Sickled and normal

red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending that LJPC-401, a novel formulation of hepcidin, receive orphan designation to treat chronic iron overload requiring chelation therapy.

Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease, and hereditary hemochromatosis.

The COMP’s opinion, which is subject to review and approval by the European Commission, may include all or a subset of these conditions.

About LJPC-401

LJPC-401 is a novel formulation of hepcidin, an endogenous peptide hormone that is the body’s naturally occurring regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in tissues, such as the liver and heart, where it can cause significant damage and even result in death.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload occurring as a results of hereditary hemochromatosis, beta thalassemia, and sickle cell disease.

LJPC-401 has been shown to be effective in reducing serum iron in preclinical testing, according to La Jolla. The company said it expects to release preliminary results from a phase 1 trial of LJPC-401 by the end of this year.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for endorsement.

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity if the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Sickled and normal

red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending that LJPC-401, a novel formulation of hepcidin, receive orphan designation to treat chronic iron overload requiring chelation therapy.

Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease, and hereditary hemochromatosis.

The COMP’s opinion, which is subject to review and approval by the European Commission, may include all or a subset of these conditions.

About LJPC-401

LJPC-401 is a novel formulation of hepcidin, an endogenous peptide hormone that is the body’s naturally occurring regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in tissues, such as the liver and heart, where it can cause significant damage and even result in death.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload occurring as a results of hereditary hemochromatosis, beta thalassemia, and sickle cell disease.

LJPC-401 has been shown to be effective in reducing serum iron in preclinical testing, according to La Jolla. The company said it expects to release preliminary results from a phase 1 trial of LJPC-401 by the end of this year.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for endorsement.

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity if the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Sickled and normal

red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending that LJPC-401, a novel formulation of hepcidin, receive orphan designation to treat chronic iron overload requiring chelation therapy.

Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease, and hereditary hemochromatosis.

The COMP’s opinion, which is subject to review and approval by the European Commission, may include all or a subset of these conditions.

About LJPC-401

LJPC-401 is a novel formulation of hepcidin, an endogenous peptide hormone that is the body’s naturally occurring regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in tissues, such as the liver and heart, where it can cause significant damage and even result in death.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload occurring as a results of hereditary hemochromatosis, beta thalassemia, and sickle cell disease.

LJPC-401 has been shown to be effective in reducing serum iron in preclinical testing, according to La Jolla. The company said it expects to release preliminary results from a phase 1 trial of LJPC-401 by the end of this year.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for endorsement.

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity if the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Posttraumatic stress disorder can be hard to spot in kids after natural or manmade disasters.

They may not understand that intrusive thoughts, panic attacks, and other symptoms are problems that can be addressed, and are unlikely to mention them.

As a result, parents, teachers, and others often underestimate children’s distress levels and overestimate their resilience. One way around the problem is to ask children how they’re doing, and probe for signs of trouble. It helps to let them know that PTSD and adjustment problems are normal after a frightening event, and to teach them how to anticipate and cope with PTSD triggers.

That’s just a small fraction of the useful advice in new guidance from the American Academy of Pediatrics on the psychosocial support of children and families after disasters, published online Sept. 14 (Pediatrics. 2015 Sept. 14. doi:10.1542/peds.2015-2861).

“Children are particularly vulnerable to the effects of disasters and other traumatic events because of a lack of experience, skills, and resources to be able to independently meet their developmental, socioemotional, mental, and behavioral health needs,” said the authors, led by Dr. David Schonfeld of St. Christopher’s Hospital for Children, and Thomas Demaria, Ph.D., of Long Island (N.Y.) University.

Mental health triage should come right after medical stabilization. Dissociative symptoms; extreme confusion or inability to concentrate or make even simple decisions; intense fear, anxiety, panic, helplessness, or horror; depression at the time of the event; uncontrollable and intense grief; suicidal ideation; and marked somatization are among the warning signs that kids are in trouble.

Psychiatric medications to blunt such reactions are usually the wrong call. “Children need to develop an understanding of the event and learn to express and cope with their reactions.” If medication does seem necessary, its best to let an expert in childhood trauma make the decision, the authors said.

Dismissing children’s concerns is a mistake. “In reality, if children feel worried, then they are worried. Telling them that they should not be worried is usually ineffective.” It’s also a mistake to avoid talking about grief for fear of making it worse. Children’s “distress is caused by the reaction to the death itself, rather than any question or invitation to talk. Talking may provide some relief if not coerced. Avoiding discussion is rarely helpful and often isolates children at a time when they are most in need of support and assistance,” they said.

