Cutis

The management of acne vulgaris (AV) in women has been the subject of considerable attention over the last few years. It has become increasingly recognized that a greater number of patient encounters in dermatology offices involve women with AV who are beyond their adolescent years. Overall, it is estimated that up to approximately 22% of women in the United States are affected by AV, with approximately half of women in their 20s and one-third of women in their 30s reporting some degree of AV.^1-4 Among women, the disease shows no predilection for certain skin types or ethnicities, can start during the preteenaged or adolescent years, can persist or recur in adulthood (persistent acne, 75%), or can start in adulthood (late-onset acne, 25%) in females with minimal or no history of AV occurring earlier in life.^3,5-7 In the subpopulation of adult women, AV occurs at a time when many expect to be far beyond this “teenage affliction.” Women who are affected commonly express feeling embarrassed and frustrated.^5-8

Most of the emphasis in the literature and in presentations at dermatology meetings regarding the management of AV in adult women has focused on excluding underlying disorders that cause excess androgens (eg, polycystic ovary syndrome, congenital adrenal hyperplasia, tumors, exogenous sources) as well as the use of systemic therapies such as oral contraceptives (OCs) and spironolactone.^5-7,9,10 Little attention has been given to the selection of topical therapies in this patient population, especially with regard to evidence from clinical studies. To date, results from published study analyses using topical agents specifically for adult females with facial AV have only included adapalene gel 0.3% applied once daily and dapsone gel 5% applied twice daily.^11-13 Both agents have been evaluated in subset analysis comparisons of outcomes in women aged 18 years and older versus adolescents aged 12 to 17 years based on data from 12-week phase 3 pivotal trials.^14-16

Are there clinically relevant differences between AV in adult versus adolescent females?

Although much has been written about AV in women, epidemiology, demographics, assessment of clinical presentation, and correlation of clinical presentation with excess androgens have not been emphasized,^1-3,5-10,17 likely due to marketing campaigns that emphasize AV as a disorder that predominantly affects teenagers as well as the focus on optimal use of oral spironolactone and/or OCs in the management of AV in the adult female population. Attention to spironolactone use is important because it is not approved by the US Food and Drug Administration for the treatment of AV. Spironolactone carries certain black-box warnings that may not be clinically relevant in all patients but still require attention. It also is associated with risks if taken during pregnancy, and it is a potassium-sparing diuretic with potential for hyperkalemia, especially in patients with reduced renal function or those who are taking potassium supplements or certain other medications.^6,9,11,17 Use of OCs to treat AV also is not without potential risks, with specific warnings and relative contraindications reported, especially in relation to increased risks for cardiac complications, stroke, and thromboembolism.^6,9,11,12 Because adult females are in a different stage of life than teenagers, there are defined psychosocial and medical considerations in managing AV in these patients compared with adolescents.^5-8,17 Importantly for both clinicians and patients, addressing these differences and considerations can have a major impact on whether or not women with AV experience successful treatment outcomes.^{1-3,5,6,8,10,13} Skin color and ethnicity also can affect the psychosocial and physical factors that influence the overall management of adult female patients with AV, including selection of therapies and handling long-term visible sequelae that occur in some AV patients, such as dyschromia (eg, persistent or postinflammatory erythema or hyperpigmentation) and acne scarring.^5-8,13,17-20

Psychosocial Considerations

With regard to psychosocial, emotional, and attitudinal considerations in women with AV, common findings include concern or frustration regarding the presence of AV beyond adolescence; anxiety; symptoms of depression; decreased self-confidence; increased self-consciousness, especially during public interactions or intimate situations; and interference with steady concentration at work or school.^5,6,8,13 Long-term complications of AV, such as dyschromia and acne scarring, are more likely to be encountered in adult patients, especially if they had AV as a teenager, with women reporting that they remain conscious of these adverse sequelae.⁸ It is estimated that approximately three-fourths of women with AV also had AV as teenagers; therefore, most of them have already used many over-the-counter and prescription therapies and are likely to want treatments that are newer, well-tolerated, safe, and known to be effective in adult women.^8,16,17 Convenience and simplicity are vital components of treatment selection and regimen design, as many women with AV frequently face time constraints in their daily routines due to family, social, employment, and home-related demands and responsibilities.^6-8,17

Medical Considerations

It is apparent from reports in the literature as well as from clinical experience that some women with AV present with a U-shaped pattern of involvement on the face,^5-7,10,13,17 which refers to the presence of predominantly inflammatory papules (many of them deep) and some nodules on the lower face, jawline, and anterolateral neck region, with comedones often sparse or absent.^5-7 It often is perceived and may be true that women who present with this pattern of distribution are more androgen sensitive despite having normal serum androgen levels or in some cases exhibit detectable excess androgens (eg, in the setting of polycystic ovary syndrome) and may be more likely to respond to hormonal therapies (eg, spironolactone, OCs) than those with mixed facial AV (ie, multiple comedonal and inflammatory acne lesions, not limited to a U-shaped pattern, similar to adolescent AV), but data are limited to support differentiation between the U-shaped pattern group and the conventional mixed facial AV group.^5-7,17 Adult and adolescent females in both groups sometimes report perimenstrual flares and frequent persistent papular AV that tends to concentrate on the perioral and chin area.

It is also important to consider that the current literature suggests approximately three-fourths of women with AV report that they also had AV as a teenager, with many indicating the same clinical pattern of AV and approximately one-third reporting AV that is more severe in adulthood than adolescence.^5-8,17 The available literature on topical and oral therapies used to treat AV in both adolescent and adult females predominantly focuses on inclusion of both inflammatory and noninflammatory (comedonal) facial AV lesions, does not specifically address or include the U-shaped pattern of AV in adult women for inclusion in studies that evaluate efficacy in this subgroup, and does not include AV involving the neck region and below the jawline margin as part of any study protocols and/or discussions about therapy.^{5-7,9-12,17,21-26} Involvement of the neck and lower jawline is common in women presenting with the U-shaped pattern of AV, and available studies only evaluate AV involving the face and do not include AV lesions present below the jawline margin. As a result, there is a considerable need for well-designed studies with laboratory assessments to include or exclude underlying detectable excess androgens and to assess the efficacy, tolerability, and safety of specific therapeutic agents both alone and in combination in adult women who present with a U-shaped pattern of AV.¹⁷

Other medical considerations that can influence treatment selection and are more likely to be present in adult versus adolescent females include underlying chronic medical disorders; concomitant medications that may interact with other oral agents; potential for pregnancy; age, particularly when prescribing OCs; and the  potential desire to stop taking OCs if already used over a prolonged period.^6,7

Age-Related Differentiation of Female Subgroups With AV

The age-based dividing line that defines AV in adults versus adolescent females has been described in the literature; however, the basis for published definitions of female subgroups with AV is not well-supported by strong scientific evidence.^1-3,5-7,17 The conventional dividing line that was originally selected to define adult females with AV was 25 years of age or older; persistent acne is present both during adolescence and at or after 25 years of age, while late-onset acne is described as AV that first presents at 25 years of age or older.^3,5-7

More recently, a range of 18 years or older has been used to classify adult female AV and a range of 12 to 17 years for adolescent female AV in subset analyses that evaluated treatment outcomes in both patient populations from phase 3 pivotal trials completed with adapalene gel 0.3% applied once daily and dapsone gel 5% applied twice daily.^14-16 These subanalyses included participants with facial AV that was predominantly moderate in severity, mandated specific lesion count ranges for both comedonal and inflammatory lesions, and included only facial AV that was above the mandibular (jawline) margin.^15,16,21,26 Therefore, patients with AV presenting in a U-shaped pattern with involvement below the jawline and on the neck were not included in these study analyses, as these patients were excluded from the phase 3 trials on which the analyses were based. The outcomes of these analyses apply to treatment in women who present with both inflammatory and noninflammatory facial AV lesions, which supports the observation that AV in this patient population is not always predominantly inflammatory and does not always present in a U-shaped distribution.^14-16 In fact, a U-shaped pattern of distribution appears to be less common in women with AV than a mixed inflammatory and comedonal distribution that involves the face more diffusely, though more data are needed from well-designed and large-scale epidemiologic and demographic studies.^5,14,17

Are there data available on the use of benzoyl peroxide with or without a topical antibiotic in women with AV?

There is a conspicuous absence of prospective clinical trials and retrospective analyses evaluating the specific use of individual AV therapies in adult females, with a particular lack of studies with topical agents (eg, benzoyl peroxide [BP]).¹⁴ Subset analyses have been completed for adapalene gel 0.3% and dapsone gel 5%.^15,16 Additionally, an age-based subset analysis in females with facial AV also has been completed with clindamycin phosphate (CP) 1.2%–BP 2.5% gel once daily, with data presented but not yet fully published.¹⁴

Two identical phase 3, double-blind, randomized, 12-week, 4-arm trials compared treatment outcomes in groups treated with an aqueous-based combination gel formulation containing BP 2.5% and CP 1.2% (n=797), active monad gels (BP [n=809] or CP [n=812]), or vehicle gel (n=395), all applied once daily in patients with facial AV.²² Participants were 12 years or older (mean age range, 19.1–19.6 years; age range, 12.1–70.2 years), were of either gender (approximately 50% split in each study arm), and presented with moderate (approximately 80% of participants) or severe AV (approximately 20% of participants) at baseline. The entry criteria for lesion types and number of lesions were 17 to 40 inflammatory lesions (ie, papules, pustules, <2 nodules)(range of mean number of lesions, 25.8–26.4) and 20 to 100 noninflammatory lesions (ie, closed comedones, open comedones)(range of mean number of lesions, 44.0–47.4). Participant demographics included white (73.9%–77.5%), black/African American (16.1%–20.4%), and Asian (2.1%–3.3%), with the remaining participants distributed among a variety of other ethnic groups such as Native Hawaiian/Native Pacific Islander and Native American Indian/Native Alaskan (collectively <5% in each study arm). Therefore, approximately 1 of every 4 patients had skin of color, which provided good diversity of patients considering the large study size (N=2813). Data analysis included dichotomization of participants by severity rating (moderate or severe based on evaluator global severity score) and skin phototype (Fitzpatrick skin types I–III or IV–VI).²²

The pooled results from both studies completed at 68 investigative sites demonstrated that CP 1.2%–BP 2.5% gel was superior in efficacy to each individual monad and to the vehicle in inflammatory, noninflammatory, and total lesion reductions as early as week 4 (P<.001) and at week 12, which was the study end point (P<.001), with superiority also demonstrated in achieving treatment success (defined as a >2 grade improvement according to the evaluator global severity score) compared to the 3 other study arms (P<.001).²² Subject assessments also were consistent with outcomes noted by the investigators. Cutaneous tolerability was favorable and comparable in all 4 study arms with less than 1% of participants discontinuing treatment due to adverse events.²²

A subset analysis of the data from the phase 3 pivotal trials with CP 1.2%–BP 2.5% gel was completed to compare reductions in both inflammatory and noninflammatory lesions in female participants who were younger than 25 years and 25 years of age or older in all 4 study arms. This information has been presented^14,17 but has not been previously published. Based on the overall results reported in the phase 3 studies, there were no differentiations in skin tolerability or safety based on participant age, gender, or skin type.²² The subanalysis included a total of 1080 females who were younger than 25 years and 395 females who were 25 years of age or older. The lesion reduction outcomes of this subanalysis are presented in the Table. Statistical analyses of the results among these age groups in the 4 study arms were not completed because the objective was to determine if there were any major or obvious differences in reduction of AV lesions based on the conventional dividing line of 25 years of age in adult women as compared to adolescent females treated with CP 1.2%–BP 2.5% gel. In addition, the large difference in numbers of female participants between the 2 age groups (>25 years of age, n=395; <25 years of age, n=1080) at least partially confounds both statistical and observational analysis. Among the women who were 25 years of age or older who were included in the subanalysis, 67.0% and 25.8% were between the ages of 25 to 35 years and 36 to 45 years, respectively. Based on the outcomes reported in the phase 3 trials and in this subgroup analysis, CP 1.2%–BP 2.5% gel applied once daily over a 12-week period appeared overall to be comparably effective in females regardless of age and with no apparent adverse events regarding differences in skin tolerability or safety.^14,22 One observation that was noted was the possible trend of greater reduction in both lesion types in women older than 35 years versus younger females with the use of the combination gel or BP alone; however, the number of female participants who were older than 35 years of age was substantially less (n=102) than those who were 35 years of age or younger (n=1345), thus precluding support for any definitive conclusions about this possible trend.²²

How can CP 1.2%–BP 2.5% gel be incorporated into a treatment regimen for women with facial AV?

The incorporation of CP 1.2%–BP 2.5% gel into a treatment regimen for women with facial AV is similar to the general use of BP-containing formulations in the overall management of AV.^9,14,27,28 Because women with AV commonly present with facial inflammatory lesions and many also with facial comedones, CP 1.2%–BP 2.5% gel is best used once daily in the morning in combination with a topical retinoid in the evening,^9,27 which can be achieved with use of CP 1.2%–BP 2.5% gel in the morning and a topical retinoid (ie, tretinoin, adapalene, tazarotene) in the evening or CP 1.2%–tretinoin 0.025% gel in the evening. It is important to note that cutaneous irritation may be more likely if neck lesions are present; the potential for bleaching of colored fabric by BP also is a practical concern.²⁸ In addition, CP 1.2%–BP 2.5% gel may also be used in combination with topical dapsone, but both products should be applied separately at different times of the day to avoid temporary orange discoloration of the skin, which appears to be an uncommon side effect but remains a possibility based on the product information for dapsone gel 5% with regard to its concomitant use with BP.^29,30

The management of acne vulgaris (AV) in women has been the subject of considerable attention over the last few years. It has become increasingly recognized that a greater number of patient encounters in dermatology offices involve women with AV who are beyond their adolescent years. Overall, it is estimated that up to approximately 22% of women in the United States are affected by AV, with approximately half of women in their 20s and one-third of women in their 30s reporting some degree of AV.^1-4 Among women, the disease shows no predilection for certain skin types or ethnicities, can start during the preteenaged or adolescent years, can persist or recur in adulthood (persistent acne, 75%), or can start in adulthood (late-onset acne, 25%) in females with minimal or no history of AV occurring earlier in life.^3,5-7 In the subpopulation of adult women, AV occurs at a time when many expect to be far beyond this “teenage affliction.” Women who are affected commonly express feeling embarrassed and frustrated.^5-8

Most of the emphasis in the literature and in presentations at dermatology meetings regarding the management of AV in adult women has focused on excluding underlying disorders that cause excess androgens (eg, polycystic ovary syndrome, congenital adrenal hyperplasia, tumors, exogenous sources) as well as the use of systemic therapies such as oral contraceptives (OCs) and spironolactone.^5-7,9,10 Little attention has been given to the selection of topical therapies in this patient population, especially with regard to evidence from clinical studies. To date, results from published study analyses using topical agents specifically for adult females with facial AV have only included adapalene gel 0.3% applied once daily and dapsone gel 5% applied twice daily.^11-13 Both agents have been evaluated in subset analysis comparisons of outcomes in women aged 18 years and older versus adolescents aged 12 to 17 years based on data from 12-week phase 3 pivotal trials.^14-16

Are there clinically relevant differences between AV in adult versus adolescent females?

