask what each attending prefers. Safe advice is to avoid foods that make noise, such as chewing gum and chips, and food that has a strong odor, such as microwaved leftovers.

5. Limit use of a laptop, cell phone, and smartwatch. If you think that using any of these is necessary, it generally is best to announce that you are looking up something related to the case and then share your findings (but not the most recent post on your Facebook News Feed).

6. If you notice that something needs correcting on the report, speak up! We are all human; we all make typos. Do not hesitate to mention this as soon as possible, especially before the case is signed out. You will likely be thanked by your attending because it is harder to rectify once the report has been signed out.

7. Small talk often is welcome during large excisions. This is a great time to ask what others are doing next weekend or what happened in clinic earlier that day, or just to tell a good (clean) joke that is making the rounds. Conversely, if the case is complex, it often is best to wait until it is completed before asking questions.

8. When participating in a roundtable diagnosis, you are welcome to directly state the diagnosis for bread-and-butter cases, such as basal cell carcinomas and seborrheic keratoses. It is appropriate to be more descriptive and methodical in more complex cases. When evaluating a rash, give the general inflammatory pattern first. For example, is it spongiotic? Psoriasiform? Interface? Or a mixed pattern?

9. Extra points for identifying special sites! These include mucosal, genital, and acral sites. You might even get bonus points if you can determine something about the patient (child or adult) based on the pathologic features, such as variation in collagen patterns.

10. Whenever you are in doubt, just describe what you see. You can use the traditional top-down approach or start with stating the most evident finding, then proceed to a top-down description. If it is a neoplasm, describe the overall architecture; then, what you see at a cellular level will get you some points as well.

We acknowledge that this list of 10 tips is not comprehensive and might vary by attending and each institution’s distinctive training format. We are hopeful, however, that these 10 points of etiquette can serve as a guideline.

To the Editor:

Patients with psychocutaneous disorders present unique challenges to physicians. We illustrate the critical role that dermoscopy may play to illuminate exogenous skin pathology.

A 50-year-old woman with a reported medical history of systemic lupus erythematosus, chronic pain, and nonhealing leg ulcers presented to the emergency department with severe pain of the left lower leg and redness that was concerning for cellulitis. She sought treatment at an outside hospital for cellulitis 2 weeks prior but left against medical advice. Symptomatic review revealed chest pain, shortness of breath, nausea, vomiting, and diarrhea. The primary team started her on intravenous clindamycin and vancomycin for the presumed infection and scheduled narcotic medications due to concerns of intractable pain in the left leg. The dermatology department was consulted after failure to improve with 1 week of systemic antibiotics.

Physical examination revealed a geometric, atrophic, purple plaque on the left anterior shin from a prior leg ulcer as well as a diffuse red-pink patch extending from the knee to the ankle. Notably, the cellulitis spared the left posterior calf resting against the sheet and had a sharp line of demarcation at the distal shin. The leg was cool to the touch while the patient was distractible. She later reported that the leg was extremely tender to palpation. Dermoscopy revealed linear red pigments within skin furrows that accentuated skin lines (Figure). These findings raised suspicions of an external manipulation. The skin was wiped with an alcohol pad that removed a shimmering pink substance consistent in appearance to a cosmetic product. The skin beneath the cellulitis appeared normal.

Dermoscopy is not a standard method to diagnose cellulitis of the skin; however, when patients present with an atypical response to appropriate care, the presumed diagnosis must be challenged. This patient had dramatized symptoms, false medical history, and numerous hospitalizations that were suspicious for factitious disorder.¹ Furthermore, the physical examination was inconsistent with the classic course of cellulitis. In this case, dermoscopy had advantages over biopsies because it was noninvasive, gave immediate feedback, and provided a macroscopic view of the morphology. Via dermoscopy, we had an objective lens to distinguish cellulitis from cosmetic product and to obtain the correct diagnosis.

To the Editor:

Patients with psychocutaneous disorders present unique challenges to physicians. We illustrate the critical role that dermoscopy may play to illuminate exogenous skin pathology.

A 50-year-old woman with a reported medical history of systemic lupus erythematosus, chronic pain, and nonhealing leg ulcers presented to the emergency department with severe pain of the left lower leg and redness that was concerning for cellulitis. She sought treatment at an outside hospital for cellulitis 2 weeks prior but left against medical advice. Symptomatic review revealed chest pain, shortness of breath, nausea, vomiting, and diarrhea. The primary team started her on intravenous clindamycin and vancomycin for the presumed infection and scheduled narcotic medications due to concerns of intractable pain in the left leg. The dermatology department was consulted after failure to improve with 1 week of systemic antibiotics.

