Cutis

Onexton

Valeant Pharmaceuticals International,  Inc, an-nounces US Food and Drug Administration approval of Onexton Gel (clindamycin phosphate 1.2% and benzoyl peroxide 3.75%) for the once-daily treatment of comedonal and inflammatory acne in patients 12 years and older. This dual-action topical therapy has a favorable cutaneous tolerability profile and contains  no surfactants, alcohol, or preservatives. Onexton is expected to launch in early 2015. For more information, visit www.valeant.com.

Physical Eye UV Defense Sunscreen

SkinCeuticals presents Physical Eye UV Defense Sunscreen that provides broad-spectrum SPF 50 protection without migrating into or irritating the eyes. Physical Eye UV Defense unifies natural skin tone around the eye and provides a translucent universal tint. It should be applied around the entire eye area and is optimized for application under makeup. It also can be used following hyaluronic acid filler and botulinum toxin injections. SkinCeuticals products are physician dispensed. For more information, visit www.skinceuticals.com.

Refining Mineral Mask

Revision Skincare introduces the limited edition Refining Mineral Mask, a warming mask to reduce the appearance of pores and leave skin looking refined. It contains kaolin to purify the complexion, pumpkin enzymes to gently exfoliate skin, zeolite to provide an extra boost of radiance with its warming effect, and vitamin E microspheres to condition skin. Revision Skincare products are available exclusively through dermatologists, plastic surgeons, and medical spas. For more information, visit www.revisionskincare.com.

Resveratrol B E

SkinCeuticals launches Resveratrol B E, an intensive antioxidant night concentrate that boosts the skin’s endogenous antioxidant defense system, which loses efficiency with age and accumulated damage. It works by neutralizing age-accelerating internal free radicals, strength-ening functionality to resist new damage, and promoting skin’s natural repair to diminish the signs of accumulated damage. Resveratrol B E corrects signs of photodamage, loss of firmness and radiance, poor elasticity, and fine lines and wrinkles. SkinCeuticals products are physician dispensed. For more information, visit www.skinceuticals.com.

If you would like your product included in Product News, please e-mail a press release to the Editorial Office at cutis@frontlinemedcom.com.

Onexton

Valeant Pharmaceuticals International,  Inc, an-nounces US Food and Drug Administration approval of Onexton Gel (clindamycin phosphate 1.2% and benzoyl peroxide 3.75%) for the once-daily treatment of comedonal and inflammatory acne in patients 12 years and older. This dual-action topical therapy has a favorable cutaneous tolerability profile and contains  no surfactants, alcohol, or preservatives. Onexton is expected to launch in early 2015. For more information, visit www.valeant.com.

Physical Eye UV Defense Sunscreen

SkinCeuticals presents Physical Eye UV Defense Sunscreen that provides broad-spectrum SPF 50 protection without migrating into or irritating the eyes. Physical Eye UV Defense unifies natural skin tone around the eye and provides a translucent universal tint. It should be applied around the entire eye area and is optimized for application under makeup. It also can be used following hyaluronic acid filler and botulinum toxin injections. SkinCeuticals products are physician dispensed. For more information, visit www.skinceuticals.com.

Refining Mineral Mask

Revision Skincare introduces the limited edition Refining Mineral Mask, a warming mask to reduce the appearance of pores and leave skin looking refined. It contains kaolin to purify the complexion, pumpkin enzymes to gently exfoliate skin, zeolite to provide an extra boost of radiance with its warming effect, and vitamin E microspheres to condition skin. Revision Skincare products are available exclusively through dermatologists, plastic surgeons, and medical spas. For more information, visit www.revisionskincare.com.

Resveratrol B E

SkinCeuticals launches Resveratrol B E, an intensive antioxidant night concentrate that boosts the skin’s endogenous antioxidant defense system, which loses efficiency with age and accumulated damage. It works by neutralizing age-accelerating internal free radicals, strength-ening functionality to resist new damage, and promoting skin’s natural repair to diminish the signs of accumulated damage. Resveratrol B E corrects signs of photodamage, loss of firmness and radiance, poor elasticity, and fine lines and wrinkles. SkinCeuticals products are physician dispensed. For more information, visit www.skinceuticals.com.

If you would like your product included in Product News, please e-mail a press release to the Editorial Office at cutis@frontlinemedcom.com.

Onexton

Valeant Pharmaceuticals International,  Inc, an-nounces US Food and Drug Administration approval of Onexton Gel (clindamycin phosphate 1.2% and benzoyl peroxide 3.75%) for the once-daily treatment of comedonal and inflammatory acne in patients 12 years and older. This dual-action topical therapy has a favorable cutaneous tolerability profile and contains  no surfactants, alcohol, or preservatives. Onexton is expected to launch in early 2015. For more information, visit www.valeant.com.

Physical Eye UV Defense Sunscreen

SkinCeuticals presents Physical Eye UV Defense Sunscreen that provides broad-spectrum SPF 50 protection without migrating into or irritating the eyes. Physical Eye UV Defense unifies natural skin tone around the eye and provides a translucent universal tint. It should be applied around the entire eye area and is optimized for application under makeup. It also can be used following hyaluronic acid filler and botulinum toxin injections. SkinCeuticals products are physician dispensed. For more information, visit www.skinceuticals.com.

Refining Mineral Mask

Revision Skincare introduces the limited edition Refining Mineral Mask, a warming mask to reduce the appearance of pores and leave skin looking refined. It contains kaolin to purify the complexion, pumpkin enzymes to gently exfoliate skin, zeolite to provide an extra boost of radiance with its warming effect, and vitamin E microspheres to condition skin. Revision Skincare products are available exclusively through dermatologists, plastic surgeons, and medical spas. For more information, visit www.revisionskincare.com.

Resveratrol B E

SkinCeuticals launches Resveratrol B E, an intensive antioxidant night concentrate that boosts the skin’s endogenous antioxidant defense system, which loses efficiency with age and accumulated damage. It works by neutralizing age-accelerating internal free radicals, strength-ening functionality to resist new damage, and promoting skin’s natural repair to diminish the signs of accumulated damage. Resveratrol B E corrects signs of photodamage, loss of firmness and radiance, poor elasticity, and fine lines and wrinkles. SkinCeuticals products are physician dispensed. For more information, visit www.skinceuticals.com.

If you would like your product included in Product News, please e-mail a press release to the Editorial Office at cutis@frontlinemedcom.com.

Actinic keratoses (AKs) are common skin lesions resulting from cumulative exposure to UV radiation and are associated with an increased risk for invasive squamous cell carcinoma¹; therefore, diagnosis and treatment are important.² Individual AKs are most frequently treated with cryosurgery, while topical agents including ingenol mebutate gel are used as field treatments on areas of confluent AKs of sun-damaged skin.^2,3 Studies have shown that rates of complete clearance with topical therapy can be improved with more than a single treatment course.^4-6

Although the mechanisms of action of ingenol mebutate on AKs are not fully understood, studies indicate that it induces cell death in proliferating keratinocytes, which suggests that it may act preferentially on AKs and not on healthy skin.⁷ The field treatment of AKs of the face and scalp using ingenol mebutate gel 0.015% involves a 3-day regimen,⁸ and clearance rates are similar to those observed with topical agents that are used for longer periods of time.^3,9,10 Local skin reactions (LSRs) associated with application of ingenol mebutate gel 0.015% on the face and scalp generally are mild to moderate in intensity and resolve after 2 weeks without sequelae.³

The presumption that the cytotoxic actions of ingenol mebutate affect proliferating keratinocytes preferentially was the basis for this study. We hypothesized that application of a second sequential cycle of ingenol mebutate during AK treatment should produce lower LSR scores than the first application cycle due to the specific elimination of transformed keratinocytes from the treatment area. This open-label study compared the intensity of LSRs during 2 sequential cycles of treatment on the same site of the face or scalp using ingenol mebutate gel 0.015%.

Methods

Study Population

Eligible participants were adults with 4 to 8 clinically typical, visible, nonhypertrophic AKs in a 25-cm² contiguous area of the face or scalp. Inclusion and exclusion criteria were the same as in the pivotal studies.³ The study was approved by the institutional review board at the Icahn School of Medicine at Mount Sinai (New York, New York). Enrollment took place from March 2013 to August 2013.

Study Design and Assessments

All participants were treated with 2 sequential 4-week cycles of ingenol mebutate gel 0.015% applied once daily for 3 consecutive days starting on the first day of each cycle (day 1 and day 29). Participants were evaluated at 11 visits (days 1, 2, 4, 8, 15, 29, 30, 32, 36, 43, and 56) during the 56-day study period (Figure 1). Eligibility, demographics, and medical history were assessed at day 1, and concomitant medications and adverse events (AEs) were evaluated at all visits. Using standardized photographic guides, 6 individual LSRs—erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration—were assessed on a scale of 0 (none) to 4 (severe), with higher numbers indicating more severe reactions. For each participant, a composite score was calculated as the sum of the individual LSR scores.³ Throughout the study, 3 qualified evaluators assessed AK lesion count and graded the LSRs. The same evaluator assessed both treatment courses for each participant for the majority of assessments.

Figure 1. Time course of the composite local skin reaction (LSR) scores during cycle 1 (A) and cycle 2 (B) following initiation of a 3-day treatment course (indicated by arrow) with ingenol mebutate gel 0.015% (N=17 for days 2, 30, 32, 36, and 43; N=18 for days 4, 8, 15, 29, and 56). Error bars indicate standard deviation (SD).

The primary end point of the study was to evaluate the degree of irritation in each of the 2 sequential cycles of ingenol mebutate treatment by assessing the mean area under the curve (AUC) of the composite LSR score over time following each of the 2 applications. Actinic keratoses were counted at baseline and at the end of each treatment cycle. The paired t test was used to compare AUCs of the composite LSR scores of the 2 cycles and to compare the changes in lesion counts from baseline to day 29 and from baseline to day 56. The complete clearance rates (number of participants with no AKs) at the end of cycles 1 and 2 were compared using a logistic regression model. Participant-perceived irritation and treatment satisfaction were evaluated using a 0 to 100 visual analog scale (VAS), with higher numbers indicating greater irritation and higher satisfaction. Participant-reported scores were summarized.

Results

Participant Characteristics

A total of 20 participants were enrolled in the study. At the completion of the study, 2 participants withdrew consent but allowed use of data from their completed assessments. Consequently, a total of 18 patients completed the entire study. The mean age was 75.35 years (median, 77.5 years; age range, 49–87 years). Most of the participants (15/20 [75%]) were men. All participants were white, and 2 were of Hispanic ethnicity. Of the 20 participants, 19 (95%) were Fitzpatrick skin type II, and 1 (5%) was Fitzpatrick skin type I. Most of the participants (16/20 [80%]) received treatment of lesions on the face. With the exception of 2 (10%) participants, all had received prior treatment of AKs, including cryosurgery (16/20 [80%]), imiquimod (5/20 [25%]), fluorouracil (2/20 [10%]), diclofenac (2/20 [10%]), and photodynamic therapy (2/20 [10%]); 8 (40%) participants had received more than 1 type of treatment.