Simple, basic facts about the event – as long as they’re not graphic or overwhelming – will help children make sense of what they’ve been through, and reassurance that things will eventually be okay can be healing. Kids also have to know that the situation isn’t their fault, and how to cope with it.

Parents can share how they’re upset about losing their home, for instance, but then discuss how talking to another trusted adult, getting exercise, meditating, and helping others makes them feel better. Pediatricians can boost spirits by saying something like “the tornado created a big mess, but we are pulling together as a community” or “living in a shelter with all the other children in the neighborhood must have been a real adventure,” the authors said.

Having children contribute to food drives or draw hopeful pictures for victims in the hospital can help them regain a sense of control and usefulness. Resuming their routines as soon as possible will also help bring back a sense of normalcy.

Bereavement counseling is in order when children are struggling with the loss of a loved one, and cognitive behavioral therapy for kids with PTSD.

[email protected]

Posttraumatic stress disorder can be hard to spot in kids after natural or manmade disasters.

They may not understand that intrusive thoughts, panic attacks, and other symptoms are problems that can be addressed, and are unlikely to mention them.

As a result, parents, teachers, and others often underestimate children’s distress levels and overestimate their resilience. One way around the problem is to ask children how they’re doing, and probe for signs of trouble. It helps to let them know that PTSD and adjustment problems are normal after a frightening event, and to teach them how to anticipate and cope with PTSD triggers.

That’s just a small fraction of the useful advice in new guidance from the American Academy of Pediatrics on the psychosocial support of children and families after disasters, published online Sept. 14 (Pediatrics. 2015 Sept. 14. doi:10.1542/peds.2015-2861).

“Children are particularly vulnerable to the effects of disasters and other traumatic events because of a lack of experience, skills, and resources to be able to independently meet their developmental, socioemotional, mental, and behavioral health needs,” said the authors, led by Dr. David Schonfeld of St. Christopher’s Hospital for Children, and Thomas Demaria, Ph.D., of Long Island (N.Y.) University.

Mental health triage should come right after medical stabilization. Dissociative symptoms; extreme confusion or inability to concentrate or make even simple decisions; intense fear, anxiety, panic, helplessness, or horror; depression at the time of the event; uncontrollable and intense grief; suicidal ideation; and marked somatization are among the warning signs that kids are in trouble.

Psychiatric medications to blunt such reactions are usually the wrong call. “Children need to develop an understanding of the event and learn to express and cope with their reactions.” If medication does seem necessary, its best to let an expert in childhood trauma make the decision, the authors said.

Dismissing children’s concerns is a mistake. “In reality, if children feel worried, then they are worried. Telling them that they should not be worried is usually ineffective.” It’s also a mistake to avoid talking about grief for fear of making it worse. Children’s “distress is caused by the reaction to the death itself, rather than any question or invitation to talk. Talking may provide some relief if not coerced. Avoiding discussion is rarely helpful and often isolates children at a time when they are most in need of support and assistance,” they said.

Simple, basic facts about the event – as long as they’re not graphic or overwhelming – will help children make sense of what they’ve been through, and reassurance that things will eventually be okay can be healing. Kids also have to know that the situation isn’t their fault, and how to cope with it.

Parents can share how they’re upset about losing their home, for instance, but then discuss how talking to another trusted adult, getting exercise, meditating, and helping others makes them feel better. Pediatricians can boost spirits by saying something like “the tornado created a big mess, but we are pulling together as a community” or “living in a shelter with all the other children in the neighborhood must have been a real adventure,” the authors said.

Having children contribute to food drives or draw hopeful pictures for victims in the hospital can help them regain a sense of control and usefulness. Resuming their routines as soon as possible will also help bring back a sense of normalcy.

Bereavement counseling is in order when children are struggling with the loss of a loved one, and cognitive behavioral therapy for kids with PTSD.

[email protected]

Posttraumatic stress disorder can be hard to spot in kids after natural or manmade disasters.

They may not understand that intrusive thoughts, panic attacks, and other symptoms are problems that can be addressed, and are unlikely to mention them.

As a result, parents, teachers, and others often underestimate children’s distress levels and overestimate their resilience. One way around the problem is to ask children how they’re doing, and probe for signs of trouble. It helps to let them know that PTSD and adjustment problems are normal after a frightening event, and to teach them how to anticipate and cope with PTSD triggers.