Although much has been written about AV in women, epidemiology, demographics, assessment of clinical presentation, and correlation of clinical presentation with excess androgens have not been emphasized,^1-3,5-10,17 likely due to marketing campaigns that emphasize AV as a disorder that predominantly affects teenagers as well as the focus on optimal use of oral spironolactone and/or OCs in the management of AV in the adult female population. Attention to spironolactone use is important because it is not approved by the US Food and Drug Administration for the treatment of AV. Spironolactone carries certain black-box warnings that may not be clinically relevant in all patients but still require attention. It also is associated with risks if taken during pregnancy, and it is a potassium-sparing diuretic with potential for hyperkalemia, especially in patients with reduced renal function or those who are taking potassium supplements or certain other medications.^6,9,11,17 Use of OCs to treat AV also is not without potential risks, with specific warnings and relative contraindications reported, especially in relation to increased risks for cardiac complications, stroke, and thromboembolism.^6,9,11,12 Because adult females are in a different stage of life than teenagers, there are defined psychosocial and medical considerations in managing AV in these patients compared with adolescents.^5-8,17 Importantly for both clinicians and patients, addressing these differences and considerations can have a major impact on whether or not women with AV experience successful treatment outcomes.^{1-3,5,6,8,10,13} Skin color and ethnicity also can affect the psychosocial and physical factors that influence the overall management of adult female patients with AV, including selection of therapies and handling long-term visible sequelae that occur in some AV patients, such as dyschromia (eg, persistent or postinflammatory erythema or hyperpigmentation) and acne scarring.^5-8,13,17-20

Psychosocial Considerations

With regard to psychosocial, emotional, and attitudinal considerations in women with AV, common findings include concern or frustration regarding the presence of AV beyond adolescence; anxiety; symptoms of depression; decreased self-confidence; increased self-consciousness, especially during public interactions or intimate situations; and interference with steady concentration at work or school.^5,6,8,13 Long-term complications of AV, such as dyschromia and acne scarring, are more likely to be encountered in adult patients, especially if they had AV as a teenager, with women reporting that they remain conscious of these adverse sequelae.⁸ It is estimated that approximately three-fourths of women with AV also had AV as teenagers; therefore, most of them have already used many over-the-counter and prescription therapies and are likely to want treatments that are newer, well-tolerated, safe, and known to be effective in adult women.^8,16,17 Convenience and simplicity are vital components of treatment selection and regimen design, as many women with AV frequently face time constraints in their daily routines due to family, social, employment, and home-related demands and responsibilities.^6-8,17

Medical Considerations

It is apparent from reports in the literature as well as from clinical experience that some women with AV present with a U-shaped pattern of involvement on the face,^5-7,10,13,17 which refers to the presence of predominantly inflammatory papules (many of them deep) and some nodules on the lower face, jawline, and anterolateral neck region, with comedones often sparse or absent.^5-7 It often is perceived and may be true that women who present with this pattern of distribution are more androgen sensitive despite having normal serum androgen levels or in some cases exhibit detectable excess androgens (eg, in the setting of polycystic ovary syndrome) and may be more likely to respond to hormonal therapies (eg, spironolactone, OCs) than those with mixed facial AV (ie, multiple comedonal and inflammatory acne lesions, not limited to a U-shaped pattern, similar to adolescent AV), but data are limited to support differentiation between the U-shaped pattern group and the conventional mixed facial AV group.^5-7,17 Adult and adolescent females in both groups sometimes report perimenstrual flares and frequent persistent papular AV that tends to concentrate on the perioral and chin area.

It is also important to consider that the current literature suggests approximately three-fourths of women with AV report that they also had AV as a teenager, with many indicating the same clinical pattern of AV and approximately one-third reporting AV that is more severe in adulthood than adolescence.^5-8,17 The available literature on topical and oral therapies used to treat AV in both adolescent and adult females predominantly focuses on inclusion of both inflammatory and noninflammatory (comedonal) facial AV lesions, does not specifically address or include the U-shaped pattern of AV in adult women for inclusion in studies that evaluate efficacy in this subgroup, and does not include AV involving the neck region and below the jawline margin as part of any study protocols and/or discussions about therapy.^{5-7,9-12,17,21-26} Involvement of the neck and lower jawline is common in women presenting with the U-shaped pattern of AV, and available studies only evaluate AV involving the face and do not include AV lesions present below the jawline margin. As a result, there is a considerable need for well-designed studies with laboratory assessments to include or exclude underlying detectable excess androgens and to assess the efficacy, tolerability, and safety of specific therapeutic agents both alone and in combination in adult women who present with a U-shaped pattern of AV.¹⁷

Other medical considerations that can influence treatment selection and are more likely to be present in adult versus adolescent females include underlying chronic medical disorders; concomitant medications that may interact with other oral agents; potential for pregnancy; age, particularly when prescribing OCs; and the  potential desire to stop taking OCs if already used over a prolonged period.^6,7

Age-Related Differentiation of Female Subgroups With AV

The age-based dividing line that defines AV in adults versus adolescent females has been described in the literature; however, the basis for published definitions of female subgroups with AV is not well-supported by strong scientific evidence.^1-3,5-7,17 The conventional dividing line that was originally selected to define adult females with AV was 25 years of age or older; persistent acne is present both during adolescence and at or after 25 years of age, while late-onset acne is described as AV that first presents at 25 years of age or older.^3,5-7

More recently, a range of 18 years or older has been used to classify adult female AV and a range of 12 to 17 years for adolescent female AV in subset analyses that evaluated treatment outcomes in both patient populations from phase 3 pivotal trials completed with adapalene gel 0.3% applied once daily and dapsone gel 5% applied twice daily.^14-16 These subanalyses included participants with facial AV that was predominantly moderate in severity, mandated specific lesion count ranges for both comedonal and inflammatory lesions, and included only facial AV that was above the mandibular (jawline) margin.^15,16,21,26 Therefore, patients with AV presenting in a U-shaped pattern with involvement below the jawline and on the neck were not included in these study analyses, as these patients were excluded from the phase 3 trials on which the analyses were based. The outcomes of these analyses apply to treatment in women who present with both inflammatory and noninflammatory facial AV lesions, which supports the observation that AV in this patient population is not always predominantly inflammatory and does not always present in a U-shaped distribution.^14-16 In fact, a U-shaped pattern of distribution appears to be less common in women with AV than a mixed inflammatory and comedonal distribution that involves the face more diffusely, though more data are needed from well-designed and large-scale epidemiologic and demographic studies.^5,14,17

Are there data available on the use of benzoyl peroxide with or without a topical antibiotic in women with AV?

There is a conspicuous absence of prospective clinical trials and retrospective analyses evaluating the specific use of individual AV therapies in adult females, with a particular lack of studies with topical agents (eg, benzoyl peroxide [BP]).¹⁴ Subset analyses have been completed for adapalene gel 0.3% and dapsone gel 5%.^15,16 Additionally, an age-based subset analysis in females with facial AV also has been completed with clindamycin phosphate (CP) 1.2%–BP 2.5% gel once daily, with data presented but not yet fully published.¹⁴

Two identical phase 3, double-blind, randomized, 12-week, 4-arm trials compared treatment outcomes in groups treated with an aqueous-based combination gel formulation containing BP 2.5% and CP 1.2% (n=797), active monad gels (BP [n=809] or CP [n=812]), or vehicle gel (n=395), all applied once daily in patients with facial AV.²² Participants were 12 years or older (mean age range, 19.1–19.6 years; age range, 12.1–70.2 years), were of either gender (approximately 50% split in each study arm), and presented with moderate (approximately 80% of participants) or severe AV (approximately 20% of participants) at baseline. The entry criteria for lesion types and number of lesions were 17 to 40 inflammatory lesions (ie, papules, pustules, <2 nodules)(range of mean number of lesions, 25.8–26.4) and 20 to 100 noninflammatory lesions (ie, closed comedones, open comedones)(range of mean number of lesions, 44.0–47.4). Participant demographics included white (73.9%–77.5%), black/African American (16.1%–20.4%), and Asian (2.1%–3.3%), with the remaining participants distributed among a variety of other ethnic groups such as Native Hawaiian/Native Pacific Islander and Native American Indian/Native Alaskan (collectively <5% in each study arm). Therefore, approximately 1 of every 4 patients had skin of color, which provided good diversity of patients considering the large study size (N=2813). Data analysis included dichotomization of participants by severity rating (moderate or severe based on evaluator global severity score) and skin phototype (Fitzpatrick skin types I–III or IV–VI).²²

The pooled results from both studies completed at 68 investigative sites demonstrated that CP 1.2%–BP 2.5% gel was superior in efficacy to each individual monad and to the vehicle in inflammatory, noninflammatory, and total lesion reductions as early as week 4 (P<.001) and at week 12, which was the study end point (P<.001), with superiority also demonstrated in achieving treatment success (defined as a >2 grade improvement according to the evaluator global severity score) compared to the 3 other study arms (P<.001).²² Subject assessments also were consistent with outcomes noted by the investigators. Cutaneous tolerability was favorable and comparable in all 4 study arms with less than 1% of participants discontinuing treatment due to adverse events.²²

A subset analysis of the data from the phase 3 pivotal trials with CP 1.2%–BP 2.5% gel was completed to compare reductions in both inflammatory and noninflammatory lesions in female participants who were younger than 25 years and 25 years of age or older in all 4 study arms. This information has been presented^14,17 but has not been previously published. Based on the overall results reported in the phase 3 studies, there were no differentiations in skin tolerability or safety based on participant age, gender, or skin type.²² The subanalysis included a total of 1080 females who were younger than 25 years and 395 females who were 25 years of age or older. The lesion reduction outcomes of this subanalysis are presented in the Table. Statistical analyses of the results among these age groups in the 4 study arms were not completed because the objective was to determine if there were any major or obvious differences in reduction of AV lesions based on the conventional dividing line of 25 years of age in adult women as compared to adolescent females treated with CP 1.2%–BP 2.5% gel. In addition, the large difference in numbers of female participants between the 2 age groups (>25 years of age, n=395; <25 years of age, n=1080) at least partially confounds both statistical and observational analysis. Among the women who were 25 years of age or older who were included in the subanalysis, 67.0% and 25.8% were between the ages of 25 to 35 years and 36 to 45 years, respectively. Based on the outcomes reported in the phase 3 trials and in this subgroup analysis, CP 1.2%–BP 2.5% gel applied once daily over a 12-week period appeared overall to be comparably effective in females regardless of age and with no apparent adverse events regarding differences in skin tolerability or safety.^14,22 One observation that was noted was the possible trend of greater reduction in both lesion types in women older than 35 years versus younger females with the use of the combination gel or BP alone; however, the number of female participants who were older than 35 years of age was substantially less (n=102) than those who were 35 years of age or younger (n=1345), thus precluding support for any definitive conclusions about this possible trend.²²

How can CP 1.2%–BP 2.5% gel be incorporated into a treatment regimen for women with facial AV?

The incorporation of CP 1.2%–BP 2.5% gel into a treatment regimen for women with facial AV is similar to the general use of BP-containing formulations in the overall management of AV.^9,14,27,28 Because women with AV commonly present with facial inflammatory lesions and many also with facial comedones, CP 1.2%–BP 2.5% gel is best used once daily in the morning in combination with a topical retinoid in the evening,^9,27 which can be achieved with use of CP 1.2%–BP 2.5% gel in the morning and a topical retinoid (ie, tretinoin, adapalene, tazarotene) in the evening or CP 1.2%–tretinoin 0.025% gel in the evening. It is important to note that cutaneous irritation may be more likely if neck lesions are present; the potential for bleaching of colored fabric by BP also is a practical concern.²⁸ In addition, CP 1.2%–BP 2.5% gel may also be used in combination with topical dapsone, but both products should be applied separately at different times of the day to avoid temporary orange discoloration of the skin, which appears to be an uncommon side effect but remains a possibility based on the product information for dapsone gel 5% with regard to its concomitant use with BP.^29,30

The management of acne vulgaris (AV) in women has been the subject of considerable attention over the last few years. It has become increasingly recognized that a greater number of patient encounters in dermatology offices involve women with AV who are beyond their adolescent years. Overall, it is estimated that up to approximately 22% of women in the United States are affected by AV, with approximately half of women in their 20s and one-third of women in their 30s reporting some degree of AV.^1-4 Among women, the disease shows no predilection for certain skin types or ethnicities, can start during the preteenaged or adolescent years, can persist or recur in adulthood (persistent acne, 75%), or can start in adulthood (late-onset acne, 25%) in females with minimal or no history of AV occurring earlier in life.^3,5-7 In the subpopulation of adult women, AV occurs at a time when many expect to be far beyond this “teenage affliction.” Women who are affected commonly express feeling embarrassed and frustrated.^5-8

Most of the emphasis in the literature and in presentations at dermatology meetings regarding the management of AV in adult women has focused on excluding underlying disorders that cause excess androgens (eg, polycystic ovary syndrome, congenital adrenal hyperplasia, tumors, exogenous sources) as well as the use of systemic therapies such as oral contraceptives (OCs) and spironolactone.^5-7,9,10 Little attention has been given to the selection of topical therapies in this patient population, especially with regard to evidence from clinical studies. To date, results from published study analyses using topical agents specifically for adult females with facial AV have only included adapalene gel 0.3% applied once daily and dapsone gel 5% applied twice daily.^11-13 Both agents have been evaluated in subset analysis comparisons of outcomes in women aged 18 years and older versus adolescents aged 12 to 17 years based on data from 12-week phase 3 pivotal trials.^14-16

Are there clinically relevant differences between AV in adult versus adolescent females?