LSRs in Cycles 1 and 2

The time course for the development and resolution of LSRs during both treatment cycles was similar. Local skin reactions were evident on day 2 in each cycle, peaked at 3 days after the application of the first dose, declined rapidly by the 15th day of the cycle, and returned to baseline by the end of each 4-week cycle (Figure 1). The mean (standard deviation [SD]) composite LSR score at 3 days after application of the first dose was higher in cycle 1 than in cycle 2 (9.1 [2.83] vs 5.0 [3.24])(Figure 1). The composite LSR score assessed over time based on the mean (SD) AUC was significantly lower in cycle 2 than in cycle 1 (40.5 [28.05] vs 83.6 [36.25])(P=.0002)(Table). Statistical differences in scores for individual reactions between the 2 cycles were not determined because of the risk for a spurious indication of significance from multiple comparisons in such a limited patient sample.

The percentage of participants who had a score greater than 1 for any of the 6 components of the LSR assessment was lower in cycle 2 than in cycle 1 at all of the assessed time points (Figure 2). In both cycles, the percentage of participants with an LSR score greater than 1 was highest 3 days after the application of the first dose in the cycle (day 4 or day 32, respectively). Erythema, flaking/scaling, and crusting were the most freq-uently observed reactions. At day 29, there were no participants with an LSR score greater than 1 in any of the 6 components. At day 29 and day 56, 94% (17/18) and 100% (18/18) of participants, respectively, had a score of 0 for all reactions.

Figure 2. Percentage of participants with an individual local skin reaction score greater than 1 in cycle 1 (A) and cycle 2 (B)(N=17 for days 2, 30, 32, 36, and 43; N=18 for days 4, 8, 15, 29, and 56).

The photographs in Figure 3, taken 7 days after the application of the first dose of ingenol mebutate gel 0.015% in each cycle of treatment of AK lesions on the face, show that there was less flaking/scaling and crusting in cycle 2 than in cycle 1. A review of participant photographs from the third treatment day of each cycle showed that the areas of erythema were the same in both cycles. The other 5 LSRs—flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration—were observed in different areas of the treated field in the 2 cycles when applicable.

Adverse Events

The few AEs that were reported were considered to be mild in severity. The AEs included application-site pain (n=5), application-site pruritus (n=3), and nasopharyngitis (n=1). No serious AEs were reported. After the first treatment cycle, 1 participant experienced hypopigmentation at the treatment site that persisted as faint hypopigmentation at the last study visit (day 56).

AK Lesion Count

The lesion count in all participants at baseline ranged from 4 to 8, with a mean (SD) of 5.9 (1.55). Mean lesion count was substantially reduced at the end of cycle 1 (0.9 [1.39]) and cycle 2 (0.3 [0.57]). The change in lesion count from baseline to day 56 was greater than the change from baseline to day 29 (-5.7 [1.61] vs -5.0 [1.57])(P=.0137). Complete clearance at day 29 and day 56 was achieved in 55.6% (10/18) and 77.8% (14/18) of participants, respectively. The difference in the clearance rate between day 29 and day 56 did not reach statistical significance, most likely due to the small sample size.

Participant-Reported Outcomes

Figure 3. Local skin reactions at 7 days after application of the first dose of ingenol mebutate gel 0.015% on the same site of the patient’s face in each cycle of treatment (cycle 1, day 8 [A]; cycle 2, day 36 [B]).

Visual analog scale scores for participant-perceived irritation were less than 50 on a scale of 0 to 100 during both application cycles. At 1 day and 3 days after application of the first dose of ingenol mebutate gel 0.015% in cycle 1, the mean (SD) VAS scores for irritation were 31.8 (37.06) and 37.9 (30.77), respectively. At the same time points in cycle 2, VAS scores were 44.2 (32.45) and 49.6 (26.90), respectively. No information was available regarding resolution of participant-perceived irritation, as irritation data were not collected after day 4 of each treatment cycle; therefore, P values were not determined. Participant satisfaction with treatment was high and nearly the same at the end of cycles 1 and 2 (VAS scores: 83.7 [12.73] and 83.8 [20.46], respectively).

Comment

Our findings show that a second course of treatment with ingenol mebutate gel 0.015% on the same site on the face or scalp produced a less intense inflammatory reaction than the first course of treatment. Composite LSR scores at each time point after the start of treatment were lower in cycle 2 than in cycle 1. The percentage of participants who demonstrated a severity score greater than 1 for any of the 6 components of the LSR assessment also was lower at time points in cycle 2 than in cycle 1. These results are consistent with the hypothesis that the activity of ingenol mebutate includes a mechanism that specifically targets transformed keratinocytes, which are reduced by the start of a second cycle of treatment.

The mechanism for the clinical efficacy of ingenol mebutate has not been fully described. Studies in preclinical models suggest at least 2 components, including direct cytotoxic effects on tumor cells and a localized inflammatory reaction that includes protein kinase C activation.¹¹ Ingenol mebutate preferentially induces death in tumor cells and in proliferating undifferentiated keratinocytes.^7,12 Cell death and protein kinase C activation lead to an inflammatory response dominated by neutrophils and other immunocompetent cells that add to the destruction of transformed cells.¹¹

The reduced inflammatory response observed in participants during the second cycle of treatment in this study is consistent with the theory of a preferential action on transformed keratinocytes by ingenol mebutate. Once transformed keratinocytes are substantially cleared in cycle 1, fewer target cells remain, and therefore the inflammatory response is less intense in cycle 2. If ingenol mebutate were uniformly cytotoxic and inflammatory to all cells, the LSR scores in both cycles would be expected to be similar.

Assessment of participant-perceived irritation supplemented the measurement of the 6 visible manifestations of inflammation over each 4-week cycle. Participant-perceived irritation was recorded early in the cycles at 1 and 3 days after the first dose. Although it is difficult to standardize patient perceptions, VAS scores for irritation in cycle 2 were higher than those reported in cycle 1, which suggests an increased perception of irritation. The clinical relevance of this perception is not certain and may be due to the small number of participants and/or the time interval between the 2 treatment courses.

The results of this study were limited by the small patient sample. Additionally, LSR assessments were limited by the quality of the photographs. However, LSRs and AK clearance rates were similar to the pooled findings seen in the phase 3 studies of ingenol mebutate.³ Adverse events were predominantly conditions that occurred at the application site, as in phase 3 studies.³ Similarly, the time course of LSR development and resolution followed the same pattern as in those trials. The peak composite LSR score for the face and scalp was approximately 9 in both the present study (cycle 1) and in the pooled phase 3 studies.³

Conclusion

Ingenol mebutate gel 0.015% may specifically target and remove transformed proliferating keratinocytes, cumulatively reducing the burden of sun-damaged skin over the course of 2 treatment cycles. Patients may experience fewer LSRs on reapplication of ingenol mebutate to a previously treated site.

Acknowledgment

Editorial support was provided by Tanya MacNeil, PhD, of p-value communications, LLC, Cedar Knolls, New Jersey.

Actinic keratoses (AKs) are common skin lesions resulting from cumulative exposure to UV radiation and are associated with an increased risk for invasive squamous cell carcinoma¹; therefore, diagnosis and treatment are important.² Individual AKs are most frequently treated with cryosurgery, while topical agents including ingenol mebutate gel are used as field treatments on areas of confluent AKs of sun-damaged skin.^2,3 Studies have shown that rates of complete clearance with topical therapy can be improved with more than a single treatment course.^4-6

Although the mechanisms of action of ingenol mebutate on AKs are not fully understood, studies indicate that it induces cell death in proliferating keratinocytes, which suggests that it may act preferentially on AKs and not on healthy skin.⁷ The field treatment of AKs of the face and scalp using ingenol mebutate gel 0.015% involves a 3-day regimen,⁸ and clearance rates are similar to those observed with topical agents that are used for longer periods of time.^3,9,10 Local skin reactions (LSRs) associated with application of ingenol mebutate gel 0.015% on the face and scalp generally are mild to moderate in intensity and resolve after 2 weeks without sequelae.³

The presumption that the cytotoxic actions of ingenol mebutate affect proliferating keratinocytes preferentially was the basis for this study. We hypothesized that application of a second sequential cycle of ingenol mebutate during AK treatment should produce lower LSR scores than the first application cycle due to the specific elimination of transformed keratinocytes from the treatment area. This open-label study compared the intensity of LSRs during 2 sequential cycles of treatment on the same site of the face or scalp using ingenol mebutate gel 0.015%.

Methods

Study Population

Eligible participants were adults with 4 to 8 clinically typical, visible, nonhypertrophic AKs in a 25-cm² contiguous area of the face or scalp. Inclusion and exclusion criteria were the same as in the pivotal studies.³ The study was approved by the institutional review board at the Icahn School of Medicine at Mount Sinai (New York, New York). Enrollment took place from March 2013 to August 2013.

Study Design and Assessments

All participants were treated with 2 sequential 4-week cycles of ingenol mebutate gel 0.015% applied once daily for 3 consecutive days starting on the first day of each cycle (day 1 and day 29). Participants were evaluated at 11 visits (days 1, 2, 4, 8, 15, 29, 30, 32, 36, 43, and 56) during the 56-day study period (Figure 1). Eligibility, demographics, and medical history were assessed at day 1, and concomitant medications and adverse events (AEs) were evaluated at all visits. Using standardized photographic guides, 6 individual LSRs—erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration—were assessed on a scale of 0 (none) to 4 (severe), with higher numbers indicating more severe reactions. For each participant, a composite score was calculated as the sum of the individual LSR scores.³ Throughout the study, 3 qualified evaluators assessed AK lesion count and graded the LSRs. The same evaluator assessed both treatment courses for each participant for the majority of assessments.

Figure 1. Time course of the composite local skin reaction (LSR) scores during cycle 1 (A) and cycle 2 (B) following initiation of a 3-day treatment course (indicated by arrow) with ingenol mebutate gel 0.015% (N=17 for days 2, 30, 32, 36, and 43; N=18 for days 4, 8, 15, 29, and 56). Error bars indicate standard deviation (SD).

The primary end point of the study was to evaluate the degree of irritation in each of the 2 sequential cycles of ingenol mebutate treatment by assessing the mean area under the curve (AUC) of the composite LSR score over time following each of the 2 applications. Actinic keratoses were counted at baseline and at the end of each treatment cycle. The paired t test was used to compare AUCs of the composite LSR scores of the 2 cycles and to compare the changes in lesion counts from baseline to day 29 and from baseline to day 56. The complete clearance rates (number of participants with no AKs) at the end of cycles 1 and 2 were compared using a logistic regression model. Participant-perceived irritation and treatment satisfaction were evaluated using a 0 to 100 visual analog scale (VAS), with higher numbers indicating greater irritation and higher satisfaction. Participant-reported scores were summarized.

Results

Participant Characteristics

A total of 20 participants were enrolled in the study. At the completion of the study, 2 participants withdrew consent but allowed use of data from their completed assessments. Consequently, a total of 18 patients completed the entire study. The mean age was 75.35 years (median, 77.5 years; age range, 49–87 years). Most of the participants (15/20 [75%]) were men. All participants were white, and 2 were of Hispanic ethnicity. Of the 20 participants, 19 (95%) were Fitzpatrick skin type II, and 1 (5%) was Fitzpatrick skin type I. Most of the participants (16/20 [80%]) received treatment of lesions on the face. With the exception of 2 (10%) participants, all had received prior treatment of AKs, including cryosurgery (16/20 [80%]), imiquimod (5/20 [25%]), fluorouracil (2/20 [10%]), diclofenac (2/20 [10%]), and photodynamic therapy (2/20 [10%]); 8 (40%) participants had received more than 1 type of treatment.