That’s just a small fraction of the useful advice in new guidance from the American Academy of Pediatrics on the psychosocial support of children and families after disasters, published online Sept. 14 (Pediatrics. 2015 Sept. 14. doi:10.1542/peds.2015-2861).

“Children are particularly vulnerable to the effects of disasters and other traumatic events because of a lack of experience, skills, and resources to be able to independently meet their developmental, socioemotional, mental, and behavioral health needs,” said the authors, led by Dr. David Schonfeld of St. Christopher’s Hospital for Children, and Thomas Demaria, Ph.D., of Long Island (N.Y.) University.

Mental health triage should come right after medical stabilization. Dissociative symptoms; extreme confusion or inability to concentrate or make even simple decisions; intense fear, anxiety, panic, helplessness, or horror; depression at the time of the event; uncontrollable and intense grief; suicidal ideation; and marked somatization are among the warning signs that kids are in trouble.

Psychiatric medications to blunt such reactions are usually the wrong call. “Children need to develop an understanding of the event and learn to express and cope with their reactions.” If medication does seem necessary, its best to let an expert in childhood trauma make the decision, the authors said.

Dismissing children’s concerns is a mistake. “In reality, if children feel worried, then they are worried. Telling them that they should not be worried is usually ineffective.” It’s also a mistake to avoid talking about grief for fear of making it worse. Children’s “distress is caused by the reaction to the death itself, rather than any question or invitation to talk. Talking may provide some relief if not coerced. Avoiding discussion is rarely helpful and often isolates children at a time when they are most in need of support and assistance,” they said.

Simple, basic facts about the event – as long as they’re not graphic or overwhelming – will help children make sense of what they’ve been through, and reassurance that things will eventually be okay can be healing. Kids also have to know that the situation isn’t their fault, and how to cope with it.

Parents can share how they’re upset about losing their home, for instance, but then discuss how talking to another trusted adult, getting exercise, meditating, and helping others makes them feel better. Pediatricians can boost spirits by saying something like “the tornado created a big mess, but we are pulling together as a community” or “living in a shelter with all the other children in the neighborhood must have been a real adventure,” the authors said.

Having children contribute to food drives or draw hopeful pictures for victims in the hospital can help them regain a sense of control and usefulness. Resuming their routines as soon as possible will also help bring back a sense of normalcy.

Bereavement counseling is in order when children are struggling with the loss of a loved one, and cognitive behavioral therapy for kids with PTSD.

[email protected]

Cyclosporine A

Immune Pharmaceuticals acquires a nanoparticle topical formulation of cyclosporine A for the treatment of psoriasis, atopic dermatitis, pemphigus vulgaris, and other severe inflammatory dermatoses. Researchers have incorporated cyclosporine A into biodegradable nanocapsules and have developed stable topical formulations that are able to achieve therapeutic cyclosporine A levels in the targeted skin layers. This topical treatment provides a potential alternative to oral cyclosporine A and other topical immunosuppressive drugs. For more information, visit www.immunepharmaceuticals.com.

Picato Gel Warning

The US Food and Drug Administration (FDA) issues a warning about reports of severe allergic reactions and herpes zoster associated with the use of Picato Gel (ingenol mebutate) for the treatment of actinic keratosis. The allergic reaction may include throat tightness, difficulty breathing, feeling faint, or swelling of the lips or tongue. The FDA received reports of cases involving severe eye injuries associated with Picato Gel not being used according to the instructions for use on the label. Changes to the labeling have been requested by the FDA to warn about these new safety risks. Patients should not use Picato Gel for a longer period or on an area of skin larger than instructed on the drug label. Patients also should avoid application in, near, and around the mouth, lips, and eye area. For more information, visit www.fda.gov/MedWatch.

Ximino Extended-Release Capsules

Sun Pharmaceutical Industries Ltd announces US Food and Drug Administration approval of the Supplemental New Drug Application for Ximino (minocycline hydrochloride) extended-release 
capsules (45, 90, and 135 mg). Ximino 
extended-release capsules are indicated for the treatment of inflammatory lesions of nonnodular moderate to severe acne vulgaris in patients 
12 years and older. Ximino extended-release capsules are expected to be available for patients during the fourth quarter of 2015. For more information, visit www.sunpharma.com.

If you would like your product included in Product News, please e-mail a press release to the Editorial Office at [email protected].