Although much has been written about AV in women, epidemiology, demographics, assessment of clinical presentation, and correlation of clinical presentation with excess androgens have not been emphasized,^1-3,5-10,17 likely due to marketing campaigns that emphasize AV as a disorder that predominantly affects teenagers as well as the focus on optimal use of oral spironolactone and/or OCs in the management of AV in the adult female population. Attention to spironolactone use is important because it is not approved by the US Food and Drug Administration for the treatment of AV. Spironolactone carries certain black-box warnings that may not be clinically relevant in all patients but still require attention. It also is associated with risks if taken during pregnancy, and it is a potassium-sparing diuretic with potential for hyperkalemia, especially in patients with reduced renal function or those who are taking potassium supplements or certain other medications.^6,9,11,17 Use of OCs to treat AV also is not without potential risks, with specific warnings and relative contraindications reported, especially in relation to increased risks for cardiac complications, stroke, and thromboembolism.^6,9,11,12 Because adult females are in a different stage of life than teenagers, there are defined psychosocial and medical considerations in managing AV in these patients compared with adolescents.^5-8,17 Importantly for both clinicians and patients, addressing these differences and considerations can have a major impact on whether or not women with AV experience successful treatment outcomes.^{1-3,5,6,8,10,13} Skin color and ethnicity also can affect the psychosocial and physical factors that influence the overall management of adult female patients with AV, including selection of therapies and handling long-term visible sequelae that occur in some AV patients, such as dyschromia (eg, persistent or postinflammatory erythema or hyperpigmentation) and acne scarring.^5-8,13,17-20

Psychosocial Considerations

With regard to psychosocial, emotional, and attitudinal considerations in women with AV, common findings include concern or frustration regarding the presence of AV beyond adolescence; anxiety; symptoms of depression; decreased self-confidence; increased self-consciousness, especially during public interactions or intimate situations; and interference with steady concentration at work or school.^5,6,8,13 Long-term complications of AV, such as dyschromia and acne scarring, are more likely to be encountered in adult patients, especially if they had AV as a teenager, with women reporting that they remain conscious of these adverse sequelae.⁸ It is estimated that approximately three-fourths of women with AV also had AV as teenagers; therefore, most of them have already used many over-the-counter and prescription therapies and are likely to want treatments that are newer, well-tolerated, safe, and known to be effective in adult women.^8,16,17 Convenience and simplicity are vital components of treatment selection and regimen design, as many women with AV frequently face time constraints in their daily routines due to family, social, employment, and home-related demands and responsibilities.^6-8,17

Medical Considerations

It is apparent from reports in the literature as well as from clinical experience that some women with AV present with a U-shaped pattern of involvement on the face,^5-7,10,13,17 which refers to the presence of predominantly inflammatory papules (many of them deep) and some nodules on the lower face, jawline, and anterolateral neck region, with comedones often sparse or absent.^5-7 It often is perceived and may be true that women who present with this pattern of distribution are more androgen sensitive despite having normal serum androgen levels or in some cases exhibit detectable excess androgens (eg, in the setting of polycystic ovary syndrome) and may be more likely to respond to hormonal therapies (eg, spironolactone, OCs) than those with mixed facial AV (ie, multiple comedonal and inflammatory acne lesions, not limited to a U-shaped pattern, similar to adolescent AV), but data are limited to support differentiation between the U-shaped pattern group and the conventional mixed facial AV group.^5-7,17 Adult and adolescent females in both groups sometimes report perimenstrual flares and frequent persistent papular AV that tends to concentrate on the perioral and chin area.

It is also important to consider that the current literature suggests approximately three-fourths of women with AV report that they also had AV as a teenager, with many indicating the same clinical pattern of AV and approximately one-third reporting AV that is more severe in adulthood than adolescence.^5-8,17 The available literature on topical and oral therapies used to treat AV in both adolescent and adult females predominantly focuses on inclusion of both inflammatory and noninflammatory (comedonal) facial AV lesions, does not specifically address or include the U-shaped pattern of AV in adult women for inclusion in studies that evaluate efficacy in this subgroup, and does not include AV involving the neck region and below the jawline margin as part of any study protocols and/or discussions about therapy.^{5-7,9-12,17,21-26} Involvement of the neck and lower jawline is common in women presenting with the U-shaped pattern of AV, and available studies only evaluate AV involving the face and do not include AV lesions present below the jawline margin. As a result, there is a considerable need for well-designed studies with laboratory assessments to include or exclude underlying detectable excess androgens and to assess the efficacy, tolerability, and safety of specific therapeutic agents both alone and in combination in adult women who present with a U-shaped pattern of AV.¹⁷

Other medical considerations that can influence treatment selection and are more likely to be present in adult versus adolescent females include underlying chronic medical disorders; concomitant medications that may interact with other oral agents; potential for pregnancy; age, particularly when prescribing OCs; and the  potential desire to stop taking OCs if already used over a prolonged period.^6,7

Age-Related Differentiation of Female Subgroups With AV

The age-based dividing line that defines AV in adults versus adolescent females has been described in the literature; however, the basis for published definitions of female subgroups with AV is not well-supported by strong scientific evidence.^1-3,5-7,17 The conventional dividing line that was originally selected to define adult females with AV was 25 years of age or older; persistent acne is present both during adolescence and at or after 25 years of age, while late-onset acne is described as AV that first presents at 25 years of age or older.^3,5-7

More recently, a range of 18 years or older has been used to classify adult female AV and a range of 12 to 17 years for adolescent female AV in subset analyses that evaluated treatment outcomes in both patient populations from phase 3 pivotal trials completed with adapalene gel 0.3% applied once daily and dapsone gel 5% applied twice daily.^14-16 These subanalyses included participants with facial AV that was predominantly moderate in severity, mandated specific lesion count ranges for both comedonal and inflammatory lesions, and included only facial AV that was above the mandibular (jawline) margin.^15,16,21,26 Therefore, patients with AV presenting in a U-shaped pattern with involvement below the jawline and on the neck were not included in these study analyses, as these patients were excluded from the phase 3 trials on which the analyses were based. The outcomes of these analyses apply to treatment in women who present with both inflammatory and noninflammatory facial AV lesions, which supports the observation that AV in this patient population is not always predominantly inflammatory and does not always present in a U-shaped distribution.^14-16 In fact, a U-shaped pattern of distribution appears to be less common in women with AV than a mixed inflammatory and comedonal distribution that involves the face more diffusely, though more data are needed from well-designed and large-scale epidemiologic and demographic studies.^5,14,17

Are there data available on the use of benzoyl peroxide with or without a topical antibiotic in women with AV?

There is a conspicuous absence of prospective clinical trials and retrospective analyses evaluating the specific use of individual AV therapies in adult females, with a particular lack of studies with topical agents (eg, benzoyl peroxide [BP]).¹⁴ Subset analyses have been completed for adapalene gel 0.3% and dapsone gel 5%.^15,16 Additionally, an age-based subset analysis in females with facial AV also has been completed with clindamycin phosphate (CP) 1.2%–BP 2.5% gel once daily, with data presented but not yet fully published.¹⁴

Two identical phase 3, double-blind, randomized, 12-week, 4-arm trials compared treatment outcomes in groups treated with an aqueous-based combination gel formulation containing BP 2.5% and CP 1.2% (n=797), active monad gels (BP [n=809] or CP [n=812]), or vehicle gel (n=395), all applied once daily in patients with facial AV.²² Participants were 12 years or older (mean age range, 19.1–19.6 years; age range, 12.1–70.2 years), were of either gender (approximately 50% split in each study arm), and presented with moderate (approximately 80% of participants) or severe AV (approximately 20% of participants) at baseline. The entry criteria for lesion types and number of lesions were 17 to 40 inflammatory lesions (ie, papules, pustules, <2 nodules)(range of mean number of lesions, 25.8–26.4) and 20 to 100 noninflammatory lesions (ie, closed comedones, open comedones)(range of mean number of lesions, 44.0–47.4). Participant demographics included white (73.9%–77.5%), black/African American (16.1%–20.4%), and Asian (2.1%–3.3%), with the remaining participants distributed among a variety of other ethnic groups such as Native Hawaiian/Native Pacific Islander and Native American Indian/Native Alaskan (collectively <5% in each study arm). Therefore, approximately 1 of every 4 patients had skin of color, which provided good diversity of patients considering the large study size (N=2813). Data analysis included dichotomization of participants by severity rating (moderate or severe based on evaluator global severity score) and skin phototype (Fitzpatrick skin types I–III or IV–VI).²²

The pooled results from both studies completed at 68 investigative sites demonstrated that CP 1.2%–BP 2.5% gel was superior in efficacy to each individual monad and to the vehicle in inflammatory, noninflammatory, and total lesion reductions as early as week 4 (P<.001) and at week 12, which was the study end point (P<.001), with superiority also demonstrated in achieving treatment success (defined as a >2 grade improvement according to the evaluator global severity score) compared to the 3 other study arms (P<.001).²² Subject assessments also were consistent with outcomes noted by the investigators. Cutaneous tolerability was favorable and comparable in all 4 study arms with less than 1% of participants discontinuing treatment due to adverse events.²²

A subset analysis of the data from the phase 3 pivotal trials with CP 1.2%–BP 2.5% gel was completed to compare reductions in both inflammatory and noninflammatory lesions in female participants who were younger than 25 years and 25 years of age or older in all 4 study arms. This information has been presented^14,17 but has not been previously published. Based on the overall results reported in the phase 3 studies, there were no differentiations in skin tolerability or safety based on participant age, gender, or skin type.²² The subanalysis included a total of 1080 females who were younger than 25 years and 395 females who were 25 years of age or older. The lesion reduction outcomes of this subanalysis are presented in the Table. Statistical analyses of the results among these age groups in the 4 study arms were not completed because the objective was to determine if there were any major or obvious differences in reduction of AV lesions based on the conventional dividing line of 25 years of age in adult women as compared to adolescent females treated with CP 1.2%–BP 2.5% gel. In addition, the large difference in numbers of female participants between the 2 age groups (>25 years of age, n=395; <25 years of age, n=1080) at least partially confounds both statistical and observational analysis. Among the women who were 25 years of age or older who were included in the subanalysis, 67.0% and 25.8% were between the ages of 25 to 35 years and 36 to 45 years, respectively. Based on the outcomes reported in the phase 3 trials and in this subgroup analysis, CP 1.2%–BP 2.5% gel applied once daily over a 12-week period appeared overall to be comparably effective in females regardless of age and with no apparent adverse events regarding differences in skin tolerability or safety.^14,22 One observation that was noted was the possible trend of greater reduction in both lesion types in women older than 35 years versus younger females with the use of the combination gel or BP alone; however, the number of female participants who were older than 35 years of age was substantially less (n=102) than those who were 35 years of age or younger (n=1345), thus precluding support for any definitive conclusions about this possible trend.²²

How can CP 1.2%–BP 2.5% gel be incorporated into a treatment regimen for women with facial AV?

The incorporation of CP 1.2%–BP 2.5% gel into a treatment regimen for women with facial AV is similar to the general use of BP-containing formulations in the overall management of AV.^9,14,27,28 Because women with AV commonly present with facial inflammatory lesions and many also with facial comedones, CP 1.2%–BP 2.5% gel is best used once daily in the morning in combination with a topical retinoid in the evening,^9,27 which can be achieved with use of CP 1.2%–BP 2.5% gel in the morning and a topical retinoid (ie, tretinoin, adapalene, tazarotene) in the evening or CP 1.2%–tretinoin 0.025% gel in the evening. It is important to note that cutaneous irritation may be more likely if neck lesions are present; the potential for bleaching of colored fabric by BP also is a practical concern.²⁸ In addition, CP 1.2%–BP 2.5% gel may also be used in combination with topical dapsone, but both products should be applied separately at different times of the day to avoid temporary orange discoloration of the skin, which appears to be an uncommon side effect but remains a possibility based on the product information for dapsone gel 5% with regard to its concomitant use with BP.^29,30

Lipidized dermatofibromas most commonly are found on the ankles, which has led some authors to refer to these lesions as ankle-type fibrous histiocytomas.¹ Compared to ordinary dermatofibromas, patients with lipidized dermatofibromas tend to be older, most commonly presenting in the fifth or sixth decades of life, and are predominantly male. Lipidized dermatofibromas typically present as well-circumscribed solitary nodules in the dermis. Characteristic features include numerous xanthomatous cells dissected by distinctive hyalinized wiry collagen fibers (Figures 1 and 2).¹ Xanthomatous cells can be round, polygonal, or stellate in shape. These characteristic features in combination with others of dermatofibromas (eg, epidermal acanthosis [Figure 1]) fulfill the criteria for diagnosis of a lipidized dermatofibroma. Additionally, lipidized dermatofibromas tend to be larger than ordinary dermatofibromas, which typically are less than 2 cm in diameter.¹

Figure 1. Lipidized dermatofibromas are characterized by classic epidermal features of dermatofibromas, such as acanthosis, along with numerous foam cells and extensive stromal hyalinization (H&E, original magnification ×1.5).

Figure 2. Higher-power view of a lipidized dermatofibroma shows the characteristic irregular dissection of hyalinized wiry collagen fibers between the xanthomatous cells (H&E, original magnification ×20).