LSRs in Cycles 1 and 2

The time course for the development and resolution of LSRs during both treatment cycles was similar. Local skin reactions were evident on day 2 in each cycle, peaked at 3 days after the application of the first dose, declined rapidly by the 15th day of the cycle, and returned to baseline by the end of each 4-week cycle (Figure 1). The mean (standard deviation [SD]) composite LSR score at 3 days after application of the first dose was higher in cycle 1 than in cycle 2 (9.1 [2.83] vs 5.0 [3.24])(Figure 1). The composite LSR score assessed over time based on the mean (SD) AUC was significantly lower in cycle 2 than in cycle 1 (40.5 [28.05] vs 83.6 [36.25])(P=.0002)(Table). Statistical differences in scores for individual reactions between the 2 cycles were not determined because of the risk for a spurious indication of significance from multiple comparisons in such a limited patient sample.

The percentage of participants who had a score greater than 1 for any of the 6 components of the LSR assessment was lower in cycle 2 than in cycle 1 at all of the assessed time points (Figure 2). In both cycles, the percentage of participants with an LSR score greater than 1 was highest 3 days after the application of the first dose in the cycle (day 4 or day 32, respectively). Erythema, flaking/scaling, and crusting were the most freq-uently observed reactions. At day 29, there were no participants with an LSR score greater than 1 in any of the 6 components. At day 29 and day 56, 94% (17/18) and 100% (18/18) of participants, respectively, had a score of 0 for all reactions.

Figure 2. Percentage of participants with an individual local skin reaction score greater than 1 in cycle 1 (A) and cycle 2 (B)(N=17 for days 2, 30, 32, 36, and 43; N=18 for days 4, 8, 15, 29, and 56).

The photographs in Figure 3, taken 7 days after the application of the first dose of ingenol mebutate gel 0.015% in each cycle of treatment of AK lesions on the face, show that there was less flaking/scaling and crusting in cycle 2 than in cycle 1. A review of participant photographs from the third treatment day of each cycle showed that the areas of erythema were the same in both cycles. The other 5 LSRs—flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration—were observed in different areas of the treated field in the 2 cycles when applicable.

Adverse Events

The few AEs that were reported were considered to be mild in severity. The AEs included application-site pain (n=5), application-site pruritus (n=3), and nasopharyngitis (n=1). No serious AEs were reported. After the first treatment cycle, 1 participant experienced hypopigmentation at the treatment site that persisted as faint hypopigmentation at the last study visit (day 56).

AK Lesion Count

The lesion count in all participants at baseline ranged from 4 to 8, with a mean (SD) of 5.9 (1.55). Mean lesion count was substantially reduced at the end of cycle 1 (0.9 [1.39]) and cycle 2 (0.3 [0.57]). The change in lesion count from baseline to day 56 was greater than the change from baseline to day 29 (-5.7 [1.61] vs -5.0 [1.57])(P=.0137). Complete clearance at day 29 and day 56 was achieved in 55.6% (10/18) and 77.8% (14/18) of participants, respectively. The difference in the clearance rate between day 29 and day 56 did not reach statistical significance, most likely due to the small sample size.

Participant-Reported Outcomes

Figure 3. Local skin reactions at 7 days after application of the first dose of ingenol mebutate gel 0.015% on the same site of the patient’s face in each cycle of treatment (cycle 1, day 8 [A]; cycle 2, day 36 [B]).

Visual analog scale scores for participant-perceived irritation were less than 50 on a scale of 0 to 100 during both application cycles. At 1 day and 3 days after application of the first dose of ingenol mebutate gel 0.015% in cycle 1, the mean (SD) VAS scores for irritation were 31.8 (37.06) and 37.9 (30.77), respectively. At the same time points in cycle 2, VAS scores were 44.2 (32.45) and 49.6 (26.90), respectively. No information was available regarding resolution of participant-perceived irritation, as irritation data were not collected after day 4 of each treatment cycle; therefore, P values were not determined. Participant satisfaction with treatment was high and nearly the same at the end of cycles 1 and 2 (VAS scores: 83.7 [12.73] and 83.8 [20.46], respectively).

Comment

Our findings show that a second course of treatment with ingenol mebutate gel 0.015% on the same site on the face or scalp produced a less intense inflammatory reaction than the first course of treatment. Composite LSR scores at each time point after the start of treatment were lower in cycle 2 than in cycle 1. The percentage of participants who demonstrated a severity score greater than 1 for any of the 6 components of the LSR assessment also was lower at time points in cycle 2 than in cycle 1. These results are consistent with the hypothesis that the activity of ingenol mebutate includes a mechanism that specifically targets transformed keratinocytes, which are reduced by the start of a second cycle of treatment.

The mechanism for the clinical efficacy of ingenol mebutate has not been fully described. Studies in preclinical models suggest at least 2 components, including direct cytotoxic effects on tumor cells and a localized inflammatory reaction that includes protein kinase C activation.¹¹ Ingenol mebutate preferentially induces death in tumor cells and in proliferating undifferentiated keratinocytes.^7,12 Cell death and protein kinase C activation lead to an inflammatory response dominated by neutrophils and other immunocompetent cells that add to the destruction of transformed cells.¹¹

The reduced inflammatory response observed in participants during the second cycle of treatment in this study is consistent with the theory of a preferential action on transformed keratinocytes by ingenol mebutate. Once transformed keratinocytes are substantially cleared in cycle 1, fewer target cells remain, and therefore the inflammatory response is less intense in cycle 2. If ingenol mebutate were uniformly cytotoxic and inflammatory to all cells, the LSR scores in both cycles would be expected to be similar.

Assessment of participant-perceived irritation supplemented the measurement of the 6 visible manifestations of inflammation over each 4-week cycle. Participant-perceived irritation was recorded early in the cycles at 1 and 3 days after the first dose. Although it is difficult to standardize patient perceptions, VAS scores for irritation in cycle 2 were higher than those reported in cycle 1, which suggests an increased perception of irritation. The clinical relevance of this perception is not certain and may be due to the small number of participants and/or the time interval between the 2 treatment courses.

The results of this study were limited by the small patient sample. Additionally, LSR assessments were limited by the quality of the photographs. However, LSRs and AK clearance rates were similar to the pooled findings seen in the phase 3 studies of ingenol mebutate.³ Adverse events were predominantly conditions that occurred at the application site, as in phase 3 studies.³ Similarly, the time course of LSR development and resolution followed the same pattern as in those trials. The peak composite LSR score for the face and scalp was approximately 9 in both the present study (cycle 1) and in the pooled phase 3 studies.³

Conclusion

Ingenol mebutate gel 0.015% may specifically target and remove transformed proliferating keratinocytes, cumulatively reducing the burden of sun-damaged skin over the course of 2 treatment cycles. Patients may experience fewer LSRs on reapplication of ingenol mebutate to a previously treated site.

Acknowledgment

Editorial support was provided by Tanya MacNeil, PhD, of p-value communications, LLC, Cedar Knolls, New Jersey.

Actinic keratoses (AKs) are common skin lesions resulting from cumulative exposure to UV radiation and are associated with an increased risk for invasive squamous cell carcinoma¹; therefore, diagnosis and treatment are important.² Individual AKs are most frequently treated with cryosurgery, while topical agents including ingenol mebutate gel are used as field treatments on areas of confluent AKs of sun-damaged skin.^2,3 Studies have shown that rates of complete clearance with topical therapy can be improved with more than a single treatment course.^4-6

Although the mechanisms of action of ingenol mebutate on AKs are not fully understood, studies indicate that it induces cell death in proliferating keratinocytes, which suggests that it may act preferentially on AKs and not on healthy skin.⁷ The field treatment of AKs of the face and scalp using ingenol mebutate gel 0.015% involves a 3-day regimen,⁸ and clearance rates are similar to those observed with topical agents that are used for longer periods of time.^3,9,10 Local skin reactions (LSRs) associated with application of ingenol mebutate gel 0.015% on the face and scalp generally are mild to moderate in intensity and resolve after 2 weeks without sequelae.³

The presumption that the cytotoxic actions of ingenol mebutate affect proliferating keratinocytes preferentially was the basis for this study. We hypothesized that application of a second sequential cycle of ingenol mebutate during AK treatment should produce lower LSR scores than the first application cycle due to the specific elimination of transformed keratinocytes from the treatment area. This open-label study compared the intensity of LSRs during 2 sequential cycles of treatment on the same site of the face or scalp using ingenol mebutate gel 0.015%.

Methods

Study Population

Eligible participants were adults with 4 to 8 clinically typical, visible, nonhypertrophic AKs in a 25-cm² contiguous area of the face or scalp. Inclusion and exclusion criteria were the same as in the pivotal studies.³ The study was approved by the institutional review board at the Icahn School of Medicine at Mount Sinai (New York, New York). Enrollment took place from March 2013 to August 2013.

Study Design and Assessments

All participants were treated with 2 sequential 4-week cycles of ingenol mebutate gel 0.015% applied once daily for 3 consecutive days starting on the first day of each cycle (day 1 and day 29). Participants were evaluated at 11 visits (days 1, 2, 4, 8, 15, 29, 30, 32, 36, 43, and 56) during the 56-day study period (Figure 1). Eligibility, demographics, and medical history were assessed at day 1, and concomitant medications and adverse events (AEs) were evaluated at all visits. Using standardized photographic guides, 6 individual LSRs—erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration—were assessed on a scale of 0 (none) to 4 (severe), with higher numbers indicating more severe reactions. For each participant, a composite score was calculated as the sum of the individual LSR scores.³ Throughout the study, 3 qualified evaluators assessed AK lesion count and graded the LSRs. The same evaluator assessed both treatment courses for each participant for the majority of assessments.

Figure 1. Time course of the composite local skin reaction (LSR) scores during cycle 1 (A) and cycle 2 (B) following initiation of a 3-day treatment course (indicated by arrow) with ingenol mebutate gel 0.015% (N=17 for days 2, 30, 32, 36, and 43; N=18 for days 4, 8, 15, 29, and 56). Error bars indicate standard deviation (SD).

The primary end point of the study was to evaluate the degree of irritation in each of the 2 sequential cycles of ingenol mebutate treatment by assessing the mean area under the curve (AUC) of the composite LSR score over time following each of the 2 applications. Actinic keratoses were counted at baseline and at the end of each treatment cycle. The paired t test was used to compare AUCs of the composite LSR scores of the 2 cycles and to compare the changes in lesion counts from baseline to day 29 and from baseline to day 56. The complete clearance rates (number of participants with no AKs) at the end of cycles 1 and 2 were compared using a logistic regression model. Participant-perceived irritation and treatment satisfaction were evaluated using a 0 to 100 visual analog scale (VAS), with higher numbers indicating greater irritation and higher satisfaction. Participant-reported scores were summarized.

Results

Participant Characteristics

A total of 20 participants were enrolled in the study. At the completion of the study, 2 participants withdrew consent but allowed use of data from their completed assessments. Consequently, a total of 18 patients completed the entire study. The mean age was 75.35 years (median, 77.5 years; age range, 49–87 years). Most of the participants (15/20 [75%]) were men. All participants were white, and 2 were of Hispanic ethnicity. Of the 20 participants, 19 (95%) were Fitzpatrick skin type II, and 1 (5%) was Fitzpatrick skin type I. Most of the participants (16/20 [80%]) received treatment of lesions on the face. With the exception of 2 (10%) participants, all had received prior treatment of AKs, including cryosurgery (16/20 [80%]), imiquimod (5/20 [25%]), fluorouracil (2/20 [10%]), diclofenac (2/20 [10%]), and photodynamic therapy (2/20 [10%]); 8 (40%) participants had received more than 1 type of treatment.