Cyclosporine A

Immune Pharmaceuticals acquires a nanoparticle topical formulation of cyclosporine A for the treatment of psoriasis, atopic dermatitis, pemphigus vulgaris, and other severe inflammatory dermatoses. Researchers have incorporated cyclosporine A into biodegradable nanocapsules and have developed stable topical formulations that are able to achieve therapeutic cyclosporine A levels in the targeted skin layers. This topical treatment provides a potential alternative to oral cyclosporine A and other topical immunosuppressive drugs. For more information, visit www.immunepharmaceuticals.com.

Picato Gel Warning

The US Food and Drug Administration (FDA) issues a warning about reports of severe allergic reactions and herpes zoster associated with the use of Picato Gel (ingenol mebutate) for the treatment of actinic keratosis. The allergic reaction may include throat tightness, difficulty breathing, feeling faint, or swelling of the lips or tongue. The FDA received reports of cases involving severe eye injuries associated with Picato Gel not being used according to the instructions for use on the label. Changes to the labeling have been requested by the FDA to warn about these new safety risks. Patients should not use Picato Gel for a longer period or on an area of skin larger than instructed on the drug label. Patients also should avoid application in, near, and around the mouth, lips, and eye area. For more information, visit www.fda.gov/MedWatch.

Ximino Extended-Release Capsules

Sun Pharmaceutical Industries Ltd announces US Food and Drug Administration approval of the Supplemental New Drug Application for Ximino (minocycline hydrochloride) extended-release 
capsules (45, 90, and 135 mg). Ximino 
extended-release capsules are indicated for the treatment of inflammatory lesions of nonnodular moderate to severe acne vulgaris in patients 
12 years and older. Ximino extended-release capsules are expected to be available for patients during the fourth quarter of 2015. For more information, visit www.sunpharma.com.

If you would like your product included in Product News, please e-mail a press release to the Editorial Office at [email protected].

Cyclosporine A

Immune Pharmaceuticals acquires a nanoparticle topical formulation of cyclosporine A for the treatment of psoriasis, atopic dermatitis, pemphigus vulgaris, and other severe inflammatory dermatoses. Researchers have incorporated cyclosporine A into biodegradable nanocapsules and have developed stable topical formulations that are able to achieve therapeutic cyclosporine A levels in the targeted skin layers. This topical treatment provides a potential alternative to oral cyclosporine A and other topical immunosuppressive drugs. For more information, visit www.immunepharmaceuticals.com.

Picato Gel Warning

The US Food and Drug Administration (FDA) issues a warning about reports of severe allergic reactions and herpes zoster associated with the use of Picato Gel (ingenol mebutate) for the treatment of actinic keratosis. The allergic reaction may include throat tightness, difficulty breathing, feeling faint, or swelling of the lips or tongue. The FDA received reports of cases involving severe eye injuries associated with Picato Gel not being used according to the instructions for use on the label. Changes to the labeling have been requested by the FDA to warn about these new safety risks. Patients should not use Picato Gel for a longer period or on an area of skin larger than instructed on the drug label. Patients also should avoid application in, near, and around the mouth, lips, and eye area. For more information, visit www.fda.gov/MedWatch.

Ximino Extended-Release Capsules

Sun Pharmaceutical Industries Ltd announces US Food and Drug Administration approval of the Supplemental New Drug Application for Ximino (minocycline hydrochloride) extended-release 
capsules (45, 90, and 135 mg). Ximino 
extended-release capsules are indicated for the treatment of inflammatory lesions of nonnodular moderate to severe acne vulgaris in patients 
12 years and older. Ximino extended-release capsules are expected to be available for patients during the fourth quarter of 2015. For more information, visit www.sunpharma.com.

If you would like your product included in Product News, please e-mail a press release to the Editorial Office at [email protected].

Due to a submission error, the article “Reduced Degree of Irritation During a Second Cycle of Ingenol Mebutate Gel 0.015% for the Treatment of Actinic Keratosis” (Cutis. 2015;95:47-51) contained the incorrect scale for local skin reactions (LSRs). The text in the Methods should have stated:

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.

The staff of Cutis^® makes every possible effort to ensure accuracy in its articles and apologizes for the mistake.

Due to a submission error, the article “Reduced Degree of Irritation During a Second Cycle of Ingenol Mebutate Gel 0.015% for the Treatment of Actinic Keratosis” (Cutis. 2015;95:47-51) contained the incorrect scale for local skin reactions (LSRs). The text in the Methods should have stated:

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.