Eruptive xanthomas are characterized by a lacelike infiltrate of extravascular lipid deposits between collagen bundles (Figure 3).² Granular cell tumors are composed of sheets and/or nests of large cells with abundant eosinophilic cytoplasm and may be confused with lipidized dermatofibromas, as they also may induce overlying pseudoepitheliomatous hyperplasia³; however, on closer examination of the cells, the cytoplasm is found to be granular (Figure 4), which contrasts the finely vacuolated cytoplasm of xanthomatous cells found in lipidized dermatofibromas. Giant lysosomal granules (eg, pustulo-ovoid bodies of Milian) are present in some cases.² Of note, an unusual variant of dermatofibroma exists that features prominent granular cells.⁴

Figure 3. Lacelike deposition of extravascular lipid deposits is seen infiltrating between collagen bundles in an eruptive xanthoma (H&E, original magnification ×20).

Figure 4. An abundant eosinophilic, finely granular cytoplasm is characteristic of granular cell tumor (H&E, original magnification ×40).

Tuberous xanthomas most commonly occur around the pressure areas, such as the knees, elbows, and buttocks. Foam cells are a main feature of tuberous xanthomas and are arranged in large aggregates throughout the dermis.² Tuberous xanthomas lack Touton giant cells or inflammatory cells. Older lesions tend to develop substantial fibrosis (Figure 5). Although foam cells can be present in older lesions, they are never as conspicuous as those found in other xanthomas.

Xanthogranulomas commonly occur on the head and neck. Findings noted on low magnification include a well-circumscribed exophytic nodule and an epidermal collarette, which help to easily distinguish xanthogranulomas from lipidized dermatofibromas. Additionally, the presence of a more prominent inflammatory infiltrate, which often includes eosinophils, as well as multinucleated Touton giant cells (Figure 6) and histiocytes with more eosinophilic and less xanthomatous cytoplasm can help distinguish between the lesions.^1,5 Notably, Touton giant cells also can be seen in lipidized dermatofibromas,¹ but the presence of unique features such as distinctive stromal hyalinization are clues to the correct diagnosis of a lipidized dermatofibroma.

Lipidized dermatofibromas most commonly are found on the ankles, which has led some authors to refer to these lesions as ankle-type fibrous histiocytomas.¹ Compared to ordinary dermatofibromas, patients with lipidized dermatofibromas tend to be older, most commonly presenting in the fifth or sixth decades of life, and are predominantly male. Lipidized dermatofibromas typically present as well-circumscribed solitary nodules in the dermis. Characteristic features include numerous xanthomatous cells dissected by distinctive hyalinized wiry collagen fibers (Figures 1 and 2).¹ Xanthomatous cells can be round, polygonal, or stellate in shape. These characteristic features in combination with others of dermatofibromas (eg, epidermal acanthosis [Figure 1]) fulfill the criteria for diagnosis of a lipidized dermatofibroma. Additionally, lipidized dermatofibromas tend to be larger than ordinary dermatofibromas, which typically are less than 2 cm in diameter.¹

Figure 1. Lipidized dermatofibromas are characterized by classic epidermal features of dermatofibromas, such as acanthosis, along with numerous foam cells and extensive stromal hyalinization (H&E, original magnification ×1.5).

Figure 2. Higher-power view of a lipidized dermatofibroma shows the characteristic irregular dissection of hyalinized wiry collagen fibers between the xanthomatous cells (H&E, original magnification ×20).

Eruptive xanthomas are characterized by a lacelike infiltrate of extravascular lipid deposits between collagen bundles (Figure 3).² Granular cell tumors are composed of sheets and/or nests of large cells with abundant eosinophilic cytoplasm and may be confused with lipidized dermatofibromas, as they also may induce overlying pseudoepitheliomatous hyperplasia³; however, on closer examination of the cells, the cytoplasm is found to be granular (Figure 4), which contrasts the finely vacuolated cytoplasm of xanthomatous cells found in lipidized dermatofibromas. Giant lysosomal granules (eg, pustulo-ovoid bodies of Milian) are present in some cases.² Of note, an unusual variant of dermatofibroma exists that features prominent granular cells.⁴

Figure 3. Lacelike deposition of extravascular lipid deposits is seen infiltrating between collagen bundles in an eruptive xanthoma (H&E, original magnification ×20).

Figure 4. An abundant eosinophilic, finely granular cytoplasm is characteristic of granular cell tumor (H&E, original magnification ×40).

Tuberous xanthomas most commonly occur around the pressure areas, such as the knees, elbows, and buttocks. Foam cells are a main feature of tuberous xanthomas and are arranged in large aggregates throughout the dermis.² Tuberous xanthomas lack Touton giant cells or inflammatory cells. Older lesions tend to develop substantial fibrosis (Figure 5). Although foam cells can be present in older lesions, they are never as conspicuous as those found in other xanthomas.

Xanthogranulomas commonly occur on the head and neck. Findings noted on low magnification include a well-circumscribed exophytic nodule and an epidermal collarette, which help to easily distinguish xanthogranulomas from lipidized dermatofibromas. Additionally, the presence of a more prominent inflammatory infiltrate, which often includes eosinophils, as well as multinucleated Touton giant cells (Figure 6) and histiocytes with more eosinophilic and less xanthomatous cytoplasm can help distinguish between the lesions.^1,5 Notably, Touton giant cells also can be seen in lipidized dermatofibromas,¹ but the presence of unique features such as distinctive stromal hyalinization are clues to the correct diagnosis of a lipidized dermatofibroma.

Lipidized dermatofibromas most commonly are found on the ankles, which has led some authors to refer to these lesions as ankle-type fibrous histiocytomas.¹ Compared to ordinary dermatofibromas, patients with lipidized dermatofibromas tend to be older, most commonly presenting in the fifth or sixth decades of life, and are predominantly male. Lipidized dermatofibromas typically present as well-circumscribed solitary nodules in the dermis. Characteristic features include numerous xanthomatous cells dissected by distinctive hyalinized wiry collagen fibers (Figures 1 and 2).¹ Xanthomatous cells can be round, polygonal, or stellate in shape. These characteristic features in combination with others of dermatofibromas (eg, epidermal acanthosis [Figure 1]) fulfill the criteria for diagnosis of a lipidized dermatofibroma. Additionally, lipidized dermatofibromas tend to be larger than ordinary dermatofibromas, which typically are less than 2 cm in diameter.¹

Figure 1. Lipidized dermatofibromas are characterized by classic epidermal features of dermatofibromas, such as acanthosis, along with numerous foam cells and extensive stromal hyalinization (H&E, original magnification ×1.5).

Figure 2. Higher-power view of a lipidized dermatofibroma shows the characteristic irregular dissection of hyalinized wiry collagen fibers between the xanthomatous cells (H&E, original magnification ×20).

Eruptive xanthomas are characterized by a lacelike infiltrate of extravascular lipid deposits between collagen bundles (Figure 3).² Granular cell tumors are composed of sheets and/or nests of large cells with abundant eosinophilic cytoplasm and may be confused with lipidized dermatofibromas, as they also may induce overlying pseudoepitheliomatous hyperplasia³; however, on closer examination of the cells, the cytoplasm is found to be granular (Figure 4), which contrasts the finely vacuolated cytoplasm of xanthomatous cells found in lipidized dermatofibromas. Giant lysosomal granules (eg, pustulo-ovoid bodies of Milian) are present in some cases.² Of note, an unusual variant of dermatofibroma exists that features prominent granular cells.⁴

Figure 3. Lacelike deposition of extravascular lipid deposits is seen infiltrating between collagen bundles in an eruptive xanthoma (H&E, original magnification ×20).

Figure 4. An abundant eosinophilic, finely granular cytoplasm is characteristic of granular cell tumor (H&E, original magnification ×40).

Tuberous xanthomas most commonly occur around the pressure areas, such as the knees, elbows, and buttocks. Foam cells are a main feature of tuberous xanthomas and are arranged in large aggregates throughout the dermis.² Tuberous xanthomas lack Touton giant cells or inflammatory cells. Older lesions tend to develop substantial fibrosis (Figure 5). Although foam cells can be present in older lesions, they are never as conspicuous as those found in other xanthomas.

Xanthogranulomas commonly occur on the head and neck. Findings noted on low magnification include a well-circumscribed exophytic nodule and an epidermal collarette, which help to easily distinguish xanthogranulomas from lipidized dermatofibromas. Additionally, the presence of a more prominent inflammatory infiltrate, which often includes eosinophils, as well as multinucleated Touton giant cells (Figure 6) and histiocytes with more eosinophilic and less xanthomatous cytoplasm can help distinguish between the lesions.^1,5 Notably, Touton giant cells also can be seen in lipidized dermatofibromas,¹ but the presence of unique features such as distinctive stromal hyalinization are clues to the correct diagnosis of a lipidized dermatofibroma.

As I have mentioned in prior columns, the key to success with International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) coding will be additional specificity, which will come in the form of more characters to communicate with payors and statisticians regarding the services that have been provided during the office visit. The addition of characters will permit more information about the visit to be delivered in the code.

Some of these additional characters will be required to submit the code for processing. Specifically look out for codes that communicate accidents or injury. Some common circumstances for dermatologists will be lacerations, abrasions, laceration repairs, and burns. The structure of the ICD-10-CM codes is outlined below to explain circumstances in which the increased number of characters will be most important for dermatologists.

The ICD-10-CM codes will be 3 to 7 characters long.¹ The first 3 characters are the general categories. For example, L70 is the 3-character category for acne and L40 is the category for psoriasis. The next 3 characters (ie, characters 4–6) correspond to the related etiology (ie, the cause, set of causes, manner of causation of a disease or condition), anatomic site, severity, and other vital clinical details.¹

Take the case of a burn on the hand. With the International Classification of Diseases, Ninth Revision, a first-degree burn on the back of the hand is coded with 5 characters (944.16).² According to the ICD-10-CM coding system, the code for an initial visit for a first-degree burn on the back of the hand would include 7 characters (T23.169A).¹ There will be times when the sixth character may not be necessary; in these instances, an X must be placed in this position as a placeholder, but the absence of a sixth character does not negate the need for a seventh. Thankfully, the seventh character can only be 1 of 3 letters. As illustrated above in the code for a first-degree burn on the back of the hand, the A designates an initial encounter; a D would designate a follow-up visit for this burn, and an S would represent a sequela from the initial burn, such as a postinflammatory change, which would have its own code.¹

Conclusion

To be reimbursed, appropriate ICD-10-CM codes must be used. Be sure to master the structure of these codes before the October 1, 2015, compliance deadline; plan now for a training and testing period.

As I have mentioned in prior columns, the key to success with International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) coding will be additional specificity, which will come in the form of more characters to communicate with payors and statisticians regarding the services that have been provided during the office visit. The addition of characters will permit more information about the visit to be delivered in the code.

Some of these additional characters will be required to submit the code for processing. Specifically look out for codes that communicate accidents or injury. Some common circumstances for dermatologists will be lacerations, abrasions, laceration repairs, and burns. The structure of the ICD-10-CM codes is outlined below to explain circumstances in which the increased number of characters will be most important for dermatologists.

The ICD-10-CM codes will be 3 to 7 characters long.¹ The first 3 characters are the general categories. For example, L70 is the 3-character category for acne and L40 is the category for psoriasis. The next 3 characters (ie, characters 4–6) correspond to the related etiology (ie, the cause, set of causes, manner of causation of a disease or condition), anatomic site, severity, and other vital clinical details.¹

Take the case of a burn on the hand. With the International Classification of Diseases, Ninth Revision, a first-degree burn on the back of the hand is coded with 5 characters (944.16).² According to the ICD-10-CM coding system, the code for an initial visit for a first-degree burn on the back of the hand would include 7 characters (T23.169A).¹ There will be times when the sixth character may not be necessary; in these instances, an X must be placed in this position as a placeholder, but the absence of a sixth character does not negate the need for a seventh. Thankfully, the seventh character can only be 1 of 3 letters. As illustrated above in the code for a first-degree burn on the back of the hand, the A designates an initial encounter; a D would designate a follow-up visit for this burn, and an S would represent a sequela from the initial burn, such as a postinflammatory change, which would have its own code.¹

Conclusion

To be reimbursed, appropriate ICD-10-CM codes must be used. Be sure to master the structure of these codes before the October 1, 2015, compliance deadline; plan now for a training and testing period.

As I have mentioned in prior columns, the key to success with International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) coding will be additional specificity, which will come in the form of more characters to communicate with payors and statisticians regarding the services that have been provided during the office visit. The addition of characters will permit more information about the visit to be delivered in the code.

Some of these additional characters will be required to submit the code for processing. Specifically look out for codes that communicate accidents or injury. Some common circumstances for dermatologists will be lacerations, abrasions, laceration repairs, and burns. The structure of the ICD-10-CM codes is outlined below to explain circumstances in which the increased number of characters will be most important for dermatologists.

The ICD-10-CM codes will be 3 to 7 characters long.¹ The first 3 characters are the general categories. For example, L70 is the 3-character category for acne and L40 is the category for psoriasis. The next 3 characters (ie, characters 4–6) correspond to the related etiology (ie, the cause, set of causes, manner of causation of a disease or condition), anatomic site, severity, and other vital clinical details.¹

Take the case of a burn on the hand. With the International Classification of Diseases, Ninth Revision, a first-degree burn on the back of the hand is coded with 5 characters (944.16).² According to the ICD-10-CM coding system, the code for an initial visit for a first-degree burn on the back of the hand would include 7 characters (T23.169A).¹ There will be times when the sixth character may not be necessary; in these instances, an X must be placed in this position as a placeholder, but the absence of a sixth character does not negate the need for a seventh. Thankfully, the seventh character can only be 1 of 3 letters. As illustrated above in the code for a first-degree burn on the back of the hand, the A designates an initial encounter; a D would designate a follow-up visit for this burn, and an S would represent a sequela from the initial burn, such as a postinflammatory change, which would have its own code.¹

Conclusion

To be reimbursed, appropriate ICD-10-CM codes must be used. Be sure to master the structure of these codes before the October 1, 2015, compliance deadline; plan now for a training and testing period.