LSRs in Cycles 1 and 2

The time course for the development and resolution of LSRs during both treatment cycles was similar. Local skin reactions were evident on day 2 in each cycle, peaked at 3 days after the application of the first dose, declined rapidly by the 15th day of the cycle, and returned to baseline by the end of each 4-week cycle (Figure 1). The mean (standard deviation [SD]) composite LSR score at 3 days after application of the first dose was higher in cycle 1 than in cycle 2 (9.1 [2.83] vs 5.0 [3.24])(Figure 1). The composite LSR score assessed over time based on the mean (SD) AUC was significantly lower in cycle 2 than in cycle 1 (40.5 [28.05] vs 83.6 [36.25])(P=.0002)(Table). Statistical differences in scores for individual reactions between the 2 cycles were not determined because of the risk for a spurious indication of significance from multiple comparisons in such a limited patient sample.

The percentage of participants who had a score greater than 1 for any of the 6 components of the LSR assessment was lower in cycle 2 than in cycle 1 at all of the assessed time points (Figure 2). In both cycles, the percentage of participants with an LSR score greater than 1 was highest 3 days after the application of the first dose in the cycle (day 4 or day 32, respectively). Erythema, flaking/scaling, and crusting were the most freq-uently observed reactions. At day 29, there were no participants with an LSR score greater than 1 in any of the 6 components. At day 29 and day 56, 94% (17/18) and 100% (18/18) of participants, respectively, had a score of 0 for all reactions.

Figure 2. Percentage of participants with an individual local skin reaction score greater than 1 in cycle 1 (A) and cycle 2 (B)(N=17 for days 2, 30, 32, 36, and 43; N=18 for days 4, 8, 15, 29, and 56).

The photographs in Figure 3, taken 7 days after the application of the first dose of ingenol mebutate gel 0.015% in each cycle of treatment of AK lesions on the face, show that there was less flaking/scaling and crusting in cycle 2 than in cycle 1. A review of participant photographs from the third treatment day of each cycle showed that the areas of erythema were the same in both cycles. The other 5 LSRs—flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration—were observed in different areas of the treated field in the 2 cycles when applicable.

Adverse Events

The few AEs that were reported were considered to be mild in severity. The AEs included application-site pain (n=5), application-site pruritus (n=3), and nasopharyngitis (n=1). No serious AEs were reported. After the first treatment cycle, 1 participant experienced hypopigmentation at the treatment site that persisted as faint hypopigmentation at the last study visit (day 56).

AK Lesion Count

The lesion count in all participants at baseline ranged from 4 to 8, with a mean (SD) of 5.9 (1.55). Mean lesion count was substantially reduced at the end of cycle 1 (0.9 [1.39]) and cycle 2 (0.3 [0.57]). The change in lesion count from baseline to day 56 was greater than the change from baseline to day 29 (-5.7 [1.61] vs -5.0 [1.57])(P=.0137). Complete clearance at day 29 and day 56 was achieved in 55.6% (10/18) and 77.8% (14/18) of participants, respectively. The difference in the clearance rate between day 29 and day 56 did not reach statistical significance, most likely due to the small sample size.

Participant-Reported Outcomes

Figure 3. Local skin reactions at 7 days after application of the first dose of ingenol mebutate gel 0.015% on the same site of the patient’s face in each cycle of treatment (cycle 1, day 8 [A]; cycle 2, day 36 [B]).

Visual analog scale scores for participant-perceived irritation were less than 50 on a scale of 0 to 100 during both application cycles. At 1 day and 3 days after application of the first dose of ingenol mebutate gel 0.015% in cycle 1, the mean (SD) VAS scores for irritation were 31.8 (37.06) and 37.9 (30.77), respectively. At the same time points in cycle 2, VAS scores were 44.2 (32.45) and 49.6 (26.90), respectively. No information was available regarding resolution of participant-perceived irritation, as irritation data were not collected after day 4 of each treatment cycle; therefore, P values were not determined. Participant satisfaction with treatment was high and nearly the same at the end of cycles 1 and 2 (VAS scores: 83.7 [12.73] and 83.8 [20.46], respectively).

Comment

Our findings show that a second course of treatment with ingenol mebutate gel 0.015% on the same site on the face or scalp produced a less intense inflammatory reaction than the first course of treatment. Composite LSR scores at each time point after the start of treatment were lower in cycle 2 than in cycle 1. The percentage of participants who demonstrated a severity score greater than 1 for any of the 6 components of the LSR assessment also was lower at time points in cycle 2 than in cycle 1. These results are consistent with the hypothesis that the activity of ingenol mebutate includes a mechanism that specifically targets transformed keratinocytes, which are reduced by the start of a second cycle of treatment.

The mechanism for the clinical efficacy of ingenol mebutate has not been fully described. Studies in preclinical models suggest at least 2 components, including direct cytotoxic effects on tumor cells and a localized inflammatory reaction that includes protein kinase C activation.¹¹ Ingenol mebutate preferentially induces death in tumor cells and in proliferating undifferentiated keratinocytes.^7,12 Cell death and protein kinase C activation lead to an inflammatory response dominated by neutrophils and other immunocompetent cells that add to the destruction of transformed cells.¹¹

The reduced inflammatory response observed in participants during the second cycle of treatment in this study is consistent with the theory of a preferential action on transformed keratinocytes by ingenol mebutate. Once transformed keratinocytes are substantially cleared in cycle 1, fewer target cells remain, and therefore the inflammatory response is less intense in cycle 2. If ingenol mebutate were uniformly cytotoxic and inflammatory to all cells, the LSR scores in both cycles would be expected to be similar.

Assessment of participant-perceived irritation supplemented the measurement of the 6 visible manifestations of inflammation over each 4-week cycle. Participant-perceived irritation was recorded early in the cycles at 1 and 3 days after the first dose. Although it is difficult to standardize patient perceptions, VAS scores for irritation in cycle 2 were higher than those reported in cycle 1, which suggests an increased perception of irritation. The clinical relevance of this perception is not certain and may be due to the small number of participants and/or the time interval between the 2 treatment courses.

The results of this study were limited by the small patient sample. Additionally, LSR assessments were limited by the quality of the photographs. However, LSRs and AK clearance rates were similar to the pooled findings seen in the phase 3 studies of ingenol mebutate.³ Adverse events were predominantly conditions that occurred at the application site, as in phase 3 studies.³ Similarly, the time course of LSR development and resolution followed the same pattern as in those trials. The peak composite LSR score for the face and scalp was approximately 9 in both the present study (cycle 1) and in the pooled phase 3 studies.³

Conclusion

Ingenol mebutate gel 0.015% may specifically target and remove transformed proliferating keratinocytes, cumulatively reducing the burden of sun-damaged skin over the course of 2 treatment cycles. Patients may experience fewer LSRs on reapplication of ingenol mebutate to a previously treated site.

Acknowledgment

Editorial support was provided by Tanya MacNeil, PhD, of p-value communications, LLC, Cedar Knolls, New Jersey.

Localized cutaneous argyria often presents as asymptomatic black or blue-gray pigmented macules in areas of the skin exposed to silver-containing compounds.¹ Silver may enter the skin by traumatic implantation or absorption via eccrine sweat glands.² Our patient witnessed a gun fight several years ago while on a mission trip and sustained multiple shrapnel wounds.

As in our patient, hyperpigmentation may appear years following initial exposure. Over time, incident light reduces colorless silver salts and compounds to black elemental silver.³ It also has been suggested that metallic silver granules stimulate tyrosine kinase activity, leading to locally increased melanin production.⁴ Together, these processes result in the clinical appearance of a blue-black macule. Despite its long-standing association with silver, this appearance also has been noted with deposition of other metals.⁵ Histologically, metal deposits can be seen as black granules surrounding eccrine glands, blood vessels, and elastic fibers on higher magnification.⁶ Granules also may be found in sebaceous glands and arrector pili muscle fibers. These findings do not distinguish from generalized argyria due to increased serum silver levels; however, some cases of localized cutaneous argyria have demonstrated spheroid black globules with surrounding collagen necrosis,¹ which have not been reported with generalized disease. Localized cutaneous argyria also may be associated with ocher pigmentation of thickened collagen fibers, resembling changes typically found in alkaptonuria, an inherited deficiency of homogentisic acid oxidase (an enzyme involved in tyrosine metabolism).⁷ The resulting buildup of metabolic intermediates leads to ochronosis, a deposition of ocher-pigmented intermediates in connective tissue throughout the body. In the skin, ocher pigmentation occurs in elastic fibers of the reticular dermis.¹ Grossly, these changes result in a blue-gray discoloration of the skin due to a light-scattering phenomenon known as the Tyndall effect. Exogenous ochronosis also can occur, most commonly from the topical application of hydroquinone or other skin-lightening compounds.^1,5 Ocher  pigmentation occurring in the setting of localized cutaneous argyria is referred to as pseudo-ochronosis, a finding first described by Robinson-Bostom et al.¹ The etiology of this condition is poorly understood, but Robinson-Bostom et al¹ noted the appearance of dark metal granules surrounding collagen bundles and hypothesized that metal aggregates surrounding collagen bundles in pseudo-ochronosis cause a homogenized appearance under light microscopy. Yellow-brown, swollen, homogenized collagen bundles can be visualized in the reticular dermis with surrounding deposition of metal granules (Figures 1 and 2).¹ Typical patterns of granule deposition in localized argyria also are present.

A blue nevus is a collection of proliferating dermal melanocytes. Many histologic subtypes exist and there may be extensive variability in the extent of sclerosis, cellular architecture, and tissue cellularity between each variant.⁸ Blue nevi commonly present as blue-black hyperpigmentation in the dermis and subcutaneous tissue.⁹ Histologically, they are characterized by slender, bipolar, dendritic melanocytes in a sclerotic stroma (Figure 3).⁸ Melanocytes are highly pigmented and contain small monomorphic nuclei. Lesions are relatively homogenous and typically are restricted to the dermis with epidermal sparing.⁹ Dark granules and ocher fibers are absent.

Long-term use of hydroxychloroquine or other antimalarials may cause a macular pattern of blue-gray hyperpigmentation.¹⁰ Biopsy specimens typically reveal coarse, yellow-brown pigment granules primarily affecting the superficial dermis (Figure 4). Granules are found both extracellularly and within macrophages. Fontana-Masson silver staining may identify melanin, as hydroxychloroquine-melanin binding may contribute to patterns of hyperpigmentation.¹⁰ Hemosiderin often is present in cases of hydroxychloroquine pigmentation. Preceding ecchymosis appears to favor the deposition of hydroxychloroquine in the skin.¹¹ The absence of dark metal granules helps distinguish hydroxychloroquine pigmentation from argyria.