The staff of Cutis^® makes every possible effort to ensure accuracy in its articles and apologizes for the mistake.

Due to a submission error, the article “Reduced Degree of Irritation During a Second Cycle of Ingenol Mebutate Gel 0.015% for the Treatment of Actinic Keratosis” (Cutis. 2015;95:47-51) contained the incorrect scale for local skin reactions (LSRs). The text in the Methods should have stated:

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.

The staff of Cutis^® makes every possible effort to ensure accuracy in its articles and apologizes for the mistake.

The Diagnosis: Idiopathic Guttate Hypomelanosis

A biopsy of the largest lesion from the left leg 
superior to the lateral malleolus was performed. 
 Histopathologic examination revealed solar elastosis, diminished number of focal melanocytes and pigment within keratinocytes compared to uninvolved skin, and presence of hyperkeratosis with flattening of rete ridges. The clinical presentation along with histopathologic analysis confirmed a diagnosis of idiopathic guttate hypomelanosis (IGH). The lesions were treated with short-exposure cryotherapy, which resulted in partial repigmentation after several treatments.

Idiopathic guttate hypomelanosis is a common but underreported condition in elderly patients that usually presents with small, discrete, asymptomatic, hypopigmented macules. The frequency of IGH increases with age.¹ Frequency of the condition is much lower in patients aged 21 to 30 years and does not exceed 7%. Lesions of IGH have a predilection for sun-exposed areas such as the arms and legs but rarely can be seen on the face and trunk. Facial lesions of IGH are more frequently reported in women.¹ The size of lesions can be up to 1.5 cm in diameter. The condition generally is self-limited, but some patients may express aesthetic concerns. Rare cases of IGH in children have been associated with prolonged sun exposure.²

The etiology of IGH is unknown but an association with sun exposure has been noted. Patients with IGH frequently show other signs of photoaging, such as numerous seborrheic keratoses, solar lentigines, xeroses, freckles, and actinic keratoses.¹ Short-term exposure to UVB radiation and psoralen plus UVA therapy has been shown to cause IGH in patients with chronic diseases such as mycosis fungoides.^3-5 One small study that examined renal transplant recipients determined an association between HLA-DQ3 antigens and IGH, whereas HLA-DR8 antigens were not identified in any patients with IGH, indicating it may have some advantage in preventing the development of IGH.⁶ Shin et al¹ reported that IGH was prevalent among patients who regularly traumatized their skin by scrubbing.

Clinically, IGH should be differentiated from other conditions characterized by hypopigmentation, such as pityriasis alba, pityriasis versicolor, postinflammatory hypopigmentation, progressive macular hypomelanosis, and vitiligo. Aside from clinical examination, histopathologic studies are helpful in making a definitive diagnosis. The differential diagnosis of IGH is presented in the Table.

Histopathology of IGH lesions usually reveals slight atrophy of the epidermis with flattening of rete ridges and concomitant hyperkeratosis. A thickened stratum granulosum also has been noted in lesions of IGH.² The diminished number of melanocytes and melanin pigment granules along with hyperkeratosis both appear to contribute to the hypopigmentation noted in IGH.⁷ Ultrastructural studies of lesions of IGH can confirm melanocytic degeneration and a decreased number of melanosomes in melanocytes and keratinocytes.^2,8

There is no uniformly effective treatment of IGH. Topical application of tacrolimus and tretinoin have shown efficacy in repigmenting IGH lesions.^8,9 Short-exposure cryotherapy with a duration of 3 to 
5 seconds, localized chemical peels, and/or local dermabrasion can be helpful.^10-12 CO₂ lasers also have demonstrated promising results.¹³

The Diagnosis: Idiopathic Guttate Hypomelanosis

A biopsy of the largest lesion from the left leg 
superior to the lateral malleolus was performed. 
 Histopathologic examination revealed solar elastosis, diminished number of focal melanocytes and pigment within keratinocytes compared to uninvolved skin, and presence of hyperkeratosis with flattening of rete ridges. The clinical presentation along with histopathologic analysis confirmed a diagnosis of idiopathic guttate hypomelanosis (IGH). The lesions were treated with short-exposure cryotherapy, which resulted in partial repigmentation after several treatments.