For many years I have advised physicians that aggressive management of accounts receivable is the key to financial health for any private practice. In the current health care reform climate, it has become more important than ever. A crucial step toward proper management of accounts receivable in the age of the Patient Protection and Affordable Care Act is minimization, if not outright elimination, of patient billing, which is a hallowed yet obsolete tradition in private practice. Billing, in effect, is extending free credit to patients, and independent physicians can no longer afford it.

Some physicians of a traditional bent cling to the idea that accepting credit cards or even asking for payment at the time of service smacks of “storekeeping.” They feel more comfortable billing patients for outstanding balances but complain that their bills often are ignored; with each passing day following treatment in your office, the likelihood decreases that a patient will pay the bill.

Patient billing also is expensive. When you total the costs of materials, postage, and staff labor, each bill can cost anywhere from $2 to $10 or more. Every minute the office staff spends producing and mailing bills is time not spent on more productive work. Billing services are an alternative, but they also are expensive, and those bills get ignored too. Requiring immediate payment may seem distasteful to some physicians, but for physicians who wish to keep their office private and independent, it is rapidly becoming the only viable option.

Health Savings Accounts

Private practices will need to become increasingly flexible in how they accept payments as the population continues to age. This flexibility becomes increasingly important as more and more patients rely on health savings accounts (HSAs). Enrollment in these specialized, tax-deductible, tax-free accounts has increased 10-fold over the last decade.¹ Private practice physicians will want to accommodate for HSAs as much as possible.

A few credit companies are already promoting cards to finance HSAs and other private-pay portions of health care expenses, such as The HELPcard (www.helpcard.com). Major credit card companies also have begun to appreciate this largely untapped segment of potential business for them. Soon you may begin receiving help from them in setting up creative payment plans for your patients. Some financial institutions have even begun creating medical credit and debit cards called health benefit cards that are designed specifically for use at physicians’ offices.²

Credit and Debit Cards

Credit and debit cards eliminate many of the problems associated with patient billing. They allow you to collect more fees at the time of service while you still have the patient’s attention and the service you provided is still appreciated.

Charging to a credit or debit card also reduces the chances of a balance owed falling through the cracks, getting lost in the mail, or getting embezzled, and it cannot bounce so it is better than a check. Card payments also can improve your practice’s cash flow, which is always a welcome benefit. Additionally, if a patient is delinquent in paying a credit card bill, it is the credit card company’s problem, not yours.

Credit cards also offer more payment flexibility for patients. In the case of a large balance, offer your patient the option of charging all of the services to a credit card, which he/she can then pay off in affordable monthly installments. Your practice will get reimbursed in full, even as the patient is paying it off slowly, and the patient is able to pay off the debt at a pace that makes sense for his/her finances.

Payment Policies

Beyond simply accepting credit cards, the next step is one that every hotel, rental car agency, and many other businesses have used for years: Retain a card number in each patient’s file, and bill balances as they come in.

Every new patient in my office receives a letter at his/her first visit explaining our policy: We will keep a credit card number on file and use it to bill any outstanding balances after third parties pay their portion. At the bottom of the letter is a brief statement of consent for the patient to sign, along with a place to write the credit card number and expiration date. This policy also comes in handy for patients who claim to have come to the office without cash, a checkbook, credit cards, or any other method of payment. In such situations, my office manager can say, “No problem, we have your credit card information on file!”

Do patients object to this policy? Some do, mostly older patients. But when we explain that we are doing nothing different than hotels do at check-in and that this policy also will work to their advantage by decreasing the number of bills they receive and checks they must write, most come around. Make it an option at first if you wish; then, when everyone is accustomed, you can make it a mandatory policy. My office manager has the authority to make exceptions on a case-by-case basis when necessary.

Do patients worry about confidentiality or unauthorized use? Most individuals do not worry when they use a credit card at a restaurant, hotel, or the Internet. Guard your patients’ financial information as carefully as their medical information. If you have electronic health records, the patient’s credit card number can go in the medical chart. Otherwise use a separate portable filing system that can be locked up each night.

Does this policy work? In only 1 year, my total accounts receivable dropped by nearly 50%; after another year they stabilized at 30% to 35% of prior levels and have remained there ever since, which was a source of consternation for our new accountant who we hired shortly thereafter. “Something must be wrong,” he said nervously after his first look at our books. “Accounts receivable totals are never that low in a medical office with your level of volume.” His eyes widened as I explained our system. “Why doesn’t every private practice do that?” he asked. Why, indeed.

Final Thoughts

The business of health care delivery is currently being rocked at its foundations, as I have been detailing in this column. Without considerable adaptation to these fundamental changes, a private practice can do little more than survive, and even that will take luck. A crucial component of adaptation involves doing more of what we do best, treating patients. Leave the business of extending credit to the banks and credit card companies.

For many years I have advised physicians that aggressive management of accounts receivable is the key to financial health for any private practice. In the current health care reform climate, it has become more important than ever. A crucial step toward proper management of accounts receivable in the age of the Patient Protection and Affordable Care Act is minimization, if not outright elimination, of patient billing, which is a hallowed yet obsolete tradition in private practice. Billing, in effect, is extending free credit to patients, and independent physicians can no longer afford it.

Some physicians of a traditional bent cling to the idea that accepting credit cards or even asking for payment at the time of service smacks of “storekeeping.” They feel more comfortable billing patients for outstanding balances but complain that their bills often are ignored; with each passing day following treatment in your office, the likelihood decreases that a patient will pay the bill.

Patient billing also is expensive. When you total the costs of materials, postage, and staff labor, each bill can cost anywhere from $2 to $10 or more. Every minute the office staff spends producing and mailing bills is time not spent on more productive work. Billing services are an alternative, but they also are expensive, and those bills get ignored too. Requiring immediate payment may seem distasteful to some physicians, but for physicians who wish to keep their office private and independent, it is rapidly becoming the only viable option.

Health Savings Accounts

Private practices will need to become increasingly flexible in how they accept payments as the population continues to age. This flexibility becomes increasingly important as more and more patients rely on health savings accounts (HSAs). Enrollment in these specialized, tax-deductible, tax-free accounts has increased 10-fold over the last decade.¹ Private practice physicians will want to accommodate for HSAs as much as possible.

A few credit companies are already promoting cards to finance HSAs and other private-pay portions of health care expenses, such as The HELPcard (www.helpcard.com). Major credit card companies also have begun to appreciate this largely untapped segment of potential business for them. Soon you may begin receiving help from them in setting up creative payment plans for your patients. Some financial institutions have even begun creating medical credit and debit cards called health benefit cards that are designed specifically for use at physicians’ offices.²

Credit and Debit Cards

Credit and debit cards eliminate many of the problems associated with patient billing. They allow you to collect more fees at the time of service while you still have the patient’s attention and the service you provided is still appreciated.

Charging to a credit or debit card also reduces the chances of a balance owed falling through the cracks, getting lost in the mail, or getting embezzled, and it cannot bounce so it is better than a check. Card payments also can improve your practice’s cash flow, which is always a welcome benefit. Additionally, if a patient is delinquent in paying a credit card bill, it is the credit card company’s problem, not yours.

Credit cards also offer more payment flexibility for patients. In the case of a large balance, offer your patient the option of charging all of the services to a credit card, which he/she can then pay off in affordable monthly installments. Your practice will get reimbursed in full, even as the patient is paying it off slowly, and the patient is able to pay off the debt at a pace that makes sense for his/her finances.

Payment Policies

Beyond simply accepting credit cards, the next step is one that every hotel, rental car agency, and many other businesses have used for years: Retain a card number in each patient’s file, and bill balances as they come in.

Every new patient in my office receives a letter at his/her first visit explaining our policy: We will keep a credit card number on file and use it to bill any outstanding balances after third parties pay their portion. At the bottom of the letter is a brief statement of consent for the patient to sign, along with a place to write the credit card number and expiration date. This policy also comes in handy for patients who claim to have come to the office without cash, a checkbook, credit cards, or any other method of payment. In such situations, my office manager can say, “No problem, we have your credit card information on file!”

Do patients object to this policy? Some do, mostly older patients. But when we explain that we are doing nothing different than hotels do at check-in and that this policy also will work to their advantage by decreasing the number of bills they receive and checks they must write, most come around. Make it an option at first if you wish; then, when everyone is accustomed, you can make it a mandatory policy. My office manager has the authority to make exceptions on a case-by-case basis when necessary.

Do patients worry about confidentiality or unauthorized use? Most individuals do not worry when they use a credit card at a restaurant, hotel, or the Internet. Guard your patients’ financial information as carefully as their medical information. If you have electronic health records, the patient’s credit card number can go in the medical chart. Otherwise use a separate portable filing system that can be locked up each night.

Does this policy work? In only 1 year, my total accounts receivable dropped by nearly 50%; after another year they stabilized at 30% to 35% of prior levels and have remained there ever since, which was a source of consternation for our new accountant who we hired shortly thereafter. “Something must be wrong,” he said nervously after his first look at our books. “Accounts receivable totals are never that low in a medical office with your level of volume.” His eyes widened as I explained our system. “Why doesn’t every private practice do that?” he asked. Why, indeed.

Final Thoughts

The business of health care delivery is currently being rocked at its foundations, as I have been detailing in this column. Without considerable adaptation to these fundamental changes, a private practice can do little more than survive, and even that will take luck. A crucial component of adaptation involves doing more of what we do best, treating patients. Leave the business of extending credit to the banks and credit card companies.

For many years I have advised physicians that aggressive management of accounts receivable is the key to financial health for any private practice. In the current health care reform climate, it has become more important than ever. A crucial step toward proper management of accounts receivable in the age of the Patient Protection and Affordable Care Act is minimization, if not outright elimination, of patient billing, which is a hallowed yet obsolete tradition in private practice. Billing, in effect, is extending free credit to patients, and independent physicians can no longer afford it.

Some physicians of a traditional bent cling to the idea that accepting credit cards or even asking for payment at the time of service smacks of “storekeeping.” They feel more comfortable billing patients for outstanding balances but complain that their bills often are ignored; with each passing day following treatment in your office, the likelihood decreases that a patient will pay the bill.

Patient billing also is expensive. When you total the costs of materials, postage, and staff labor, each bill can cost anywhere from $2 to $10 or more. Every minute the office staff spends producing and mailing bills is time not spent on more productive work. Billing services are an alternative, but they also are expensive, and those bills get ignored too. Requiring immediate payment may seem distasteful to some physicians, but for physicians who wish to keep their office private and independent, it is rapidly becoming the only viable option.

Health Savings Accounts

Private practices will need to become increasingly flexible in how they accept payments as the population continues to age. This flexibility becomes increasingly important as more and more patients rely on health savings accounts (HSAs). Enrollment in these specialized, tax-deductible, tax-free accounts has increased 10-fold over the last decade.¹ Private practice physicians will want to accommodate for HSAs as much as possible.

A few credit companies are already promoting cards to finance HSAs and other private-pay portions of health care expenses, such as The HELPcard (www.helpcard.com). Major credit card companies also have begun to appreciate this largely untapped segment of potential business for them. Soon you may begin receiving help from them in setting up creative payment plans for your patients. Some financial institutions have even begun creating medical credit and debit cards called health benefit cards that are designed specifically for use at physicians’ offices.²

Credit and Debit Cards

Credit and debit cards eliminate many of the problems associated with patient billing. They allow you to collect more fees at the time of service while you still have the patient’s attention and the service you provided is still appreciated.

Charging to a credit or debit card also reduces the chances of a balance owed falling through the cracks, getting lost in the mail, or getting embezzled, and it cannot bounce so it is better than a check. Card payments also can improve your practice’s cash flow, which is always a welcome benefit. Additionally, if a patient is delinquent in paying a credit card bill, it is the credit card company’s problem, not yours.

Credit cards also offer more payment flexibility for patients. In the case of a large balance, offer your patient the option of charging all of the services to a credit card, which he/she can then pay off in affordable monthly installments. Your practice will get reimbursed in full, even as the patient is paying it off slowly, and the patient is able to pay off the debt at a pace that makes sense for his/her finances.

Payment Policies

Beyond simply accepting credit cards, the next step is one that every hotel, rental car agency, and many other businesses have used for years: Retain a card number in each patient’s file, and bill balances as they come in.

Every new patient in my office receives a letter at his/her first visit explaining our policy: We will keep a credit card number on file and use it to bill any outstanding balances after third parties pay their portion. At the bottom of the letter is a brief statement of consent for the patient to sign, along with a place to write the credit card number and expiration date. This policy also comes in handy for patients who claim to have come to the office without cash, a checkbook, credit cards, or any other method of payment. In such situations, my office manager can say, “No problem, we have your credit card information on file!”

Do patients object to this policy? Some do, mostly older patients. But when we explain that we are doing nothing different than hotels do at check-in and that this policy also will work to their advantage by decreasing the number of bills they receive and checks they must write, most come around. Make it an option at first if you wish; then, when everyone is accustomed, you can make it a mandatory policy. My office manager has the authority to make exceptions on a case-by-case basis when necessary.

Do patients worry about confidentiality or unauthorized use? Most individuals do not worry when they use a credit card at a restaurant, hotel, or the Internet. Guard your patients’ financial information as carefully as their medical information. If you have electronic health records, the patient’s credit card number can go in the medical chart. Otherwise use a separate portable filing system that can be locked up each night.

Does this policy work? In only 1 year, my total accounts receivable dropped by nearly 50%; after another year they stabilized at 30% to 35% of prior levels and have remained there ever since, which was a source of consternation for our new accountant who we hired shortly thereafter. “Something must be wrong,” he said nervously after his first look at our books. “Accounts receivable totals are never that low in a medical office with your level of volume.” His eyes widened as I explained our system. “Why doesn’t every private practice do that?” he asked. Why, indeed.