Regressed melanomas may appear clinically as gray macules. These lesions arise in cases of malignant melanoma that spontaneously regress without treatment. Spontaneous regression occurs in 10% to 35% of cases depending on tumor subtype.¹² Lesions can have a variable appearance based on the degree of regression. Partial regression is demonstrated by mixed melanosis and fibrosis in the dermis (Figure 5).^13,14 Melanin is housed within melanophages present in a variably expanded papillary dermis. Tumors in early stages of regression can be surrounded by an inflammatory infiltrate, which becomes diminished at later stages. However, a few exceptional cases have been noted with extensive inflammatory infiltrate and no residual tumor.¹⁴ Completely regressed lesions typically appear as a band of dermal melanophages in the absence of inflammation or melanocytic atypia.¹⁵ The finding of regressed melanoma should prompt further investigation including sentinel lymph node biopsy, as it may be associated with metastasis.

Tattooing occurs following traumatic penetration of the skin with impregnation of pigmented foreign material into deep dermal layers.¹⁶ Histologic examination usually reveals clumps of fine particulate material in the dermis (Figure 6). The color of the pigment depends on the agent used. For example, graphite appears as black particles that may be confused with localized cutaneous argyria. Distinction can be made using elemental identification techniques such as energy-dispersive X-ray spectroscopy.¹ The intensity of the pigment in granules found in tattoos or localized cutaneous argyria will fail to diminish with the application of melanin bleach.⁶

Localized cutaneous argyria often presents as asymptomatic black or blue-gray pigmented macules in areas of the skin exposed to silver-containing compounds.¹ Silver may enter the skin by traumatic implantation or absorption via eccrine sweat glands.² Our patient witnessed a gun fight several years ago while on a mission trip and sustained multiple shrapnel wounds.

As in our patient, hyperpigmentation may appear years following initial exposure. Over time, incident light reduces colorless silver salts and compounds to black elemental silver.³ It also has been suggested that metallic silver granules stimulate tyrosine kinase activity, leading to locally increased melanin production.⁴ Together, these processes result in the clinical appearance of a blue-black macule. Despite its long-standing association with silver, this appearance also has been noted with deposition of other metals.⁵ Histologically, metal deposits can be seen as black granules surrounding eccrine glands, blood vessels, and elastic fibers on higher magnification.⁶ Granules also may be found in sebaceous glands and arrector pili muscle fibers. These findings do not distinguish from generalized argyria due to increased serum silver levels; however, some cases of localized cutaneous argyria have demonstrated spheroid black globules with surrounding collagen necrosis,¹ which have not been reported with generalized disease. Localized cutaneous argyria also may be associated with ocher pigmentation of thickened collagen fibers, resembling changes typically found in alkaptonuria, an inherited deficiency of homogentisic acid oxidase (an enzyme involved in tyrosine metabolism).⁷ The resulting buildup of metabolic intermediates leads to ochronosis, a deposition of ocher-pigmented intermediates in connective tissue throughout the body. In the skin, ocher pigmentation occurs in elastic fibers of the reticular dermis.¹ Grossly, these changes result in a blue-gray discoloration of the skin due to a light-scattering phenomenon known as the Tyndall effect. Exogenous ochronosis also can occur, most commonly from the topical application of hydroquinone or other skin-lightening compounds.^1,5 Ocher  pigmentation occurring in the setting of localized cutaneous argyria is referred to as pseudo-ochronosis, a finding first described by Robinson-Bostom et al.¹ The etiology of this condition is poorly understood, but Robinson-Bostom et al¹ noted the appearance of dark metal granules surrounding collagen bundles and hypothesized that metal aggregates surrounding collagen bundles in pseudo-ochronosis cause a homogenized appearance under light microscopy. Yellow-brown, swollen, homogenized collagen bundles can be visualized in the reticular dermis with surrounding deposition of metal granules (Figures 1 and 2).¹ Typical patterns of granule deposition in localized argyria also are present.

A blue nevus is a collection of proliferating dermal melanocytes. Many histologic subtypes exist and there may be extensive variability in the extent of sclerosis, cellular architecture, and tissue cellularity between each variant.⁸ Blue nevi commonly present as blue-black hyperpigmentation in the dermis and subcutaneous tissue.⁹ Histologically, they are characterized by slender, bipolar, dendritic melanocytes in a sclerotic stroma (Figure 3).⁸ Melanocytes are highly pigmented and contain small monomorphic nuclei. Lesions are relatively homogenous and typically are restricted to the dermis with epidermal sparing.⁹ Dark granules and ocher fibers are absent.

Long-term use of hydroxychloroquine or other antimalarials may cause a macular pattern of blue-gray hyperpigmentation.¹⁰ Biopsy specimens typically reveal coarse, yellow-brown pigment granules primarily affecting the superficial dermis (Figure 4). Granules are found both extracellularly and within macrophages. Fontana-Masson silver staining may identify melanin, as hydroxychloroquine-melanin binding may contribute to patterns of hyperpigmentation.¹⁰ Hemosiderin often is present in cases of hydroxychloroquine pigmentation. Preceding ecchymosis appears to favor the deposition of hydroxychloroquine in the skin.¹¹ The absence of dark metal granules helps distinguish hydroxychloroquine pigmentation from argyria.

Regressed melanomas may appear clinically as gray macules. These lesions arise in cases of malignant melanoma that spontaneously regress without treatment. Spontaneous regression occurs in 10% to 35% of cases depending on tumor subtype.¹² Lesions can have a variable appearance based on the degree of regression. Partial regression is demonstrated by mixed melanosis and fibrosis in the dermis (Figure 5).^13,14 Melanin is housed within melanophages present in a variably expanded papillary dermis. Tumors in early stages of regression can be surrounded by an inflammatory infiltrate, which becomes diminished at later stages. However, a few exceptional cases have been noted with extensive inflammatory infiltrate and no residual tumor.¹⁴ Completely regressed lesions typically appear as a band of dermal melanophages in the absence of inflammation or melanocytic atypia.¹⁵ The finding of regressed melanoma should prompt further investigation including sentinel lymph node biopsy, as it may be associated with metastasis.

Tattooing occurs following traumatic penetration of the skin with impregnation of pigmented foreign material into deep dermal layers.¹⁶ Histologic examination usually reveals clumps of fine particulate material in the dermis (Figure 6). The color of the pigment depends on the agent used. For example, graphite appears as black particles that may be confused with localized cutaneous argyria. Distinction can be made using elemental identification techniques such as energy-dispersive X-ray spectroscopy.¹ The intensity of the pigment in granules found in tattoos or localized cutaneous argyria will fail to diminish with the application of melanin bleach.⁶

Localized cutaneous argyria often presents as asymptomatic black or blue-gray pigmented macules in areas of the skin exposed to silver-containing compounds.¹ Silver may enter the skin by traumatic implantation or absorption via eccrine sweat glands.² Our patient witnessed a gun fight several years ago while on a mission trip and sustained multiple shrapnel wounds.

As in our patient, hyperpigmentation may appear years following initial exposure. Over time, incident light reduces colorless silver salts and compounds to black elemental silver.³ It also has been suggested that metallic silver granules stimulate tyrosine kinase activity, leading to locally increased melanin production.⁴ Together, these processes result in the clinical appearance of a blue-black macule. Despite its long-standing association with silver, this appearance also has been noted with deposition of other metals.⁵ Histologically, metal deposits can be seen as black granules surrounding eccrine glands, blood vessels, and elastic fibers on higher magnification.⁶ Granules also may be found in sebaceous glands and arrector pili muscle fibers. These findings do not distinguish from generalized argyria due to increased serum silver levels; however, some cases of localized cutaneous argyria have demonstrated spheroid black globules with surrounding collagen necrosis,¹ which have not been reported with generalized disease. Localized cutaneous argyria also may be associated with ocher pigmentation of thickened collagen fibers, resembling changes typically found in alkaptonuria, an inherited deficiency of homogentisic acid oxidase (an enzyme involved in tyrosine metabolism).⁷ The resulting buildup of metabolic intermediates leads to ochronosis, a deposition of ocher-pigmented intermediates in connective tissue throughout the body. In the skin, ocher pigmentation occurs in elastic fibers of the reticular dermis.¹ Grossly, these changes result in a blue-gray discoloration of the skin due to a light-scattering phenomenon known as the Tyndall effect. Exogenous ochronosis also can occur, most commonly from the topical application of hydroquinone or other skin-lightening compounds.^1,5 Ocher  pigmentation occurring in the setting of localized cutaneous argyria is referred to as pseudo-ochronosis, a finding first described by Robinson-Bostom et al.¹ The etiology of this condition is poorly understood, but Robinson-Bostom et al¹ noted the appearance of dark metal granules surrounding collagen bundles and hypothesized that metal aggregates surrounding collagen bundles in pseudo-ochronosis cause a homogenized appearance under light microscopy. Yellow-brown, swollen, homogenized collagen bundles can be visualized in the reticular dermis with surrounding deposition of metal granules (Figures 1 and 2).¹ Typical patterns of granule deposition in localized argyria also are present.

A blue nevus is a collection of proliferating dermal melanocytes. Many histologic subtypes exist and there may be extensive variability in the extent of sclerosis, cellular architecture, and tissue cellularity between each variant.⁸ Blue nevi commonly present as blue-black hyperpigmentation in the dermis and subcutaneous tissue.⁹ Histologically, they are characterized by slender, bipolar, dendritic melanocytes in a sclerotic stroma (Figure 3).⁸ Melanocytes are highly pigmented and contain small monomorphic nuclei. Lesions are relatively homogenous and typically are restricted to the dermis with epidermal sparing.⁹ Dark granules and ocher fibers are absent.

Long-term use of hydroxychloroquine or other antimalarials may cause a macular pattern of blue-gray hyperpigmentation.¹⁰ Biopsy specimens typically reveal coarse, yellow-brown pigment granules primarily affecting the superficial dermis (Figure 4). Granules are found both extracellularly and within macrophages. Fontana-Masson silver staining may identify melanin, as hydroxychloroquine-melanin binding may contribute to patterns of hyperpigmentation.¹⁰ Hemosiderin often is present in cases of hydroxychloroquine pigmentation. Preceding ecchymosis appears to favor the deposition of hydroxychloroquine in the skin.¹¹ The absence of dark metal granules helps distinguish hydroxychloroquine pigmentation from argyria.

Regressed melanomas may appear clinically as gray macules. These lesions arise in cases of malignant melanoma that spontaneously regress without treatment. Spontaneous regression occurs in 10% to 35% of cases depending on tumor subtype.¹² Lesions can have a variable appearance based on the degree of regression. Partial regression is demonstrated by mixed melanosis and fibrosis in the dermis (Figure 5).^13,14 Melanin is housed within melanophages present in a variably expanded papillary dermis. Tumors in early stages of regression can be surrounded by an inflammatory infiltrate, which becomes diminished at later stages. However, a few exceptional cases have been noted with extensive inflammatory infiltrate and no residual tumor.¹⁴ Completely regressed lesions typically appear as a band of dermal melanophages in the absence of inflammation or melanocytic atypia.¹⁵ The finding of regressed melanoma should prompt further investigation including sentinel lymph node biopsy, as it may be associated with metastasis.