Physical examination revealed a geometric, atrophic, purple plaque on the left anterior shin from a prior leg ulcer as well as a diffuse red-pink patch extending from the knee to the ankle. Notably, the cellulitis spared the left posterior calf resting against the sheet and had a sharp line of demarcation at the distal shin. The leg was cool to the touch while the patient was distractible. She later reported that the leg was extremely tender to palpation. Dermoscopy revealed linear red pigments within skin furrows that accentuated skin lines (Figure). These findings raised suspicions of an external manipulation. The skin was wiped with an alcohol pad that removed a shimmering pink substance consistent in appearance to a cosmetic product. The skin beneath the cellulitis appeared normal.

Dermoscopy is not a standard method to diagnose cellulitis of the skin; however, when patients present with an atypical response to appropriate care, the presumed diagnosis must be challenged. This patient had dramatized symptoms, false medical history, and numerous hospitalizations that were suspicious for factitious disorder.¹ Furthermore, the physical examination was inconsistent with the classic course of cellulitis. In this case, dermoscopy had advantages over biopsies because it was noninvasive, gave immediate feedback, and provided a macroscopic view of the morphology. Via dermoscopy, we had an objective lens to distinguish cellulitis from cosmetic product and to obtain the correct diagnosis.

To the Editor:

Patients with psychocutaneous disorders present unique challenges to physicians. We illustrate the critical role that dermoscopy may play to illuminate exogenous skin pathology.

A 50-year-old woman with a reported medical history of systemic lupus erythematosus, chronic pain, and nonhealing leg ulcers presented to the emergency department with severe pain of the left lower leg and redness that was concerning for cellulitis. She sought treatment at an outside hospital for cellulitis 2 weeks prior but left against medical advice. Symptomatic review revealed chest pain, shortness of breath, nausea, vomiting, and diarrhea. The primary team started her on intravenous clindamycin and vancomycin for the presumed infection and scheduled narcotic medications due to concerns of intractable pain in the left leg. The dermatology department was consulted after failure to improve with 1 week of systemic antibiotics.

Physical examination revealed a geometric, atrophic, purple plaque on the left anterior shin from a prior leg ulcer as well as a diffuse red-pink patch extending from the knee to the ankle. Notably, the cellulitis spared the left posterior calf resting against the sheet and had a sharp line of demarcation at the distal shin. The leg was cool to the touch while the patient was distractible. She later reported that the leg was extremely tender to palpation. Dermoscopy revealed linear red pigments within skin furrows that accentuated skin lines (Figure). These findings raised suspicions of an external manipulation. The skin was wiped with an alcohol pad that removed a shimmering pink substance consistent in appearance to a cosmetic product. The skin beneath the cellulitis appeared normal.

Dermoscopy is not a standard method to diagnose cellulitis of the skin; however, when patients present with an atypical response to appropriate care, the presumed diagnosis must be challenged. This patient had dramatized symptoms, false medical history, and numerous hospitalizations that were suspicious for factitious disorder.¹ Furthermore, the physical examination was inconsistent with the classic course of cellulitis. In this case, dermoscopy had advantages over biopsies because it was noninvasive, gave immediate feedback, and provided a macroscopic view of the morphology. Via dermoscopy, we had an objective lens to distinguish cellulitis from cosmetic product and to obtain the correct diagnosis.

To the Editor:

Annular leukoderma, or the halo phenomenon, is a circular reaction of hypopigmentation that most commonly is observed alongside congenital nevi, acquired melanocytic nevi, blue nevi, Spitz nevi, vitiligo, and rarely melanoma.¹ There is limited literature on the mechanism of the halo phenomenon. Most of the literature proposes a T cell–mediated immune response to antigens, which causes not only surrounding pigment loss but also heralds the regression of central lesions.² Others have suggested a vascular mechanism, with blood shunted away from the lesions.³ Because guidelines discourage biopsy of typical halo nevi, it becomes important to evaluate lesions for worrisome features such as ulceration or asymmetry, especially in older patients. We present a case of a pigmented basal cell carcinoma (BCC) that exhibited the halo phenomenon. Four other cases have been described in the literature.^3-6

A 53-year-old man presented for evaluation of an asymptomatic lesion on the left side of the abdomen of approximately 8 months’ duration. He had no personal or family history of skin cancer. Physical examination revealed a central 1-cm, pink, verrucous papule surrounded by a 2×1.2-cm, depigmented, circular patch on the left side of the inferior abdomen (Figure 1). Upon questioning, the patient produced cell phone photographs of the trunk from 3 years prior, which did not show any lesions present. Full-body skin examination did not reveal any other concerning pigmented lesions. Excisional biopsy was performed due to concern for amelanotic melanoma, and histopathology revealed a superficial and pigmented BCC (Figure 2). Immunohistochemistry with Melan-A was negative for atypical melanocytes, with no uptake in the leukoderma areas.

