Letter - Acneiform Rash as a Reaction to Radiotherapy in a Breast Cancer Patient

Discussion

The development of localized comedos or an acneiform rash is a relatively rare reaction to radiation therapy. This observation was first reported in 1947 as a concentric ring of comedones forming at the margin of a superficial radiation field after 3 months of treatment.⁵ Subsequently, reports have been published in the literature, occurring in the setting of different types of radiotherapy. Comedonal or acneiform eruptions have been described as sequelae of superficial radiation for treatment of cutaneous nonmelanoma skin cancers (NMSCs);^{[5] and [6]} cobalt radiation utilized in breast,⁷ brain,⁸ NMSC,⁹ lymphoma,¹⁰ and lung^{[10] and [11]} cancer patients; and following megavoltage radiotherapy.¹² A spectrum of lesion morphologies can be seen, with some patients presenting with only open⁸ or closed^{[9] and [13]} comedones, occasional scattered inflammatory papules,¹⁴ or a florid eruption with erythematous papules, pustules, and comedones,^{[7] and [15]} as was seen in our patient. Acneiform rash has been reported to occur following the resolution of acute radiation dermatitis,^{[7], [16] and [17]} in those without a preceding acute skin reaction,^{[9] and [11]} or superimposed on changes of chronic radiation dermatitis, characterized by pigmentary abnormalities and fibrosis.^{[8] and [11]} Interestingly, in addition to skin directly affected by the incident radiation, the eruption can involve skin regions where a fraction of penetrating radiation exits directly opposite of the irradiated site, such as the back of a breast cancer patient.¹¹

Martin and Bardsley¹⁷ reviewed 27 cases of radiation-induced acne in an attempt to better characterize the rash and its clinical presentation. This analysis demonstrated a variable latent period, ranging from 2 weeks to 6 months following radiation treatment. While involved body sites included any irradiated skin area, from the scalp to the pelvis, the majority of cases manifested on the scalp, face, or neck (16 out of 27). Notably, the upper trunk was another common site of involvement (10 cases). There was also a suggestion that the reaction was more common in patients who had recently been treated with agents known to induce acne, such as corticosteroids, sex hormones, isoniazid, and anticonvulsants. In contrast, previous personal history of acne did not appear as a significant predisposing factor.¹⁷

The pathophysiology of radiation-induced acne is currently unknown. However, the underlying mechanisms responsible for the development of acne vulgaris can offer insights into our understanding of radiation-induced changes. The pilosebaceous unit is the site of acne formation in normal skin. Formation of a microcomedone, a critical initial step in the development of acne, and its progression to noninflammatory lesions such as open comedone (black head), closed comedone (white head), and inflammation, characterized by erythematous papules, pustules, and nodules, is a complex multifactorial process. The principal event currently thought to drive comedogenesis is hyperproliferation of keratinocytes in the pilosebaceous ducts, leading to accumulation of corneocytes (anucleate cells filled with keratin) and sebum with subsequent occlusion of the follicular infundibulum.¹⁸ The triggers that initiate this process, however, are not completely understood. Several pathogenic factors have been implicated as potential etiologies. Testosterone and its more active form 5α-dihydrotestosterone stimulate excessive sebum production and may contribute to ductal hyperproliferation.^{[19] and [20]} Aberrations in sebaceous lipids such as an increase in fatty acids, which possess proinflammatory and comedogenic properties, and low levels of linoleic acid may be important factors in inducing ductal hyperproliferation and comedogenesis.²¹ Interleukin (IL)-1α has been shown to induce comedogenesis in in vitro models^{[22] and [23]} and is found at high concentration in open comedones, potentially playing a role in the progression of comedones to inflammatory lesions.²⁴ Secondary colonization and overgrowth of Propionibacterium acnes can result in increased production of IL-8 and tumor necrosis factor (TNF)-α,²⁵ lead to recruitment of neutrophils and lymphocytes,²⁶ and induce a hypersensitivity reaction,²⁷ events that may contribute to the development of inflammatory lesions.