Final Thoughts

The business of health care delivery is currently being rocked at its foundations, as I have been detailing in this column. Without considerable adaptation to these fundamental changes, a private practice can do little more than survive, and even that will take luck. A crucial component of adaptation involves doing more of what we do best, treating patients. Leave the business of extending credit to the banks and credit card companies.

To improve patient care and outcomes, leading dermatologists offered their recommendations on the top OTC pigment control products. Consideration must be given to:

• Even Better
  Clinique Laboratories, LLC
  “It also is useful as prevention and offers many different options.”—Antonella Tosti, MD, Miami, Florida
  “These OTC products have good clinical data to support use for hyperpigmentation. Patients tell me that they feel good on their skin and aren’t irritating.”—Gary Goldenberg, MD, New York, New York

•  Lumixyl Brightening System
  Envy Medical, Inc
  “A great option for patients who may be experiencing modest issues with pigmentation. Use of a retinoid with this product also may enhance its efficacy.”—Joel Schlessinger, MD, Omaha, Nebraska

• Lytera Skin Brightening Complex
  SkinMedica
  “With key ingredients such as hexylresorcinol, retinol, and niacinamide, it has been clinically shown to lighten dark patches in its trials as well as adding luminosity to the skin.”—Anthony Rossi, MD, New York, New York
  Recommended by Elizabeth K. Hale, MD, New York, New York

•  Pigmentclar Serum
  La-Roche Posay Laboratoire Dermatologique  
  “It attacks pigment production at every stage.”—Whitney Bowe, MD, Brooklyn, New York

Cutis invites readers to send us their recommendations. Mineral makeup, eyelash enhancers, and facial scrubs will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to cutis@frontlinemedcom.com.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on the top OTC pigment control products. Consideration must be given to:

• Even Better
  Clinique Laboratories, LLC
  “It also is useful as prevention and offers many different options.”—Antonella Tosti, MD, Miami, Florida
  “These OTC products have good clinical data to support use for hyperpigmentation. Patients tell me that they feel good on their skin and aren’t irritating.”—Gary Goldenberg, MD, New York, New York

•  Lumixyl Brightening System
  Envy Medical, Inc
  “A great option for patients who may be experiencing modest issues with pigmentation. Use of a retinoid with this product also may enhance its efficacy.”—Joel Schlessinger, MD, Omaha, Nebraska

• Lytera Skin Brightening Complex
  SkinMedica
  “With key ingredients such as hexylresorcinol, retinol, and niacinamide, it has been clinically shown to lighten dark patches in its trials as well as adding luminosity to the skin.”—Anthony Rossi, MD, New York, New York
  Recommended by Elizabeth K. Hale, MD, New York, New York

•  Pigmentclar Serum
  La-Roche Posay Laboratoire Dermatologique  
  “It attacks pigment production at every stage.”—Whitney Bowe, MD, Brooklyn, New York

Cutis invites readers to send us their recommendations. Mineral makeup, eyelash enhancers, and facial scrubs will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to cutis@frontlinemedcom.com.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on the top OTC pigment control products. Consideration must be given to:

• Even Better
  Clinique Laboratories, LLC
  “It also is useful as prevention and offers many different options.”—Antonella Tosti, MD, Miami, Florida
  “These OTC products have good clinical data to support use for hyperpigmentation. Patients tell me that they feel good on their skin and aren’t irritating.”—Gary Goldenberg, MD, New York, New York

•  Lumixyl Brightening System
  Envy Medical, Inc
  “A great option for patients who may be experiencing modest issues with pigmentation. Use of a retinoid with this product also may enhance its efficacy.”—Joel Schlessinger, MD, Omaha, Nebraska

• Lytera Skin Brightening Complex
  SkinMedica
  “With key ingredients such as hexylresorcinol, retinol, and niacinamide, it has been clinically shown to lighten dark patches in its trials as well as adding luminosity to the skin.”—Anthony Rossi, MD, New York, New York
  Recommended by Elizabeth K. Hale, MD, New York, New York

•  Pigmentclar Serum
  La-Roche Posay Laboratoire Dermatologique  
  “It attacks pigment production at every stage.”—Whitney Bowe, MD, Brooklyn, New York

Cutis invites readers to send us their recommendations. Mineral makeup, eyelash enhancers, and facial scrubs will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to cutis@frontlinemedcom.com.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

Pigmented purpuric dermatoses (PPDs) are a group of common chronic disorders characterized by speckled, cayenne pepper–like petechiae and orange-brown discoloration of the skin resulting from capillaritis.¹ Pigmented purpuric dermatoses typically occur in the absence of underlying vascular insufficiency or other hematologic dysfunction. The 5 well-known clinicopathologic variants of PPD include Schamberg disease; purpura annularis telangiectodes of Majocchi; pigmented purpuric lichenoid dermatitis of Gougerot and Blum; eczematoidlike purpura of Doucas and Kapetanakis; and lichen aureus.² All PPDs share common characteristic clinical and histologic features. Clinically, patients generally present with symmetric petechiae and/or pigmented macules. All 5 PPD variants share similar histologic findings, including a vasculocentric lymphocytic infiltrate in the papillary dermis, swelling of the endothelial cells, erythrocyte extravasation, and often hemosiderin-laden macrophages.¹ Despite these clinical and histopathologic similarities, each variant contains additional distinctive features, such as telangiectasia (purpura annularis telangiectodes of Majocchi), a lichenoid infiltrate (pigmented purpuric lichenoid dermatitis of Gougerot and Blum), eczematous changes (eczematoidlike purpura of Doucas and Kapetanakis), and marked hemosiderin deposition (lichen aureus).

Granulomatous pigmented purpuric dermatosis (GPPD) is a rare variant of PPD.^3-7 Clinically, these lesions appear similar to other PPDs; however, in addition to the characteristic changes associated with conventional PPD, histologic examination of GPPD reveals a granulomatous inflammatory reaction pattern. Although the pathogenesis of GPPD is not well understood, its association with hyperlipidemia may suggest a granulomatous response to capillaritis mediated by lipid deposition in the microvasculature.^6,7

We present 3 cases of GPPD and provide a review of the literature. In all of our patients, biopsy specimens were fixed in 10% buffered formalin and embedded in paraffin by standard methodologies, and all stains were performed on sections by standard methodologies. Based on a PubMed search of articles indexed for MEDLINE using the terms granulomatous pigmented purpuric dermatosis, sarcoidosis, pigmented purpuric dermatosis, granulomas, and pigmented purpuric dermatosis, we review 5 additional reports describing 10 total patients.^3-7

Case Reports

Patient 1

A 9-year-old white boy presented with a 3-cm asymptomatic light brown patch with a nonblanching violaceous center on the right posterior thigh that was studded with pinpoint yellow papules (Figure, A). The lesion appeared 3 to 4 years prior to presentation but had become progressively darker and centrally indurated over the last 2 years. The patient and his mother denied any history of trauma to the area. His medical history was unremarkable, and his current medications included fish oil and multivitamin tablets.

Histologic examination of a punch biopsy specimen taken from the center of the lesion revealed a lichenoid lymphohistiocytic infiltrate with marked red blood cell (RBC) extravasation and associated hemosiderin-laden macrophages. The lymphocytes comprising this infiltrate lacked cytologic atypia and exhibited minimal epidermotropism (Figure, B). Additionally, there was a superficial and deep perivascular mononuclear inflammatory infiltrate intermixed with numerous small granulomas comprised ofepithelioid histiocytes in the mid and deep dermis (Figure, C). Periodic acid–Schiff, acid-fast bacilli (AFB), and Fite stains were negative for organisms. Polarization was negative for refractile foreign material. Due to the patient’s age, no treatment was performed, and the lesion remains unchanged 1 year after biopsy.

Patient 2

A 49-year-old white woman presented with a 2-cm yellow-brown patch with a faint, nonblanchable, violaceous center on the right lateral thigh of 4 months’ duration. The patch initially appeared as a small asymptomatic purple papule. The patient denied any history of trauma to the area. A purified protein derivative (tuberculin) skin test was negative at the time of examination. The patient’s medical history was remarkable for renal calculi. Her current medications included progesterone; estradiol; lansoprazole; prenatal vitamins; vitamins C and E; zinc; and calcium. The patient had no family history of sarcoidosis. Complete blood cell count, urinalysis, liver function tests, and angiotensin-converting enzyme levels were unremarkable. Pulmonary function tests were normal, and there was no evidence of sarcoidosis on chest radiography. Initial biopsy of the lesion revealed a perivascular and interstitial lymphohistiocytic infiltrate with abundant extravasated RBCs in the papillary dermis (Figure, D). Similar to patient 1, the infiltrate lacked cytologic atypia and did not involve the overlying epidermis. There was perivascular granulomatous inflammation in the mid dermis (Figure, E). Periodic acid–Schiff, Warthin-Starry, and AFB stains were negative for organisms. Polarization was negative for refractile foreign material.

The lesion was treated with clobetasol propionate ointment 0.05% twice daily for 6 weeks with transient improvement, but the lesion recurred upon treatment cessation. Subsequent treatment with intralesional triamcinolone resulted in slight improvement of the lesion. A therapeutic trial of targeted pulsed dye laser treatment was ineffective. The lesion gradually increased in size over the next year with no therapy, and a repeat biopsy revealed a lichenoid lymphohistiocytic infiltrate with abundant extravasated RBCs consistent with persistent PPD. A granulomatous infiltrate was not evident in the superficial shave biopsy specimen.

Patient 3

A 75-year-old white woman presented with scattered, speckled, cayenne pepper–like, red-brown macules on the legs. Two years prior to presentation, a few scattered symmetrical macules appeared on the dorsal aspects of the feet, which gradually increased in number to form larger confluent patches that spread to the lower legs. The patient denied itching or burning but reported that the patches became painful when scratched and were aggravated by sun exposure. Her medical history was remarkable for asthma, chronic renal insufficiency, coronary artery disease, Barrett esophagus, obstructive sleep apnea, hypothyroidism, renal calculi, type 2 diabetes mellitus, and hyperlipidemia. Her current medications included carvedilol, valsartan, levothyroxine, aspirin, clopidogrel, furosemide, nitrofurantoin, temazepam, insulin, ezetimibe-simvastatin, and lansoprazole. Computed tomography of the chest revealed no signs of sarcoidosis. Pulmonary function tests revealed moderate obstructive lung disease. An ophthalmology examination showed no evidence of sarcoidosis. Laboratory results revealed an elevated glucose, blood urea nitrogen, creatinine, and triglyceride levels, as well as low hematocrit and vitamin D levels. Urinalysis, thyroid-stimulating hormone (thyrotropin) test, liver function tests, angiotensin-converting enzyme test, hepatitis B surface antigen, and IFN-g release assay were normal.

Histologic examination of a punch biopsy specimen revealed an inflammatory infiltrate confined to the papillary dermis. This infiltrate was comprised of an admixture of lymphocytes and histiocytes in a perivascular distribution with associated RBC extravasation and intimately associated granulomas (Figure, F). Additional inflammation in the deeper aspects of the dermis was not identified. Periodic acid–Schiff, AFB, and Fite stains were negative for organisms. Polarization was negative for refractile foreign material.

A 3-cm asymptomatic light brown patch with a nonblanching violaceous center on the right posterior thigh that was studded with pinpoint yellow papules (A). Lichenoid lymphohistiocytic infiltrate in the papillary dermis with marked red blood cell extravasation (B)(H&E, original magnification ×20). Superficial and deep perivascular mononuclear inflammatory infiltrate intermixed with numerous small granulomas comprised of epithelioid histiocytes in the mid and deep dermis (C)(H&E, original magnification ×20). Perivascular and interstitial lymphohistiocytic infiltrate with abundant extravasated red blood cells in the papillary dermis (D)(H&E, original magnification ×10). Perivascular lymphohistiocytic inflammation with epithelioid granulomas in the mid dermis (E)(H&E, original magnification ×20). Lymphohistiocytic inflammation in the papillary dermis comprised of an admixture of lymphocytes and histiocytes in a perivascular distribution with associated red blood cell extravasation and intimately associated granulomas (F)(H&E, original magnification ×20).

The patient was treated with topical steroids and minocycline 50 mg twice daily without improvement. The lesions improved after the patient underwent treatment with oral corticosteroids for pulmonary disease.

Comment

Pigmented purpuric dermatoses comprise a spectrum of clinical and pathologic conditions.^1,2 Granulomatous PPD is a much less common variant, characterized by a granulomatous infiltrate admixed with PPD. We report 3 additional cases and review the literature on this rare and interesting variant of PPD.

We noted several unifying clinicopathologic features among our patients and those previously reported in the literature (Table).^3-7 Including our cases, our review yielded 13 GPPD patients ranging in age from 9 to 75 years, with a mean age of 49.1 years. Two of our patients—patients 1 and 3—were the youngest and oldest patients, respectively, among the cases we reviewed. The majority of the cases we reviewed included patients of East Asian descent (6 Taiwanese; 2 Japanese; 1 Korean) as well as 4 white patients. No distinctive gender predilection was apparent, as our review included 8 females and 5 males.