Tattooing occurs following traumatic penetration of the skin with impregnation of pigmented foreign material into deep dermal layers.¹⁶ Histologic examination usually reveals clumps of fine particulate material in the dermis (Figure 6). The color of the pigment depends on the agent used. For example, graphite appears as black particles that may be confused with localized cutaneous argyria. Distinction can be made using elemental identification techniques such as energy-dispersive X-ray spectroscopy.¹ The intensity of the pigment in granules found in tattoos or localized cutaneous argyria will fail to diminish with the application of melanin bleach.⁶

Pediatric oncology patients can present with various skin lesions related to both their primary disease and immunosuppressive treatments. In the majority of cases, cutaneous findings are associated with the use of chemotherapeutic agents. The toxic effects of chemotherapeutic agents, which generally are associated with treatment of solid organ malignancies (eg, liver, kidneys), can be detected by oncologists using clinical signs and laboratory tests.^1-3 However, it also is important for dermatologists to recognize and evaluate cutaneous side effects associated with chemotherapeutic agents. Reports in the literature of cutaneous side effects of chemotherapy in pediatric patients generally are limited to case studies. This study aimed to evaluate the characteristics of cutaneous side effects of chemotherapy in pediatric oncology patients.

Materials and Methods

The study was performed through the collaboration of the departments of dermatology and venereology and pediatric oncology in the Faculty of Medicine at Ege University, Izmir, Turkey. Sixty-five pediatric oncology patients who were scheduled to undergo chemotherapy from May 2011 to May 2013 were included in the study. Clinical examination of dermatologic findings was conducted at baseline (prior to beginning chemotherapy) and at months 1, 3, and 6 of treatment. Patients were examined a total of 4 times during the study. Patients with a history of skin disease prior to diagnosis of their malignancy were excluded, as the study aimed to evaluate cutaneous side effects of chemotherapy. Patients who developed cutaneous side effects during the study period were photographed. Skin biopsy was performed to confirm clinical diagnosis. Patients were split into 5 groups according to oncological diagnoses, including hematological malignancies, solid organ tumors, bone and soft tissue tumors, central nervous system tumors, and Langerhans cell histiocytosis. Data regarding age, gender, treatments administered (ie, chemotherapeutics, antibiotics, antifungals, antivirals), and dermatologic signs were recorded. Mucocutaneous findings were classified as infectious (viral, bacterial, fungal) lesions, bullous lesions, inflammatory dermatoses (eg, diaper dermatitis, asteatotic eczema, contact dermatitis, seborrheic dermatitis), xeroderma, petechiae/ecchymoses, nail signs, alopecia, mucositis, cheilitis, oral aphthae, drug reactions confirmed by histopathology, cushingoid signs (eg, striae, acneform eruption, hypertrichosis), and cutaneous hyperpigmentation.

Statistical analysis was performed using SPSS version 15.0 and χ² test was applied to the analysis.

Results

Of 65 patients, 62 completed the study and were included in the analysis. Three patients were excluded from the results, as 2 patients died during treatment and 1 patient withdrew from the study prior to completion. Twenty-seven (43.5%) patients were female and 35 (56.5%) were male ranging in age from 1 to 17 years (mean age, 8.14 years; median age [standard deviation], 7.25 [5.42] years). There were 31 (50%) patients in the hematological malignancies group, 11 (17.7%) in the solid organ tumors group, 10 (16.1%) in the bone and soft tissue tumors group, and 9 (14.5%) in the central nervous system tumors group; Langerhans cell histiocytosis was diagnosed in 1 (1.6%) patient. Hodgkin lymphoma made up 29.0% (n=9) of hematological malignancies. Other hematological malignancies included acute myeloblastic leukemia (n=7 [22.5%]), acute lymphoblastic leukemia (n=7 [22.5%]), T-cell lymphoma (n=5 [16.1%]), non-Hodgkin lym-phoma (n=1 [3.2%]), anaplastic giant cell lymphoma (n=1 [3.2%]), and diffuse giant cell lymphoma (n=1 [3.2%]).

In addition to chemotherapeutic agents, 7 (11.3%) patients in this study also received antibiotics and 3 (4.8%) received antivirals. The most frequently employed chemotherapeutic agents were vincristine, methotrexate, cytarabine, etoposide, and dexamethasone. Cyclophosphamide, doxorubicin, ifosfamide, asparaginase, carboplatin, procarbazine, daunorubicin, actinomycin D, vinblastine, cisplatin, bleomycin, idarubicin, 6-mercaptopurine, temozolamide, and cyclosporine also were administered. The most commonly encountered dermatological side effects were alopecia, xeroderma, inflammatory skin lesions, infectious lesions, and mucositis, respectively (Table 1). Cutaneous side effects were frequently seen at months 1 and 3 of treatment.

The most commonly encountered dermatologic side effect was alopecia (31/62 [50%]). Anagen effluvium (Figure 1) was detected in half of the cases, while complete scalp hair loss was noted in the rest. Alopecia was encountered more commonly in cases with central nervous system tumors (5/9 [55.6%]) and hematological malignancies (16/31 [51.6%])(Table 2).

The second most commonly encountered side effect was xeroderma (29/62 [46.8%])(Figure 2). This side effect was most commonly encountered in patients with solid organ tumors (6/11 [54.5%]) and central nervous system tumors (4/9 [44.4%]), and occurred less frequently with bone and soft tissue tumors (4/10 [40.0%]).

Findings of eczema accounted for the majority of inflammatory lesions, which were the third most commonly encountered side effects. Among 24 cases of inflammatory skin lesions, 8 patients (33.3%) had diaper dermatitis, 7 (29.2%) had asteatotic eczema, 6 (25.0%) had contact dermatitis, and 3 (12.5%) had seborrheic dermatitis. Although inflammatory skin lesions were commonly encountered in patients with hematological malignancies (14/31 [45.2%]), the difference was not statistically significant.

Mucositis and oral aphthous lesions were observed in 15 (24.2%) and 3 (4.8%) patients, respectively. Nail signs were noted in 10 (16.1%) patients; 4 patients had transverse streaks on the nail plates, 3 had linear streaks, 2 had nail plate fragility, and 1 had increased pigmentation at the nail bed and periungual area. Figure 3 shows linear streaks on the nail plate. These side effects were most commonly encountered in patients with solid organ tumors (5/11 [45.5%]); however, the difference was not statistically significant when compared with the other diagnostic groups.

Dermatologic signs with infectious origins were detected in 15 (24.2%) patients; 2 patients had herpes labialis, 2 had verruca vulgaris, 3 had bacterial folliculitis, 1 had acute paronychia, 1 had soft tissue infection, 2 had tinea versicolor, and 4 had mucocutaneous candidiasis. Dermatologic side effects due to infectious causes were more commonly encountered in patients with bone and soft tissue tumors (4/11 [36.4%]), and the difference was statistically significant when compared with the other diagnostic groups (P=.04).

Petechiae and ecchymotic lesions were present in 13 (21.0%) patients. These side effects occurred mainly in the first month of chemotherapy, namely when patients were in the pancytopenic phase.

Comment

Variability among the oncological diagnosis and drugs used in treatment as well as increased numbers of chemotherapeutic agents available have led to many side effects and complications in pediatric oncology patients undergoing chemotherapy.^1,2 Comprehensive studies regarding the cutaneous side effects of chemotherapeuticagents in cancer treatment have been conducted in adult patients. Side effects in pediatric patients have only been documented in case reports in the literature. In our study of pediatric oncology patients undergoing treatment with chemotherapy, the most commonly observed dermatologic side effect was alopecia, followed by xeroderma, inflammatory lesions, infectious lesions, mucositis, petechiae/ecchymoses, cheilitis, nail disorders, cushingoid signs, oral aphthae, bullous lesions, and drug reactions confirmed histopathologically (Table 1).

Because the common effects of chemotherapeutic agents used in cancer treatment are greatest in areas of rapidly dividing cells, the skin and skin appendages frequently are affected by these drugs.^1-3 Cutaneous signs are frequently observed, especially in regions with increased mitotic activity such as the hair, mucosa, and nails.

Kamil et al¹ reported that the incidence of alopecia was 64.3% (74/115) in a study of adult cancer patients who underwent chemotherapy. Chemotherapeutic agents that have commonly caused alopecia are vincristine, daunorubicin, doxorubicin, cyclophosphamide, etoposide, cytarabine, and carboplatin.^1,2 In our study, alopecia was noted in 31 (50.0%) patients, especially with the use of vincristine (7/31 [22.6%]), daunorubicin (8/31 [25.8%]), doxorubicin (6/31 [19.4%]), and cyclophosphamide (10/31 [32.3%]).

Darkening of the skin and paleness accompanied the majority of cases of xeroderma in our study. Skin dryness was in an ichthyosiform appearance and was severe in 1 patient who was diagnosed with osteosarcoma. Asteatotic eczema and cheilitis were related to skin dryness. It has been reported that acquired paraneoplastic ichthyosis can develop in hematological malignancies, primarily in patients with Hodgkin lymphoma.⁴

The incidence of mucositis has been related to the doses of chemotherapeutic agents. Although it is a commonly encountered side effect, there is no standard treatment of mucositis; therefore, preventive care in patients undergoing chemotherapy is important. It has been reported that practicing good oral hygiene before the treatment period can decrease the incidence of mucositis.^5-9 The lower incidence of mucositis in our study compared to the literature (55.6%)⁵ can be attributed to the lower doses of chemotherapy drugs administered to children due to their weights; they also had active oral mucosa care during chemotherapy.

Another common complication observed in our study was nail disorders. Transverse streaks commonly are encountered due to damage in the nail matrix. Other signs are increased linear streaks, longitudinal melanonychia, nail plate fragility, and onycholysis.¹⁰

Cancer patients acquire infections more frequently because of immunosuppression from chemotherapy and malignancy.^11,12 In our study, cutaneous side effects with infectious causes were noted in 15 patients. Steroids, which are included in the majority of chemotherapeutic protocols, can cause cushingoid changes. Striae from rapid weight gain, acneform eruptions, hypertrichosis, and atrophy of the skin also have been observed among secondary changes to chemotherapy.^1,11

Other skin signs observed in the study were acute urticaria in 1 patient (1.6%) following administration of intrathecal methotrexate; Stevens-Johnson syndrome related to voriconazole was noted in 1 (1.6%) patient.

Hyperpigmentation is a common side effect observed in oncology patients.^13-15 It can be observed locally in the skin as well as the mucosa, teeth, hair, and nails, and it generally develops secondary to alkylating agents.¹⁶ Moreover, hyperpigmentation may develop in regions with occlusions (eg, electrocardiogram pads, adhesion sites of plasters), and commonly is associated with ifosfamide, etoposide, carboplatin, and cyclosporine. Although the development mechanism of hyperpigmentation related to chemotherapy drugs is not clearly known, it is thought to be due to direct toxicity, melanocyte stimulation, or postinflammatory changes.^1,6,17 In our study, xeroderma was noted in some patients with hyperpigmentation; all of them had received cyclosporine and systemic steroid treatments. The other chemotherapeutics were defined as etoposide, cytarabine, dacarbazine, and ifosfamide.¹ Our patients with hyperpigmentation were not taking these therapies.

Increased skin malignancies have been reported in adult cases with hematological malignancies.¹⁸ None of the patients in our study had a secondary skin malignancy, likely because we evaluated a pediatric population and the follow-up period (6 months) was too short for the development of a secondary malignancy.

Conclusion

A wide range of cutaneous side effects can be observed in pediatric oncology patients undergoing chemotherapy based on oncological diagnosis and treatment protocol. Although these side effects are not fatal, they may negatively affect morbidity and can lead to emotional distress. Knowing the possible cutaneous side effects of chemotherapy in pediatric patients and their causes is important for early diagnosis and minimal treatment.