It is unclear how radiation can rarely induce comedogenesis. However, it is possible that a florid inflammatory response induced by an acute radiation injury and characterized by increased expression of leukocyte adhesion molecules and inflammatory cytokines such as IL-1, IL-6, and TNF-α²⁸ may play a role. Alternatively, radiation-induced changes in the lipid composition of sebum may lead to keratinocyte hyperproliferation in the sebaceous ducts.¹⁷ Other authors have implicated chronic follicular inflammation and increased follicular hyperkeratosis as potential culprits.¹¹ Chronic sequelae of radiation injury in skin develop months to years following the period of acute exposure and are characterized by the absence of hair follicles and sebaceous glands and the presence of fibrosis, thought to be mediated by transforming growth factor (TGF)-β.²⁹ Accordingly, it had been postulated that remnants of pilosebaceous units in the skin may serve as foreign bodies that are able to induce an inflammatory reaction that clinically manifests with acne lesions.³⁰

Timely and accurate recognition of this rare adverse event may facilitate implementation of appropriate treatment strategies. Although no evidence-based data support the use of typical anti-acne treatments in this patient population due to its low incidence, similar strategies have been employed to manage radiation-associated acneiform rash. Typical agents for acne vulgaris such as topical retinoic acid, benzoyl peroxide, antiseptic cleansing solutions, and oral antibiotics have been used, usually with good response and subsequent resolution.^{[7], [8], [9], [13], [14], [15] and [30]} In addition, manual extraction of comedones with a comedo extractor has been successfully utilized.¹⁷ The use of lower concentrations of benzoyl peroxide (2.5% and 5%) is preferred to 10% formulations, considering their similar clinical efficacy in acne vulgaris but diminished frequency and severity of peeling, erythema, and burning.³¹ Combining benzoyl peroxide with topical antimicrobial agents such as clindamycin or with topical retinoids improves the clinical response. Of note, generic tretinoin undergoes oxidative degradation and should be applied separately from benzoyl peroxide.³² Topical retinoids possess a microcomedolytic activity and are also effective against noninflammatory and inflammatory lesions. Their combination with either topical or systemic antibiotics enhances therapeutic efficacy and can be used to manage more severe manifestations.³³ Retinoids can induce skin erythema and burning, which can be mitigated by consistent use of a moisturizing cream.³³ The benefit of systemic semisynthetic tetracycline antibiotics is derived from their antimicrobial and anti-inflammatory properties. Even though doxycycline is phototoxic, its use is preferred to minocycline, which is not more effective and may be associated with higher rates of toxicity, including more severe adverse events such as drug-induced systemic lupus erythematosus and autoimmune hepatitis.³⁴ The clinical response in patients with radiation-induced acne is not immediate and, similar to acne vulgaris, may require several months of treatment. Compliance with therapy is important, and patients may be counseled that prolonged therapy may be required but subsequent resolution can be typically achieved.

Conclusion

In conclusion, acneiform rash is a relatively rare adverse event of radiotherapy that tends to affect areas with a high density of sebaceous glands, such as the face, scalp, and upper trunk, and can be usually successfully managed with typical anti-acne agents.

Acknowledgments

M. E. L. is supported by a Career Development Award from the Dermatology Foundation and a Zell Scholarship of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, IL.

Discussion

The development of localized comedos or an acneiform rash is a relatively rare reaction to radiation therapy. This observation was first reported in 1947 as a concentric ring of comedones forming at the margin of a superficial radiation field after 3 months of treatment.⁵ Subsequently, reports have been published in the literature, occurring in the setting of different types of radiotherapy. Comedonal or acneiform eruptions have been described as sequelae of superficial radiation for treatment of cutaneous nonmelanoma skin cancers (NMSCs);^{[5] and [6]} cobalt radiation utilized in breast,⁷ brain,⁸ NMSC,⁹ lymphoma,¹⁰ and lung^{[10] and [11]} cancer patients; and following megavoltage radiotherapy.¹² A spectrum of lesion morphologies can be seen, with some patients presenting with only open⁸ or closed^{[9] and [13]} comedones, occasional scattered inflammatory papules,¹⁴ or a florid eruption with erythematous papules, pustules, and comedones,^{[7] and [15]} as was seen in our patient. Acneiform rash has been reported to occur following the resolution of acute radiation dermatitis,^{[7], [16] and [17]} in those without a preceding acute skin reaction,^{[9] and [11]} or superimposed on changes of chronic radiation dermatitis, characterized by pigmentary abnormalities and fibrosis.^{[8] and [11]} Interestingly, in addition to skin directly affected by the incident radiation, the eruption can involve skin regions where a fraction of penetrating radiation exits directly opposite of the irradiated site, such as the back of a breast cancer patient.¹¹