Our review revealed that GPPD lesions typically involve the lower extremities and usually are asymptomatic, with the exception of occasional pruritus. Additional lesions have been reported on the dorsal aspect of the hands, and 1 case noted exclusive involvement of the wrist.⁶ Lesions of GPPD can range in their clinical appearance. Three of 13 patients presented with purpuric papules and 2 had brown pigmentation with hemorrhagic papules^3,4,6; the remaining 8 patients had erythematous or brown macules, papules, or plaques.^5-7 The most commonly associated disease condition was hyperlipidemia, which was reported in 7 of 13 cases.^5-7 Additional reported comorbidities included meningioma, renal calculi, obesity, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, hepatitis C virus, ulcerative colitis, thrombocytopenia, and hyperuricemia. Reported serologic abnormalities included a rare positive antinuclear antibody, rheumatoid factor, and cryoglobulins.^3,6 Therapeutic efficacy in the management of GPPD has not been well described; however, for the rare cases in which therapies were described, they were largely unsuccessful, with 1 patient exhibiting spontaneous improvement.^3,4

Granulomatous PPD also appears to exhibit a range of histologic findings. All cases of GPPD shared fundamental components, such as a brisk perivascular infiltrate accompanied by RBC extravasation with variable hemosiderin-laden macrophages and a granulomatous infiltrate. All of the reports we reviewed described an intimate association between these components, with the granulomas being essentially superimposed on typical PPD. As for other types of PPD, obvious vasculitis characterized by a vasculocentric inflammatory infiltrate and evidence of vascular injury, such as fibrinoid necrosis of the vessel wall, has not been described in GPPD.^3-7 Finally, histologic changes suggestive of a relationship with cutaneous T-cell lymphoma, cytologic atypia, and epidermotropism have been described for some forms of PPD but have not been described for GPPD.^3-8

Our case reports expand the histologic spectrum of GPPD. Although patient 3 exhibited a relatively intimate association of granulomas and PPD, 2 of our cases (patients 1 and 2) demonstrated a granulomatous infiltrate in the mid to deep dermis, which is separate from the more superficially situated lichenoid lymphohistiocytic infiltrate, RBC extravasation, and hemosiderin-laden macrophages noted in the papillary dermis. Considered along with the absence of an obvious clinicopathologic explanation for the granulomatous infiltrates (eg, polarizable material, infectious organisms, systemic disease), these 2 cases (patients 1 and 2) suggest a composite form of PPD that combines the lichenoid pattern of PPD of Gougerot and Blum with a deep granulomatous component of GPPD. The importance of this distinction lies in the potential for physicians to overlook this potentially informative histologic pattern if only a superficial biopsy is performed. The clinical relevance is unclear; however, in our experience, it has been challenging to treat this relatively small subset of patients who have exhibited a limited response to treatment with topical steroids, intralesional steroids, pulsed dye laser, and vitamin supplementation.

The cause of the granulomatous infiltrate in GPPD is poorly understood. Seven of 13 cases included in our review occurred in patients with a history of hyperlipidemia.^5-7 Some have postulated that the constellation of findings of GPPD in hyperlipidemic patients reflects an underlying vascular injury process induced by lipid deposition in the endothelial cells with subsequent RBC extravasation and a secondary granulomatous response to the lipid deposits.^6,7 However, given the occurrence of GPPD in patients without hyperlipidemia, other mechanisms also must be considered in the pathogenesis of GPPD, including a reaction to medications, systemic diseases, and infectious etiologies (eg, hepatitis B virus).^4,6 As additional cases are described in the literature, other unifying clinical etiologies for this histopathologic reaction pattern may emerge.

Conclusion

Granulomatous PPD may comprise an underrecognized variant of PPD in cases when only a superficial biopsy is evaluated. Clinicians and pathologists should be aware of this variant, and in refractory cases of PPD, deeper sampling may be warranted to identify granulomas.

Pigmented purpuric dermatoses (PPDs) are a group of common chronic disorders characterized by speckled, cayenne pepper–like petechiae and orange-brown discoloration of the skin resulting from capillaritis.¹ Pigmented purpuric dermatoses typically occur in the absence of underlying vascular insufficiency or other hematologic dysfunction. The 5 well-known clinicopathologic variants of PPD include Schamberg disease; purpura annularis telangiectodes of Majocchi; pigmented purpuric lichenoid dermatitis of Gougerot and Blum; eczematoidlike purpura of Doucas and Kapetanakis; and lichen aureus.² All PPDs share common characteristic clinical and histologic features. Clinically, patients generally present with symmetric petechiae and/or pigmented macules. All 5 PPD variants share similar histologic findings, including a vasculocentric lymphocytic infiltrate in the papillary dermis, swelling of the endothelial cells, erythrocyte extravasation, and often hemosiderin-laden macrophages.¹ Despite these clinical and histopathologic similarities, each variant contains additional distinctive features, such as telangiectasia (purpura annularis telangiectodes of Majocchi), a lichenoid infiltrate (pigmented purpuric lichenoid dermatitis of Gougerot and Blum), eczematous changes (eczematoidlike purpura of Doucas and Kapetanakis), and marked hemosiderin deposition (lichen aureus).

Granulomatous pigmented purpuric dermatosis (GPPD) is a rare variant of PPD.^3-7 Clinically, these lesions appear similar to other PPDs; however, in addition to the characteristic changes associated with conventional PPD, histologic examination of GPPD reveals a granulomatous inflammatory reaction pattern. Although the pathogenesis of GPPD is not well understood, its association with hyperlipidemia may suggest a granulomatous response to capillaritis mediated by lipid deposition in the microvasculature.^6,7

We present 3 cases of GPPD and provide a review of the literature. In all of our patients, biopsy specimens were fixed in 10% buffered formalin and embedded in paraffin by standard methodologies, and all stains were performed on sections by standard methodologies. Based on a PubMed search of articles indexed for MEDLINE using the terms granulomatous pigmented purpuric dermatosis, sarcoidosis, pigmented purpuric dermatosis, granulomas, and pigmented purpuric dermatosis, we review 5 additional reports describing 10 total patients.^3-7

Case Reports

Patient 1

A 9-year-old white boy presented with a 3-cm asymptomatic light brown patch with a nonblanching violaceous center on the right posterior thigh that was studded with pinpoint yellow papules (Figure, A). The lesion appeared 3 to 4 years prior to presentation but had become progressively darker and centrally indurated over the last 2 years. The patient and his mother denied any history of trauma to the area. His medical history was unremarkable, and his current medications included fish oil and multivitamin tablets.

Histologic examination of a punch biopsy specimen taken from the center of the lesion revealed a lichenoid lymphohistiocytic infiltrate with marked red blood cell (RBC) extravasation and associated hemosiderin-laden macrophages. The lymphocytes comprising this infiltrate lacked cytologic atypia and exhibited minimal epidermotropism (Figure, B). Additionally, there was a superficial and deep perivascular mononuclear inflammatory infiltrate intermixed with numerous small granulomas comprised ofepithelioid histiocytes in the mid and deep dermis (Figure, C). Periodic acid–Schiff, acid-fast bacilli (AFB), and Fite stains were negative for organisms. Polarization was negative for refractile foreign material. Due to the patient’s age, no treatment was performed, and the lesion remains unchanged 1 year after biopsy.

Patient 2

A 49-year-old white woman presented with a 2-cm yellow-brown patch with a faint, nonblanchable, violaceous center on the right lateral thigh of 4 months’ duration. The patch initially appeared as a small asymptomatic purple papule. The patient denied any history of trauma to the area. A purified protein derivative (tuberculin) skin test was negative at the time of examination. The patient’s medical history was remarkable for renal calculi. Her current medications included progesterone; estradiol; lansoprazole; prenatal vitamins; vitamins C and E; zinc; and calcium. The patient had no family history of sarcoidosis. Complete blood cell count, urinalysis, liver function tests, and angiotensin-converting enzyme levels were unremarkable. Pulmonary function tests were normal, and there was no evidence of sarcoidosis on chest radiography. Initial biopsy of the lesion revealed a perivascular and interstitial lymphohistiocytic infiltrate with abundant extravasated RBCs in the papillary dermis (Figure, D). Similar to patient 1, the infiltrate lacked cytologic atypia and did not involve the overlying epidermis. There was perivascular granulomatous inflammation in the mid dermis (Figure, E). Periodic acid–Schiff, Warthin-Starry, and AFB stains were negative for organisms. Polarization was negative for refractile foreign material.

The lesion was treated with clobetasol propionate ointment 0.05% twice daily for 6 weeks with transient improvement, but the lesion recurred upon treatment cessation. Subsequent treatment with intralesional triamcinolone resulted in slight improvement of the lesion. A therapeutic trial of targeted pulsed dye laser treatment was ineffective. The lesion gradually increased in size over the next year with no therapy, and a repeat biopsy revealed a lichenoid lymphohistiocytic infiltrate with abundant extravasated RBCs consistent with persistent PPD. A granulomatous infiltrate was not evident in the superficial shave biopsy specimen.

Patient 3

A 75-year-old white woman presented with scattered, speckled, cayenne pepper–like, red-brown macules on the legs. Two years prior to presentation, a few scattered symmetrical macules appeared on the dorsal aspects of the feet, which gradually increased in number to form larger confluent patches that spread to the lower legs. The patient denied itching or burning but reported that the patches became painful when scratched and were aggravated by sun exposure. Her medical history was remarkable for asthma, chronic renal insufficiency, coronary artery disease, Barrett esophagus, obstructive sleep apnea, hypothyroidism, renal calculi, type 2 diabetes mellitus, and hyperlipidemia. Her current medications included carvedilol, valsartan, levothyroxine, aspirin, clopidogrel, furosemide, nitrofurantoin, temazepam, insulin, ezetimibe-simvastatin, and lansoprazole. Computed tomography of the chest revealed no signs of sarcoidosis. Pulmonary function tests revealed moderate obstructive lung disease. An ophthalmology examination showed no evidence of sarcoidosis. Laboratory results revealed an elevated glucose, blood urea nitrogen, creatinine, and triglyceride levels, as well as low hematocrit and vitamin D levels. Urinalysis, thyroid-stimulating hormone (thyrotropin) test, liver function tests, angiotensin-converting enzyme test, hepatitis B surface antigen, and IFN-g release assay were normal.

Histologic examination of a punch biopsy specimen revealed an inflammatory infiltrate confined to the papillary dermis. This infiltrate was comprised of an admixture of lymphocytes and histiocytes in a perivascular distribution with associated RBC extravasation and intimately associated granulomas (Figure, F). Additional inflammation in the deeper aspects of the dermis was not identified. Periodic acid–Schiff, AFB, and Fite stains were negative for organisms. Polarization was negative for refractile foreign material.

A 3-cm asymptomatic light brown patch with a nonblanching violaceous center on the right posterior thigh that was studded with pinpoint yellow papules (A). Lichenoid lymphohistiocytic infiltrate in the papillary dermis with marked red blood cell extravasation (B)(H&E, original magnification ×20). Superficial and deep perivascular mononuclear inflammatory infiltrate intermixed with numerous small granulomas comprised of epithelioid histiocytes in the mid and deep dermis (C)(H&E, original magnification ×20). Perivascular and interstitial lymphohistiocytic infiltrate with abundant extravasated red blood cells in the papillary dermis (D)(H&E, original magnification ×10). Perivascular lymphohistiocytic inflammation with epithelioid granulomas in the mid dermis (E)(H&E, original magnification ×20). Lymphohistiocytic inflammation in the papillary dermis comprised of an admixture of lymphocytes and histiocytes in a perivascular distribution with associated red blood cell extravasation and intimately associated granulomas (F)(H&E, original magnification ×20).

The patient was treated with topical steroids and minocycline 50 mg twice daily without improvement. The lesions improved after the patient underwent treatment with oral corticosteroids for pulmonary disease.

Comment

Pigmented purpuric dermatoses comprise a spectrum of clinical and pathologic conditions.^1,2 Granulomatous PPD is a much less common variant, characterized by a granulomatous infiltrate admixed with PPD. We report 3 additional cases and review the literature on this rare and interesting variant of PPD.

We noted several unifying clinicopathologic features among our patients and those previously reported in the literature (Table).^3-7 Including our cases, our review yielded 13 GPPD patients ranging in age from 9 to 75 years, with a mean age of 49.1 years. Two of our patients—patients 1 and 3—were the youngest and oldest patients, respectively, among the cases we reviewed. The majority of the cases we reviewed included patients of East Asian descent (6 Taiwanese; 2 Japanese; 1 Korean) as well as 4 white patients. No distinctive gender predilection was apparent, as our review included 8 females and 5 males.

Our review revealed that GPPD lesions typically involve the lower extremities and usually are asymptomatic, with the exception of occasional pruritus. Additional lesions have been reported on the dorsal aspect of the hands, and 1 case noted exclusive involvement of the wrist.⁶ Lesions of GPPD can range in their clinical appearance. Three of 13 patients presented with purpuric papules and 2 had brown pigmentation with hemorrhagic papules^3,4,6; the remaining 8 patients had erythematous or brown macules, papules, or plaques.^5-7 The most commonly associated disease condition was hyperlipidemia, which was reported in 7 of 13 cases.^5-7 Additional reported comorbidities included meningioma, renal calculi, obesity, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, hepatitis C virus, ulcerative colitis, thrombocytopenia, and hyperuricemia. Reported serologic abnormalities included a rare positive antinuclear antibody, rheumatoid factor, and cryoglobulins.^3,6 Therapeutic efficacy in the management of GPPD has not been well described; however, for the rare cases in which therapies were described, they were largely unsuccessful, with 1 patient exhibiting spontaneous improvement.^3,4

Granulomatous PPD also appears to exhibit a range of histologic findings. All cases of GPPD shared fundamental components, such as a brisk perivascular infiltrate accompanied by RBC extravasation with variable hemosiderin-laden macrophages and a granulomatous infiltrate. All of the reports we reviewed described an intimate association between these components, with the granulomas being essentially superimposed on typical PPD. As for other types of PPD, obvious vasculitis characterized by a vasculocentric inflammatory infiltrate and evidence of vascular injury, such as fibrinoid necrosis of the vessel wall, has not been described in GPPD.^3-7 Finally, histologic changes suggestive of a relationship with cutaneous T-cell lymphoma, cytologic atypia, and epidermotropism have been described for some forms of PPD but have not been described for GPPD.^3-8

Our case reports expand the histologic spectrum of GPPD. Although patient 3 exhibited a relatively intimate association of granulomas and PPD, 2 of our cases (patients 1 and 2) demonstrated a granulomatous infiltrate in the mid to deep dermis, which is separate from the more superficially situated lichenoid lymphohistiocytic infiltrate, RBC extravasation, and hemosiderin-laden macrophages noted in the papillary dermis. Considered along with the absence of an obvious clinicopathologic explanation for the granulomatous infiltrates (eg, polarizable material, infectious organisms, systemic disease), these 2 cases (patients 1 and 2) suggest a composite form of PPD that combines the lichenoid pattern of PPD of Gougerot and Blum with a deep granulomatous component of GPPD. The importance of this distinction lies in the potential for physicians to overlook this potentially informative histologic pattern if only a superficial biopsy is performed. The clinical relevance is unclear; however, in our experience, it has been challenging to treat this relatively small subset of patients who have exhibited a limited response to treatment with topical steroids, intralesional steroids, pulsed dye laser, and vitamin supplementation.