Pediatric oncology patients can present with various skin lesions related to both their primary disease and immunosuppressive treatments. In the majority of cases, cutaneous findings are associated with the use of chemotherapeutic agents. The toxic effects of chemotherapeutic agents, which generally are associated with treatment of solid organ malignancies (eg, liver, kidneys), can be detected by oncologists using clinical signs and laboratory tests.^1-3 However, it also is important for dermatologists to recognize and evaluate cutaneous side effects associated with chemotherapeutic agents. Reports in the literature of cutaneous side effects of chemotherapy in pediatric patients generally are limited to case studies. This study aimed to evaluate the characteristics of cutaneous side effects of chemotherapy in pediatric oncology patients.

Materials and Methods

The study was performed through the collaboration of the departments of dermatology and venereology and pediatric oncology in the Faculty of Medicine at Ege University, Izmir, Turkey. Sixty-five pediatric oncology patients who were scheduled to undergo chemotherapy from May 2011 to May 2013 were included in the study. Clinical examination of dermatologic findings was conducted at baseline (prior to beginning chemotherapy) and at months 1, 3, and 6 of treatment. Patients were examined a total of 4 times during the study. Patients with a history of skin disease prior to diagnosis of their malignancy were excluded, as the study aimed to evaluate cutaneous side effects of chemotherapy. Patients who developed cutaneous side effects during the study period were photographed. Skin biopsy was performed to confirm clinical diagnosis. Patients were split into 5 groups according to oncological diagnoses, including hematological malignancies, solid organ tumors, bone and soft tissue tumors, central nervous system tumors, and Langerhans cell histiocytosis. Data regarding age, gender, treatments administered (ie, chemotherapeutics, antibiotics, antifungals, antivirals), and dermatologic signs were recorded. Mucocutaneous findings were classified as infectious (viral, bacterial, fungal) lesions, bullous lesions, inflammatory dermatoses (eg, diaper dermatitis, asteatotic eczema, contact dermatitis, seborrheic dermatitis), xeroderma, petechiae/ecchymoses, nail signs, alopecia, mucositis, cheilitis, oral aphthae, drug reactions confirmed by histopathology, cushingoid signs (eg, striae, acneform eruption, hypertrichosis), and cutaneous hyperpigmentation.

Statistical analysis was performed using SPSS version 15.0 and χ² test was applied to the analysis.

Results

Of 65 patients, 62 completed the study and were included in the analysis. Three patients were excluded from the results, as 2 patients died during treatment and 1 patient withdrew from the study prior to completion. Twenty-seven (43.5%) patients were female and 35 (56.5%) were male ranging in age from 1 to 17 years (mean age, 8.14 years; median age [standard deviation], 7.25 [5.42] years). There were 31 (50%) patients in the hematological malignancies group, 11 (17.7%) in the solid organ tumors group, 10 (16.1%) in the bone and soft tissue tumors group, and 9 (14.5%) in the central nervous system tumors group; Langerhans cell histiocytosis was diagnosed in 1 (1.6%) patient. Hodgkin lymphoma made up 29.0% (n=9) of hematological malignancies. Other hematological malignancies included acute myeloblastic leukemia (n=7 [22.5%]), acute lymphoblastic leukemia (n=7 [22.5%]), T-cell lymphoma (n=5 [16.1%]), non-Hodgkin lym-phoma (n=1 [3.2%]), anaplastic giant cell lymphoma (n=1 [3.2%]), and diffuse giant cell lymphoma (n=1 [3.2%]).

In addition to chemotherapeutic agents, 7 (11.3%) patients in this study also received antibiotics and 3 (4.8%) received antivirals. The most frequently employed chemotherapeutic agents were vincristine, methotrexate, cytarabine, etoposide, and dexamethasone. Cyclophosphamide, doxorubicin, ifosfamide, asparaginase, carboplatin, procarbazine, daunorubicin, actinomycin D, vinblastine, cisplatin, bleomycin, idarubicin, 6-mercaptopurine, temozolamide, and cyclosporine also were administered. The most commonly encountered dermatological side effects were alopecia, xeroderma, inflammatory skin lesions, infectious lesions, and mucositis, respectively (Table 1). Cutaneous side effects were frequently seen at months 1 and 3 of treatment.

The most commonly encountered dermatologic side effect was alopecia (31/62 [50%]). Anagen effluvium (Figure 1) was detected in half of the cases, while complete scalp hair loss was noted in the rest. Alopecia was encountered more commonly in cases with central nervous system tumors (5/9 [55.6%]) and hematological malignancies (16/31 [51.6%])(Table 2).

The second most commonly encountered side effect was xeroderma (29/62 [46.8%])(Figure 2). This side effect was most commonly encountered in patients with solid organ tumors (6/11 [54.5%]) and central nervous system tumors (4/9 [44.4%]), and occurred less frequently with bone and soft tissue tumors (4/10 [40.0%]).

Findings of eczema accounted for the majority of inflammatory lesions, which were the third most commonly encountered side effects. Among 24 cases of inflammatory skin lesions, 8 patients (33.3%) had diaper dermatitis, 7 (29.2%) had asteatotic eczema, 6 (25.0%) had contact dermatitis, and 3 (12.5%) had seborrheic dermatitis. Although inflammatory skin lesions were commonly encountered in patients with hematological malignancies (14/31 [45.2%]), the difference was not statistically significant.

Mucositis and oral aphthous lesions were observed in 15 (24.2%) and 3 (4.8%) patients, respectively. Nail signs were noted in 10 (16.1%) patients; 4 patients had transverse streaks on the nail plates, 3 had linear streaks, 2 had nail plate fragility, and 1 had increased pigmentation at the nail bed and periungual area. Figure 3 shows linear streaks on the nail plate. These side effects were most commonly encountered in patients with solid organ tumors (5/11 [45.5%]); however, the difference was not statistically significant when compared with the other diagnostic groups.

Dermatologic signs with infectious origins were detected in 15 (24.2%) patients; 2 patients had herpes labialis, 2 had verruca vulgaris, 3 had bacterial folliculitis, 1 had acute paronychia, 1 had soft tissue infection, 2 had tinea versicolor, and 4 had mucocutaneous candidiasis. Dermatologic side effects due to infectious causes were more commonly encountered in patients with bone and soft tissue tumors (4/11 [36.4%]), and the difference was statistically significant when compared with the other diagnostic groups (P=.04).

Petechiae and ecchymotic lesions were present in 13 (21.0%) patients. These side effects occurred mainly in the first month of chemotherapy, namely when patients were in the pancytopenic phase.

Comment

Variability among the oncological diagnosis and drugs used in treatment as well as increased numbers of chemotherapeutic agents available have led to many side effects and complications in pediatric oncology patients undergoing chemotherapy.^1,2 Comprehensive studies regarding the cutaneous side effects of chemotherapeuticagents in cancer treatment have been conducted in adult patients. Side effects in pediatric patients have only been documented in case reports in the literature. In our study of pediatric oncology patients undergoing treatment with chemotherapy, the most commonly observed dermatologic side effect was alopecia, followed by xeroderma, inflammatory lesions, infectious lesions, mucositis, petechiae/ecchymoses, cheilitis, nail disorders, cushingoid signs, oral aphthae, bullous lesions, and drug reactions confirmed histopathologically (Table 1).

Because the common effects of chemotherapeutic agents used in cancer treatment are greatest in areas of rapidly dividing cells, the skin and skin appendages frequently are affected by these drugs.^1-3 Cutaneous signs are frequently observed, especially in regions with increased mitotic activity such as the hair, mucosa, and nails.

Kamil et al¹ reported that the incidence of alopecia was 64.3% (74/115) in a study of adult cancer patients who underwent chemotherapy. Chemotherapeutic agents that have commonly caused alopecia are vincristine, daunorubicin, doxorubicin, cyclophosphamide, etoposide, cytarabine, and carboplatin.^1,2 In our study, alopecia was noted in 31 (50.0%) patients, especially with the use of vincristine (7/31 [22.6%]), daunorubicin (8/31 [25.8%]), doxorubicin (6/31 [19.4%]), and cyclophosphamide (10/31 [32.3%]).

Darkening of the skin and paleness accompanied the majority of cases of xeroderma in our study. Skin dryness was in an ichthyosiform appearance and was severe in 1 patient who was diagnosed with osteosarcoma. Asteatotic eczema and cheilitis were related to skin dryness. It has been reported that acquired paraneoplastic ichthyosis can develop in hematological malignancies, primarily in patients with Hodgkin lymphoma.⁴

The incidence of mucositis has been related to the doses of chemotherapeutic agents. Although it is a commonly encountered side effect, there is no standard treatment of mucositis; therefore, preventive care in patients undergoing chemotherapy is important. It has been reported that practicing good oral hygiene before the treatment period can decrease the incidence of mucositis.^5-9 The lower incidence of mucositis in our study compared to the literature (55.6%)⁵ can be attributed to the lower doses of chemotherapy drugs administered to children due to their weights; they also had active oral mucosa care during chemotherapy.

Another common complication observed in our study was nail disorders. Transverse streaks commonly are encountered due to damage in the nail matrix. Other signs are increased linear streaks, longitudinal melanonychia, nail plate fragility, and onycholysis.¹⁰

Cancer patients acquire infections more frequently because of immunosuppression from chemotherapy and malignancy.^11,12 In our study, cutaneous side effects with infectious causes were noted in 15 patients. Steroids, which are included in the majority of chemotherapeutic protocols, can cause cushingoid changes. Striae from rapid weight gain, acneform eruptions, hypertrichosis, and atrophy of the skin also have been observed among secondary changes to chemotherapy.^1,11

Other skin signs observed in the study were acute urticaria in 1 patient (1.6%) following administration of intrathecal methotrexate; Stevens-Johnson syndrome related to voriconazole was noted in 1 (1.6%) patient.

Hyperpigmentation is a common side effect observed in oncology patients.^13-15 It can be observed locally in the skin as well as the mucosa, teeth, hair, and nails, and it generally develops secondary to alkylating agents.¹⁶ Moreover, hyperpigmentation may develop in regions with occlusions (eg, electrocardiogram pads, adhesion sites of plasters), and commonly is associated with ifosfamide, etoposide, carboplatin, and cyclosporine. Although the development mechanism of hyperpigmentation related to chemotherapy drugs is not clearly known, it is thought to be due to direct toxicity, melanocyte stimulation, or postinflammatory changes.^1,6,17 In our study, xeroderma was noted in some patients with hyperpigmentation; all of them had received cyclosporine and systemic steroid treatments. The other chemotherapeutics were defined as etoposide, cytarabine, dacarbazine, and ifosfamide.¹ Our patients with hyperpigmentation were not taking these therapies.

Increased skin malignancies have been reported in adult cases with hematological malignancies.¹⁸ None of the patients in our study had a secondary skin malignancy, likely because we evaluated a pediatric population and the follow-up period (6 months) was too short for the development of a secondary malignancy.

Conclusion

A wide range of cutaneous side effects can be observed in pediatric oncology patients undergoing chemotherapy based on oncological diagnosis and treatment protocol. Although these side effects are not fatal, they may negatively affect morbidity and can lead to emotional distress. Knowing the possible cutaneous side effects of chemotherapy in pediatric patients and their causes is important for early diagnosis and minimal treatment.