Martin and Bardsley¹⁷ reviewed 27 cases of radiation-induced acne in an attempt to better characterize the rash and its clinical presentation. This analysis demonstrated a variable latent period, ranging from 2 weeks to 6 months following radiation treatment. While involved body sites included any irradiated skin area, from the scalp to the pelvis, the majority of cases manifested on the scalp, face, or neck (16 out of 27). Notably, the upper trunk was another common site of involvement (10 cases). There was also a suggestion that the reaction was more common in patients who had recently been treated with agents known to induce acne, such as corticosteroids, sex hormones, isoniazid, and anticonvulsants. In contrast, previous personal history of acne did not appear as a significant predisposing factor.¹⁷

The pathophysiology of radiation-induced acne is currently unknown. However, the underlying mechanisms responsible for the development of acne vulgaris can offer insights into our understanding of radiation-induced changes. The pilosebaceous unit is the site of acne formation in normal skin. Formation of a microcomedone, a critical initial step in the development of acne, and its progression to noninflammatory lesions such as open comedone (black head), closed comedone (white head), and inflammation, characterized by erythematous papules, pustules, and nodules, is a complex multifactorial process. The principal event currently thought to drive comedogenesis is hyperproliferation of keratinocytes in the pilosebaceous ducts, leading to accumulation of corneocytes (anucleate cells filled with keratin) and sebum with subsequent occlusion of the follicular infundibulum.¹⁸ The triggers that initiate this process, however, are not completely understood. Several pathogenic factors have been implicated as potential etiologies. Testosterone and its more active form 5α-dihydrotestosterone stimulate excessive sebum production and may contribute to ductal hyperproliferation.^{[19] and [20]} Aberrations in sebaceous lipids such as an increase in fatty acids, which possess proinflammatory and comedogenic properties, and low levels of linoleic acid may be important factors in inducing ductal hyperproliferation and comedogenesis.²¹ Interleukin (IL)-1α has been shown to induce comedogenesis in in vitro models^{[22] and [23]} and is found at high concentration in open comedones, potentially playing a role in the progression of comedones to inflammatory lesions.²⁴ Secondary colonization and overgrowth of Propionibacterium acnes can result in increased production of IL-8 and tumor necrosis factor (TNF)-α,²⁵ lead to recruitment of neutrophils and lymphocytes,²⁶ and induce a hypersensitivity reaction,²⁷ events that may contribute to the development of inflammatory lesions.

It is unclear how radiation can rarely induce comedogenesis. However, it is possible that a florid inflammatory response induced by an acute radiation injury and characterized by increased expression of leukocyte adhesion molecules and inflammatory cytokines such as IL-1, IL-6, and TNF-α²⁸ may play a role. Alternatively, radiation-induced changes in the lipid composition of sebum may lead to keratinocyte hyperproliferation in the sebaceous ducts.¹⁷ Other authors have implicated chronic follicular inflammation and increased follicular hyperkeratosis as potential culprits.¹¹ Chronic sequelae of radiation injury in skin develop months to years following the period of acute exposure and are characterized by the absence of hair follicles and sebaceous glands and the presence of fibrosis, thought to be mediated by transforming growth factor (TGF)-β.²⁹ Accordingly, it had been postulated that remnants of pilosebaceous units in the skin may serve as foreign bodies that are able to induce an inflammatory reaction that clinically manifests with acne lesions.³⁰