The cause of the granulomatous infiltrate in GPPD is poorly understood. Seven of 13 cases included in our review occurred in patients with a history of hyperlipidemia.^5-7 Some have postulated that the constellation of findings of GPPD in hyperlipidemic patients reflects an underlying vascular injury process induced by lipid deposition in the endothelial cells with subsequent RBC extravasation and a secondary granulomatous response to the lipid deposits.^6,7 However, given the occurrence of GPPD in patients without hyperlipidemia, other mechanisms also must be considered in the pathogenesis of GPPD, including a reaction to medications, systemic diseases, and infectious etiologies (eg, hepatitis B virus).^4,6 As additional cases are described in the literature, other unifying clinical etiologies for this histopathologic reaction pattern may emerge.

Conclusion

Granulomatous PPD may comprise an underrecognized variant of PPD in cases when only a superficial biopsy is evaluated. Clinicians and pathologists should be aware of this variant, and in refractory cases of PPD, deeper sampling may be warranted to identify granulomas.

Pigmented purpuric dermatoses (PPDs) are a group of common chronic disorders characterized by speckled, cayenne pepper–like petechiae and orange-brown discoloration of the skin resulting from capillaritis.¹ Pigmented purpuric dermatoses typically occur in the absence of underlying vascular insufficiency or other hematologic dysfunction. The 5 well-known clinicopathologic variants of PPD include Schamberg disease; purpura annularis telangiectodes of Majocchi; pigmented purpuric lichenoid dermatitis of Gougerot and Blum; eczematoidlike purpura of Doucas and Kapetanakis; and lichen aureus.² All PPDs share common characteristic clinical and histologic features. Clinically, patients generally present with symmetric petechiae and/or pigmented macules. All 5 PPD variants share similar histologic findings, including a vasculocentric lymphocytic infiltrate in the papillary dermis, swelling of the endothelial cells, erythrocyte extravasation, and often hemosiderin-laden macrophages.¹ Despite these clinical and histopathologic similarities, each variant contains additional distinctive features, such as telangiectasia (purpura annularis telangiectodes of Majocchi), a lichenoid infiltrate (pigmented purpuric lichenoid dermatitis of Gougerot and Blum), eczematous changes (eczematoidlike purpura of Doucas and Kapetanakis), and marked hemosiderin deposition (lichen aureus).

Granulomatous pigmented purpuric dermatosis (GPPD) is a rare variant of PPD.^3-7 Clinically, these lesions appear similar to other PPDs; however, in addition to the characteristic changes associated with conventional PPD, histologic examination of GPPD reveals a granulomatous inflammatory reaction pattern. Although the pathogenesis of GPPD is not well understood, its association with hyperlipidemia may suggest a granulomatous response to capillaritis mediated by lipid deposition in the microvasculature.^6,7

We present 3 cases of GPPD and provide a review of the literature. In all of our patients, biopsy specimens were fixed in 10% buffered formalin and embedded in paraffin by standard methodologies, and all stains were performed on sections by standard methodologies. Based on a PubMed search of articles indexed for MEDLINE using the terms granulomatous pigmented purpuric dermatosis, sarcoidosis, pigmented purpuric dermatosis, granulomas, and pigmented purpuric dermatosis, we review 5 additional reports describing 10 total patients.^3-7

Case Reports

Patient 1

A 9-year-old white boy presented with a 3-cm asymptomatic light brown patch with a nonblanching violaceous center on the right posterior thigh that was studded with pinpoint yellow papules (Figure, A). The lesion appeared 3 to 4 years prior to presentation but had become progressively darker and centrally indurated over the last 2 years. The patient and his mother denied any history of trauma to the area. His medical history was unremarkable, and his current medications included fish oil and multivitamin tablets.

Histologic examination of a punch biopsy specimen taken from the center of the lesion revealed a lichenoid lymphohistiocytic infiltrate with marked red blood cell (RBC) extravasation and associated hemosiderin-laden macrophages. The lymphocytes comprising this infiltrate lacked cytologic atypia and exhibited minimal epidermotropism (Figure, B). Additionally, there was a superficial and deep perivascular mononuclear inflammatory infiltrate intermixed with numerous small granulomas comprised ofepithelioid histiocytes in the mid and deep dermis (Figure, C). Periodic acid–Schiff, acid-fast bacilli (AFB), and Fite stains were negative for organisms. Polarization was negative for refractile foreign material. Due to the patient’s age, no treatment was performed, and the lesion remains unchanged 1 year after biopsy.

Patient 2

A 49-year-old white woman presented with a 2-cm yellow-brown patch with a faint, nonblanchable, violaceous center on the right lateral thigh of 4 months’ duration. The patch initially appeared as a small asymptomatic purple papule. The patient denied any history of trauma to the area. A purified protein derivative (tuberculin) skin test was negative at the time of examination. The patient’s medical history was remarkable for renal calculi. Her current medications included progesterone; estradiol; lansoprazole; prenatal vitamins; vitamins C and E; zinc; and calcium. The patient had no family history of sarcoidosis. Complete blood cell count, urinalysis, liver function tests, and angiotensin-converting enzyme levels were unremarkable. Pulmonary function tests were normal, and there was no evidence of sarcoidosis on chest radiography. Initial biopsy of the lesion revealed a perivascular and interstitial lymphohistiocytic infiltrate with abundant extravasated RBCs in the papillary dermis (Figure, D). Similar to patient 1, the infiltrate lacked cytologic atypia and did not involve the overlying epidermis. There was perivascular granulomatous inflammation in the mid dermis (Figure, E). Periodic acid–Schiff, Warthin-Starry, and AFB stains were negative for organisms. Polarization was negative for refractile foreign material.

The lesion was treated with clobetasol propionate ointment 0.05% twice daily for 6 weeks with transient improvement, but the lesion recurred upon treatment cessation. Subsequent treatment with intralesional triamcinolone resulted in slight improvement of the lesion. A therapeutic trial of targeted pulsed dye laser treatment was ineffective. The lesion gradually increased in size over the next year with no therapy, and a repeat biopsy revealed a lichenoid lymphohistiocytic infiltrate with abundant extravasated RBCs consistent with persistent PPD. A granulomatous infiltrate was not evident in the superficial shave biopsy specimen.

Patient 3

A 75-year-old white woman presented with scattered, speckled, cayenne pepper–like, red-brown macules on the legs. Two years prior to presentation, a few scattered symmetrical macules appeared on the dorsal aspects of the feet, which gradually increased in number to form larger confluent patches that spread to the lower legs. The patient denied itching or burning but reported that the patches became painful when scratched and were aggravated by sun exposure. Her medical history was remarkable for asthma, chronic renal insufficiency, coronary artery disease, Barrett esophagus, obstructive sleep apnea, hypothyroidism, renal calculi, type 2 diabetes mellitus, and hyperlipidemia. Her current medications included carvedilol, valsartan, levothyroxine, aspirin, clopidogrel, furosemide, nitrofurantoin, temazepam, insulin, ezetimibe-simvastatin, and lansoprazole. Computed tomography of the chest revealed no signs of sarcoidosis. Pulmonary function tests revealed moderate obstructive lung disease. An ophthalmology examination showed no evidence of sarcoidosis. Laboratory results revealed an elevated glucose, blood urea nitrogen, creatinine, and triglyceride levels, as well as low hematocrit and vitamin D levels. Urinalysis, thyroid-stimulating hormone (thyrotropin) test, liver function tests, angiotensin-converting enzyme test, hepatitis B surface antigen, and IFN-g release assay were normal.

Histologic examination of a punch biopsy specimen revealed an inflammatory infiltrate confined to the papillary dermis. This infiltrate was comprised of an admixture of lymphocytes and histiocytes in a perivascular distribution with associated RBC extravasation and intimately associated granulomas (Figure, F). Additional inflammation in the deeper aspects of the dermis was not identified. Periodic acid–Schiff, AFB, and Fite stains were negative for organisms. Polarization was negative for refractile foreign material.

A 3-cm asymptomatic light brown patch with a nonblanching violaceous center on the right posterior thigh that was studded with pinpoint yellow papules (A). Lichenoid lymphohistiocytic infiltrate in the papillary dermis with marked red blood cell extravasation (B)(H&E, original magnification ×20). Superficial and deep perivascular mononuclear inflammatory infiltrate intermixed with numerous small granulomas comprised of epithelioid histiocytes in the mid and deep dermis (C)(H&E, original magnification ×20). Perivascular and interstitial lymphohistiocytic infiltrate with abundant extravasated red blood cells in the papillary dermis (D)(H&E, original magnification ×10). Perivascular lymphohistiocytic inflammation with epithelioid granulomas in the mid dermis (E)(H&E, original magnification ×20). Lymphohistiocytic inflammation in the papillary dermis comprised of an admixture of lymphocytes and histiocytes in a perivascular distribution with associated red blood cell extravasation and intimately associated granulomas (F)(H&E, original magnification ×20).

The patient was treated with topical steroids and minocycline 50 mg twice daily without improvement. The lesions improved after the patient underwent treatment with oral corticosteroids for pulmonary disease.

Comment

Pigmented purpuric dermatoses comprise a spectrum of clinical and pathologic conditions.^1,2 Granulomatous PPD is a much less common variant, characterized by a granulomatous infiltrate admixed with PPD. We report 3 additional cases and review the literature on this rare and interesting variant of PPD.

We noted several unifying clinicopathologic features among our patients and those previously reported in the literature (Table).^3-7 Including our cases, our review yielded 13 GPPD patients ranging in age from 9 to 75 years, with a mean age of 49.1 years. Two of our patients—patients 1 and 3—were the youngest and oldest patients, respectively, among the cases we reviewed. The majority of the cases we reviewed included patients of East Asian descent (6 Taiwanese; 2 Japanese; 1 Korean) as well as 4 white patients. No distinctive gender predilection was apparent, as our review included 8 females and 5 males.

Our review revealed that GPPD lesions typically involve the lower extremities and usually are asymptomatic, with the exception of occasional pruritus. Additional lesions have been reported on the dorsal aspect of the hands, and 1 case noted exclusive involvement of the wrist.⁶ Lesions of GPPD can range in their clinical appearance. Three of 13 patients presented with purpuric papules and 2 had brown pigmentation with hemorrhagic papules^3,4,6; the remaining 8 patients had erythematous or brown macules, papules, or plaques.^5-7 The most commonly associated disease condition was hyperlipidemia, which was reported in 7 of 13 cases.^5-7 Additional reported comorbidities included meningioma, renal calculi, obesity, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, hepatitis C virus, ulcerative colitis, thrombocytopenia, and hyperuricemia. Reported serologic abnormalities included a rare positive antinuclear antibody, rheumatoid factor, and cryoglobulins.^3,6 Therapeutic efficacy in the management of GPPD has not been well described; however, for the rare cases in which therapies were described, they were largely unsuccessful, with 1 patient exhibiting spontaneous improvement.^3,4

Granulomatous PPD also appears to exhibit a range of histologic findings. All cases of GPPD shared fundamental components, such as a brisk perivascular infiltrate accompanied by RBC extravasation with variable hemosiderin-laden macrophages and a granulomatous infiltrate. All of the reports we reviewed described an intimate association between these components, with the granulomas being essentially superimposed on typical PPD. As for other types of PPD, obvious vasculitis characterized by a vasculocentric inflammatory infiltrate and evidence of vascular injury, such as fibrinoid necrosis of the vessel wall, has not been described in GPPD.^3-7 Finally, histologic changes suggestive of a relationship with cutaneous T-cell lymphoma, cytologic atypia, and epidermotropism have been described for some forms of PPD but have not been described for GPPD.^3-8

Our case reports expand the histologic spectrum of GPPD. Although patient 3 exhibited a relatively intimate association of granulomas and PPD, 2 of our cases (patients 1 and 2) demonstrated a granulomatous infiltrate in the mid to deep dermis, which is separate from the more superficially situated lichenoid lymphohistiocytic infiltrate, RBC extravasation, and hemosiderin-laden macrophages noted in the papillary dermis. Considered along with the absence of an obvious clinicopathologic explanation for the granulomatous infiltrates (eg, polarizable material, infectious organisms, systemic disease), these 2 cases (patients 1 and 2) suggest a composite form of PPD that combines the lichenoid pattern of PPD of Gougerot and Blum with a deep granulomatous component of GPPD. The importance of this distinction lies in the potential for physicians to overlook this potentially informative histologic pattern if only a superficial biopsy is performed. The clinical relevance is unclear; however, in our experience, it has been challenging to treat this relatively small subset of patients who have exhibited a limited response to treatment with topical steroids, intralesional steroids, pulsed dye laser, and vitamin supplementation.

The cause of the granulomatous infiltrate in GPPD is poorly understood. Seven of 13 cases included in our review occurred in patients with a history of hyperlipidemia.^5-7 Some have postulated that the constellation of findings of GPPD in hyperlipidemic patients reflects an underlying vascular injury process induced by lipid deposition in the endothelial cells with subsequent RBC extravasation and a secondary granulomatous response to the lipid deposits.^6,7 However, given the occurrence of GPPD in patients without hyperlipidemia, other mechanisms also must be considered in the pathogenesis of GPPD, including a reaction to medications, systemic diseases, and infectious etiologies (eg, hepatitis B virus).^4,6 As additional cases are described in the literature, other unifying clinical etiologies for this histopathologic reaction pattern may emerge.

Conclusion

Granulomatous PPD may comprise an underrecognized variant of PPD in cases when only a superficial biopsy is evaluated. Clinicians and pathologists should be aware of this variant, and in refractory cases of PPD, deeper sampling may be warranted to identify granulomas.