Pediatric oncology patients can present with various skin lesions related to both their primary disease and immunosuppressive treatments. In the majority of cases, cutaneous findings are associated with the use of chemotherapeutic agents. The toxic effects of chemotherapeutic agents, which generally are associated with treatment of solid organ malignancies (eg, liver, kidneys), can be detected by oncologists using clinical signs and laboratory tests.^1-3 However, it also is important for dermatologists to recognize and evaluate cutaneous side effects associated with chemotherapeutic agents. Reports in the literature of cutaneous side effects of chemotherapy in pediatric patients generally are limited to case studies. This study aimed to evaluate the characteristics of cutaneous side effects of chemotherapy in pediatric oncology patients.

Materials and Methods

The study was performed through the collaboration of the departments of dermatology and venereology and pediatric oncology in the Faculty of Medicine at Ege University, Izmir, Turkey. Sixty-five pediatric oncology patients who were scheduled to undergo chemotherapy from May 2011 to May 2013 were included in the study. Clinical examination of dermatologic findings was conducted at baseline (prior to beginning chemotherapy) and at months 1, 3, and 6 of treatment. Patients were examined a total of 4 times during the study. Patients with a history of skin disease prior to diagnosis of their malignancy were excluded, as the study aimed to evaluate cutaneous side effects of chemotherapy. Patients who developed cutaneous side effects during the study period were photographed. Skin biopsy was performed to confirm clinical diagnosis. Patients were split into 5 groups according to oncological diagnoses, including hematological malignancies, solid organ tumors, bone and soft tissue tumors, central nervous system tumors, and Langerhans cell histiocytosis. Data regarding age, gender, treatments administered (ie, chemotherapeutics, antibiotics, antifungals, antivirals), and dermatologic signs were recorded. Mucocutaneous findings were classified as infectious (viral, bacterial, fungal) lesions, bullous lesions, inflammatory dermatoses (eg, diaper dermatitis, asteatotic eczema, contact dermatitis, seborrheic dermatitis), xeroderma, petechiae/ecchymoses, nail signs, alopecia, mucositis, cheilitis, oral aphthae, drug reactions confirmed by histopathology, cushingoid signs (eg, striae, acneform eruption, hypertrichosis), and cutaneous hyperpigmentation.

Statistical analysis was performed using SPSS version 15.0 and χ² test was applied to the analysis.

Results

Of 65 patients, 62 completed the study and were included in the analysis. Three patients were excluded from the results, as 2 patients died during treatment and 1 patient withdrew from the study prior to completion. Twenty-seven (43.5%) patients were female and 35 (56.5%) were male ranging in age from 1 to 17 years (mean age, 8.14 years; median age [standard deviation], 7.25 [5.42] years). There were 31 (50%) patients in the hematological malignancies group, 11 (17.7%) in the solid organ tumors group, 10 (16.1%) in the bone and soft tissue tumors group, and 9 (14.5%) in the central nervous system tumors group; Langerhans cell histiocytosis was diagnosed in 1 (1.6%) patient. Hodgkin lymphoma made up 29.0% (n=9) of hematological malignancies. Other hematological malignancies included acute myeloblastic leukemia (n=7 [22.5%]), acute lymphoblastic leukemia (n=7 [22.5%]), T-cell lymphoma (n=5 [16.1%]), non-Hodgkin lym-phoma (n=1 [3.2%]), anaplastic giant cell lymphoma (n=1 [3.2%]), and diffuse giant cell lymphoma (n=1 [3.2%]).

In addition to chemotherapeutic agents, 7 (11.3%) patients in this study also received antibiotics and 3 (4.8%) received antivirals. The most frequently employed chemotherapeutic agents were vincristine, methotrexate, cytarabine, etoposide, and dexamethasone. Cyclophosphamide, doxorubicin, ifosfamide, asparaginase, carboplatin, procarbazine, daunorubicin, actinomycin D, vinblastine, cisplatin, bleomycin, idarubicin, 6-mercaptopurine, temozolamide, and cyclosporine also were administered. The most commonly encountered dermatological side effects were alopecia, xeroderma, inflammatory skin lesions, infectious lesions, and mucositis, respectively (Table 1). Cutaneous side effects were frequently seen at months 1 and 3 of treatment.

The most commonly encountered dermatologic side effect was alopecia (31/62 [50%]). Anagen effluvium (Figure 1) was detected in half of the cases, while complete scalp hair loss was noted in the rest. Alopecia was encountered more commonly in cases with central nervous system tumors (5/9 [55.6%]) and hematological malignancies (16/31 [51.6%])(Table 2).

The second most commonly encountered side effect was xeroderma (29/62 [46.8%])(Figure 2). This side effect was most commonly encountered in patients with solid organ tumors (6/11 [54.5%]) and central nervous system tumors (4/9 [44.4%]), and occurred less frequently with bone and soft tissue tumors (4/10 [40.0%]).

Findings of eczema accounted for the majority of inflammatory lesions, which were the third most commonly encountered side effects. Among 24 cases of inflammatory skin lesions, 8 patients (33.3%) had diaper dermatitis, 7 (29.2%) had asteatotic eczema, 6 (25.0%) had contact dermatitis, and 3 (12.5%) had seborrheic dermatitis. Although inflammatory skin lesions were commonly encountered in patients with hematological malignancies (14/31 [45.2%]), the difference was not statistically significant.

Mucositis and oral aphthous lesions were observed in 15 (24.2%) and 3 (4.8%) patients, respectively. Nail signs were noted in 10 (16.1%) patients; 4 patients had transverse streaks on the nail plates, 3 had linear streaks, 2 had nail plate fragility, and 1 had increased pigmentation at the nail bed and periungual area. Figure 3 shows linear streaks on the nail plate. These side effects were most commonly encountered in patients with solid organ tumors (5/11 [45.5%]); however, the difference was not statistically significant when compared with the other diagnostic groups.

Dermatologic signs with infectious origins were detected in 15 (24.2%) patients; 2 patients had herpes labialis, 2 had verruca vulgaris, 3 had bacterial folliculitis, 1 had acute paronychia, 1 had soft tissue infection, 2 had tinea versicolor, and 4 had mucocutaneous candidiasis. Dermatologic side effects due to infectious causes were more commonly encountered in patients with bone and soft tissue tumors (4/11 [36.4%]), and the difference was statistically significant when compared with the other diagnostic groups (P=.04).

Petechiae and ecchymotic lesions were present in 13 (21.0%) patients. These side effects occurred mainly in the first month of chemotherapy, namely when patients were in the pancytopenic phase.

Comment

Variability among the oncological diagnosis and drugs used in treatment as well as increased numbers of chemotherapeutic agents available have led to many side effects and complications in pediatric oncology patients undergoing chemotherapy.^1,2 Comprehensive studies regarding the cutaneous side effects of chemotherapeuticagents in cancer treatment have been conducted in adult patients. Side effects in pediatric patients have only been documented in case reports in the literature. In our study of pediatric oncology patients undergoing treatment with chemotherapy, the most commonly observed dermatologic side effect was alopecia, followed by xeroderma, inflammatory lesions, infectious lesions, mucositis, petechiae/ecchymoses, cheilitis, nail disorders, cushingoid signs, oral aphthae, bullous lesions, and drug reactions confirmed histopathologically (Table 1).

Because the common effects of chemotherapeutic agents used in cancer treatment are greatest in areas of rapidly dividing cells, the skin and skin appendages frequently are affected by these drugs.^1-3 Cutaneous signs are frequently observed, especially in regions with increased mitotic activity such as the hair, mucosa, and nails.

Kamil et al¹ reported that the incidence of alopecia was 64.3% (74/115) in a study of adult cancer patients who underwent chemotherapy. Chemotherapeutic agents that have commonly caused alopecia are vincristine, daunorubicin, doxorubicin, cyclophosphamide, etoposide, cytarabine, and carboplatin.^1,2 In our study, alopecia was noted in 31 (50.0%) patients, especially with the use of vincristine (7/31 [22.6%]), daunorubicin (8/31 [25.8%]), doxorubicin (6/31 [19.4%]), and cyclophosphamide (10/31 [32.3%]).

Darkening of the skin and paleness accompanied the majority of cases of xeroderma in our study. Skin dryness was in an ichthyosiform appearance and was severe in 1 patient who was diagnosed with osteosarcoma. Asteatotic eczema and cheilitis were related to skin dryness. It has been reported that acquired paraneoplastic ichthyosis can develop in hematological malignancies, primarily in patients with Hodgkin lymphoma.⁴

The incidence of mucositis has been related to the doses of chemotherapeutic agents. Although it is a commonly encountered side effect, there is no standard treatment of mucositis; therefore, preventive care in patients undergoing chemotherapy is important. It has been reported that practicing good oral hygiene before the treatment period can decrease the incidence of mucositis.^5-9 The lower incidence of mucositis in our study compared to the literature (55.6%)⁵ can be attributed to the lower doses of chemotherapy drugs administered to children due to their weights; they also had active oral mucosa care during chemotherapy.

Another common complication observed in our study was nail disorders. Transverse streaks commonly are encountered due to damage in the nail matrix. Other signs are increased linear streaks, longitudinal melanonychia, nail plate fragility, and onycholysis.¹⁰

Cancer patients acquire infections more frequently because of immunosuppression from chemotherapy and malignancy.^11,12 In our study, cutaneous side effects with infectious causes were noted in 15 patients. Steroids, which are included in the majority of chemotherapeutic protocols, can cause cushingoid changes. Striae from rapid weight gain, acneform eruptions, hypertrichosis, and atrophy of the skin also have been observed among secondary changes to chemotherapy.^1,11

Other skin signs observed in the study were acute urticaria in 1 patient (1.6%) following administration of intrathecal methotrexate; Stevens-Johnson syndrome related to voriconazole was noted in 1 (1.6%) patient.

Hyperpigmentation is a common side effect observed in oncology patients.^13-15 It can be observed locally in the skin as well as the mucosa, teeth, hair, and nails, and it generally develops secondary to alkylating agents.¹⁶ Moreover, hyperpigmentation may develop in regions with occlusions (eg, electrocardiogram pads, adhesion sites of plasters), and commonly is associated with ifosfamide, etoposide, carboplatin, and cyclosporine. Although the development mechanism of hyperpigmentation related to chemotherapy drugs is not clearly known, it is thought to be due to direct toxicity, melanocyte stimulation, or postinflammatory changes.^1,6,17 In our study, xeroderma was noted in some patients with hyperpigmentation; all of them had received cyclosporine and systemic steroid treatments. The other chemotherapeutics were defined as etoposide, cytarabine, dacarbazine, and ifosfamide.¹ Our patients with hyperpigmentation were not taking these therapies.

Increased skin malignancies have been reported in adult cases with hematological malignancies.¹⁸ None of the patients in our study had a secondary skin malignancy, likely because we evaluated a pediatric population and the follow-up period (6 months) was too short for the development of a secondary malignancy.

Conclusion

A wide range of cutaneous side effects can be observed in pediatric oncology patients undergoing chemotherapy based on oncological diagnosis and treatment protocol. Although these side effects are not fatal, they may negatively affect morbidity and can lead to emotional distress. Knowing the possible cutaneous side effects of chemotherapy in pediatric patients and their causes is important for early diagnosis and minimal treatment.