Timely and accurate recognition of this rare adverse event may facilitate implementation of appropriate treatment strategies. Although no evidence-based data support the use of typical anti-acne treatments in this patient population due to its low incidence, similar strategies have been employed to manage radiation-associated acneiform rash. Typical agents for acne vulgaris such as topical retinoic acid, benzoyl peroxide, antiseptic cleansing solutions, and oral antibiotics have been used, usually with good response and subsequent resolution.^{[7], [8], [9], [13], [14], [15] and [30]} In addition, manual extraction of comedones with a comedo extractor has been successfully utilized.¹⁷ The use of lower concentrations of benzoyl peroxide (2.5% and 5%) is preferred to 10% formulations, considering their similar clinical efficacy in acne vulgaris but diminished frequency and severity of peeling, erythema, and burning.³¹ Combining benzoyl peroxide with topical antimicrobial agents such as clindamycin or with topical retinoids improves the clinical response. Of note, generic tretinoin undergoes oxidative degradation and should be applied separately from benzoyl peroxide.³² Topical retinoids possess a microcomedolytic activity and are also effective against noninflammatory and inflammatory lesions. Their combination with either topical or systemic antibiotics enhances therapeutic efficacy and can be used to manage more severe manifestations.³³ Retinoids can induce skin erythema and burning, which can be mitigated by consistent use of a moisturizing cream.³³ The benefit of systemic semisynthetic tetracycline antibiotics is derived from their antimicrobial and anti-inflammatory properties. Even though doxycycline is phototoxic, its use is preferred to minocycline, which is not more effective and may be associated with higher rates of toxicity, including more severe adverse events such as drug-induced systemic lupus erythematosus and autoimmune hepatitis.³⁴ The clinical response in patients with radiation-induced acne is not immediate and, similar to acne vulgaris, may require several months of treatment. Compliance with therapy is important, and patients may be counseled that prolonged therapy may be required but subsequent resolution can be typically achieved.

Conclusion

In conclusion, acneiform rash is a relatively rare adverse event of radiotherapy that tends to affect areas with a high density of sebaceous glands, such as the face, scalp, and upper trunk, and can be usually successfully managed with typical anti-acne agents.

Acknowledgments

M. E. L. is supported by a Career Development Award from the Dermatology Foundation and a Zell Scholarship of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, IL.

Discussion

The development of localized comedos or an acneiform rash is a relatively rare reaction to radiation therapy. This observation was first reported in 1947 as a concentric ring of comedones forming at the margin of a superficial radiation field after 3 months of treatment.⁵ Subsequently, reports have been published in the literature, occurring in the setting of different types of radiotherapy. Comedonal or acneiform eruptions have been described as sequelae of superficial radiation for treatment of cutaneous nonmelanoma skin cancers (NMSCs);^{[5] and [6]} cobalt radiation utilized in breast,⁷ brain,⁸ NMSC,⁹ lymphoma,¹⁰ and lung^{[10] and [11]} cancer patients; and following megavoltage radiotherapy.¹² A spectrum of lesion morphologies can be seen, with some patients presenting with only open⁸ or closed^{[9] and [13]} comedones, occasional scattered inflammatory papules,¹⁴ or a florid eruption with erythematous papules, pustules, and comedones,^{[7] and [15]} as was seen in our patient. Acneiform rash has been reported to occur following the resolution of acute radiation dermatitis,^{[7], [16] and [17]} in those without a preceding acute skin reaction,^{[9] and [11]} or superimposed on changes of chronic radiation dermatitis, characterized by pigmentary abnormalities and fibrosis.^{[8] and [11]} Interestingly, in addition to skin directly affected by the incident radiation, the eruption can involve skin regions where a fraction of penetrating radiation exits directly opposite of the irradiated site, such as the back of a breast cancer patient.¹¹

Martin and Bardsley¹⁷ reviewed 27 cases of radiation-induced acne in an attempt to better characterize the rash and its clinical presentation. This analysis demonstrated a variable latent period, ranging from 2 weeks to 6 months following radiation treatment. While involved body sites included any irradiated skin area, from the scalp to the pelvis, the majority of cases manifested on the scalp, face, or neck (16 out of 27). Notably, the upper trunk was another common site of involvement (10 cases). There was also a suggestion that the reaction was more common in patients who had recently been treated with agents known to induce acne, such as corticosteroids, sex hormones, isoniazid, and anticonvulsants. In contrast, previous personal history of acne did not appear as a significant predisposing factor.¹⁷