Our patient’s final histologic diagnosis was pigmented BCC, which comprises only 6% of all BCCs.³ The proposed mechanism is that melanocytes colonize the tumor in the surrounding stroma and produce excess melanin. Basal cell carcinoma with halo phenomenon is a rare presentation. As in our case, 2 prior BCC reports also involved patients older than 50 years,^3,5 with the 2 other cases describing women in their late twenties and early thirties.^4,6 Additionally, 2 of 4 reports described patients with a history of multiple BCCs.^3,5

In summary, the seemingly benign halo phenomenon may accompany malignant processes such as nonmelanoma skin cancer. Careful consideration of lesion time course and atypia is imperative for proper clinical suspicion in such cases.

To the Editor:

Annular leukoderma, or the halo phenomenon, is a circular reaction of hypopigmentation that most commonly is observed alongside congenital nevi, acquired melanocytic nevi, blue nevi, Spitz nevi, vitiligo, and rarely melanoma.¹ There is limited literature on the mechanism of the halo phenomenon. Most of the literature proposes a T cell–mediated immune response to antigens, which causes not only surrounding pigment loss but also heralds the regression of central lesions.² Others have suggested a vascular mechanism, with blood shunted away from the lesions.³ Because guidelines discourage biopsy of typical halo nevi, it becomes important to evaluate lesions for worrisome features such as ulceration or asymmetry, especially in older patients. We present a case of a pigmented basal cell carcinoma (BCC) that exhibited the halo phenomenon. Four other cases have been described in the literature.^3-6

A 53-year-old man presented for evaluation of an asymptomatic lesion on the left side of the abdomen of approximately 8 months’ duration. He had no personal or family history of skin cancer. Physical examination revealed a central 1-cm, pink, verrucous papule surrounded by a 2×1.2-cm, depigmented, circular patch on the left side of the inferior abdomen (Figure 1). Upon questioning, the patient produced cell phone photographs of the trunk from 3 years prior, which did not show any lesions present. Full-body skin examination did not reveal any other concerning pigmented lesions. Excisional biopsy was performed due to concern for amelanotic melanoma, and histopathology revealed a superficial and pigmented BCC (Figure 2). Immunohistochemistry with Melan-A was negative for atypical melanocytes, with no uptake in the leukoderma areas.

Our patient’s final histologic diagnosis was pigmented BCC, which comprises only 6% of all BCCs.³ The proposed mechanism is that melanocytes colonize the tumor in the surrounding stroma and produce excess melanin. Basal cell carcinoma with halo phenomenon is a rare presentation. As in our case, 2 prior BCC reports also involved patients older than 50 years,^3,5 with the 2 other cases describing women in their late twenties and early thirties.^4,6 Additionally, 2 of 4 reports described patients with a history of multiple BCCs.^3,5

In summary, the seemingly benign halo phenomenon may accompany malignant processes such as nonmelanoma skin cancer. Careful consideration of lesion time course and atypia is imperative for proper clinical suspicion in such cases.

To the Editor:

Annular leukoderma, or the halo phenomenon, is a circular reaction of hypopigmentation that most commonly is observed alongside congenital nevi, acquired melanocytic nevi, blue nevi, Spitz nevi, vitiligo, and rarely melanoma.¹ There is limited literature on the mechanism of the halo phenomenon. Most of the literature proposes a T cell–mediated immune response to antigens, which causes not only surrounding pigment loss but also heralds the regression of central lesions.² Others have suggested a vascular mechanism, with blood shunted away from the lesions.³ Because guidelines discourage biopsy of typical halo nevi, it becomes important to evaluate lesions for worrisome features such as ulceration or asymmetry, especially in older patients. We present a case of a pigmented basal cell carcinoma (BCC) that exhibited the halo phenomenon. Four other cases have been described in the literature.^3-6

A 53-year-old man presented for evaluation of an asymptomatic lesion on the left side of the abdomen of approximately 8 months’ duration. He had no personal or family history of skin cancer. Physical examination revealed a central 1-cm, pink, verrucous papule surrounded by a 2×1.2-cm, depigmented, circular patch on the left side of the inferior abdomen (Figure 1). Upon questioning, the patient produced cell phone photographs of the trunk from 3 years prior, which did not show any lesions present. Full-body skin examination did not reveal any other concerning pigmented lesions. Excisional biopsy was performed due to concern for amelanotic melanoma, and histopathology revealed a superficial and pigmented BCC (Figure 2). Immunohistochemistry with Melan-A was negative for atypical melanocytes, with no uptake in the leukoderma areas.

Our patient’s final histologic diagnosis was pigmented BCC, which comprises only 6% of all BCCs.³ The proposed mechanism is that melanocytes colonize the tumor in the surrounding stroma and produce excess melanin. Basal cell carcinoma with halo phenomenon is a rare presentation. As in our case, 2 prior BCC reports also involved patients older than 50 years,^3,5 with the 2 other cases describing women in their late twenties and early thirties.^4,6 Additionally, 2 of 4 reports described patients with a history of multiple BCCs.^3,5

In summary, the seemingly benign halo phenomenon may accompany malignant processes such as nonmelanoma skin cancer. Careful consideration of lesion time course and atypia is imperative for proper clinical suspicion in such cases.