The pathophysiology of radiation-induced acne is currently unknown. However, the underlying mechanisms responsible for the development of acne vulgaris can offer insights into our understanding of radiation-induced changes. The pilosebaceous unit is the site of acne formation in normal skin. Formation of a microcomedone, a critical initial step in the development of acne, and its progression to noninflammatory lesions such as open comedone (black head), closed comedone (white head), and inflammation, characterized by erythematous papules, pustules, and nodules, is a complex multifactorial process. The principal event currently thought to drive comedogenesis is hyperproliferation of keratinocytes in the pilosebaceous ducts, leading to accumulation of corneocytes (anucleate cells filled with keratin) and sebum with subsequent occlusion of the follicular infundibulum.¹⁸ The triggers that initiate this process, however, are not completely understood. Several pathogenic factors have been implicated as potential etiologies. Testosterone and its more active form 5α-dihydrotestosterone stimulate excessive sebum production and may contribute to ductal hyperproliferation.^{[19] and [20]} Aberrations in sebaceous lipids such as an increase in fatty acids, which possess proinflammatory and comedogenic properties, and low levels of linoleic acid may be important factors in inducing ductal hyperproliferation and comedogenesis.²¹ Interleukin (IL)-1α has been shown to induce comedogenesis in in vitro models^{[22] and [23]} and is found at high concentration in open comedones, potentially playing a role in the progression of comedones to inflammatory lesions.²⁴ Secondary colonization and overgrowth of Propionibacterium acnes can result in increased production of IL-8 and tumor necrosis factor (TNF)-α,²⁵ lead to recruitment of neutrophils and lymphocytes,²⁶ and induce a hypersensitivity reaction,²⁷ events that may contribute to the development of inflammatory lesions.

It is unclear how radiation can rarely induce comedogenesis. However, it is possible that a florid inflammatory response induced by an acute radiation injury and characterized by increased expression of leukocyte adhesion molecules and inflammatory cytokines such as IL-1, IL-6, and TNF-α²⁸ may play a role. Alternatively, radiation-induced changes in the lipid composition of sebum may lead to keratinocyte hyperproliferation in the sebaceous ducts.¹⁷ Other authors have implicated chronic follicular inflammation and increased follicular hyperkeratosis as potential culprits.¹¹ Chronic sequelae of radiation injury in skin develop months to years following the period of acute exposure and are characterized by the absence of hair follicles and sebaceous glands and the presence of fibrosis, thought to be mediated by transforming growth factor (TGF)-β.²⁹ Accordingly, it had been postulated that remnants of pilosebaceous units in the skin may serve as foreign bodies that are able to induce an inflammatory reaction that clinically manifests with acne lesions.³⁰

Timely and accurate recognition of this rare adverse event may facilitate implementation of appropriate treatment strategies. Although no evidence-based data support the use of typical anti-acne treatments in this patient population due to its low incidence, similar strategies have been employed to manage radiation-associated acneiform rash. Typical agents for acne vulgaris such as topical retinoic acid, benzoyl peroxide, antiseptic cleansing solutions, and oral antibiotics have been used, usually with good response and subsequent resolution.^{[7], [8], [9], [13], [14], [15] and [30]} In addition, manual extraction of comedones with a comedo extractor has been successfully utilized.¹⁷ The use of lower concentrations of benzoyl peroxide (2.5% and 5%) is preferred to 10% formulations, considering their similar clinical efficacy in acne vulgaris but diminished frequency and severity of peeling, erythema, and burning.³¹ Combining benzoyl peroxide with topical antimicrobial agents such as clindamycin or with topical retinoids improves the clinical response. Of note, generic tretinoin undergoes oxidative degradation and should be applied separately from benzoyl peroxide.³² Topical retinoids possess a microcomedolytic activity and are also effective against noninflammatory and inflammatory lesions. Their combination with either topical or systemic antibiotics enhances therapeutic efficacy and can be used to manage more severe manifestations.³³ Retinoids can induce skin erythema and burning, which can be mitigated by consistent use of a moisturizing cream.³³ The benefit of systemic semisynthetic tetracycline antibiotics is derived from their antimicrobial and anti-inflammatory properties. Even though doxycycline is phototoxic, its use is preferred to minocycline, which is not more effective and may be associated with higher rates of toxicity, including more severe adverse events such as drug-induced systemic lupus erythematosus and autoimmune hepatitis.³⁴ The clinical response in patients with radiation-induced acne is not immediate and, similar to acne vulgaris, may require several months of treatment. Compliance with therapy is important, and patients may be counseled that prolonged therapy may be required but subsequent resolution can be typically achieved.

Conclusion

In conclusion, acneiform rash is a relatively rare adverse event of radiotherapy that tends to affect areas with a high density of sebaceous glands, such as the face, scalp, and upper trunk, and can be usually successfully managed with typical anti-acne agents.

Acknowledgments

M. E. L. is supported by a Career Development Award from the Dermatology Foundation and a Zell Scholarship of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, IL.