Idiopathic guttate hypomelanosis is a common but underreported condition in elderly patients that usually presents with small, discrete, asymptomatic, hypopigmented macules. The frequency of IGH increases with age.¹ Frequency of the condition is much lower in patients aged 21 to 30 years and does not exceed 7%. Lesions of IGH have a predilection for sun-exposed areas such as the arms and legs but rarely can be seen on the face and trunk. Facial lesions of IGH are more frequently reported in women.¹ The size of lesions can be up to 1.5 cm in diameter. The condition generally is self-limited, but some patients may express aesthetic concerns. Rare cases of IGH in children have been associated with prolonged sun exposure.²

The etiology of IGH is unknown but an association with sun exposure has been noted. Patients with IGH frequently show other signs of photoaging, such as numerous seborrheic keratoses, solar lentigines, xeroses, freckles, and actinic keratoses.¹ Short-term exposure to UVB radiation and psoralen plus UVA therapy has been shown to cause IGH in patients with chronic diseases such as mycosis fungoides.^3-5 One small study that examined renal transplant recipients determined an association between HLA-DQ3 antigens and IGH, whereas HLA-DR8 antigens were not identified in any patients with IGH, indicating it may have some advantage in preventing the development of IGH.⁶ Shin et al¹ reported that IGH was prevalent among patients who regularly traumatized their skin by scrubbing.

Clinically, IGH should be differentiated from other conditions characterized by hypopigmentation, such as pityriasis alba, pityriasis versicolor, postinflammatory hypopigmentation, progressive macular hypomelanosis, and vitiligo. Aside from clinical examination, histopathologic studies are helpful in making a definitive diagnosis. The differential diagnosis of IGH is presented in the Table.

Histopathology of IGH lesions usually reveals slight atrophy of the epidermis with flattening of rete ridges and concomitant hyperkeratosis. A thickened stratum granulosum also has been noted in lesions of IGH.² The diminished number of melanocytes and melanin pigment granules along with hyperkeratosis both appear to contribute to the hypopigmentation noted in IGH.⁷ Ultrastructural studies of lesions of IGH can confirm melanocytic degeneration and a decreased number of melanosomes in melanocytes and keratinocytes.^2,8

There is no uniformly effective treatment of IGH. Topical application of tacrolimus and tretinoin have shown efficacy in repigmenting IGH lesions.^8,9 Short-exposure cryotherapy with a duration of 3 to 
5 seconds, localized chemical peels, and/or local dermabrasion can be helpful.^10-12 CO₂ lasers also have demonstrated promising results.¹³

The Diagnosis: Idiopathic Guttate Hypomelanosis

A biopsy of the largest lesion from the left leg 
superior to the lateral malleolus was performed. 
 Histopathologic examination revealed solar elastosis, diminished number of focal melanocytes and pigment within keratinocytes compared to uninvolved skin, and presence of hyperkeratosis with flattening of rete ridges. The clinical presentation along with histopathologic analysis confirmed a diagnosis of idiopathic guttate hypomelanosis (IGH). The lesions were treated with short-exposure cryotherapy, which resulted in partial repigmentation after several treatments.

Idiopathic guttate hypomelanosis is a common but underreported condition in elderly patients that usually presents with small, discrete, asymptomatic, hypopigmented macules. The frequency of IGH increases with age.¹ Frequency of the condition is much lower in patients aged 21 to 30 years and does not exceed 7%. Lesions of IGH have a predilection for sun-exposed areas such as the arms and legs but rarely can be seen on the face and trunk. Facial lesions of IGH are more frequently reported in women.¹ The size of lesions can be up to 1.5 cm in diameter. The condition generally is self-limited, but some patients may express aesthetic concerns. Rare cases of IGH in children have been associated with prolonged sun exposure.²

The etiology of IGH is unknown but an association with sun exposure has been noted. Patients with IGH frequently show other signs of photoaging, such as numerous seborrheic keratoses, solar lentigines, xeroses, freckles, and actinic keratoses.¹ Short-term exposure to UVB radiation and psoralen plus UVA therapy has been shown to cause IGH in patients with chronic diseases such as mycosis fungoides.^3-5 One small study that examined renal transplant recipients determined an association between HLA-DQ3 antigens and IGH, whereas HLA-DR8 antigens were not identified in any patients with IGH, indicating it may have some advantage in preventing the development of IGH.⁶ Shin et al¹ reported that IGH was prevalent among patients who regularly traumatized their skin by scrubbing.

Clinically, IGH should be differentiated from other conditions characterized by hypopigmentation, such as pityriasis alba, pityriasis versicolor, postinflammatory hypopigmentation, progressive macular hypomelanosis, and vitiligo. Aside from clinical examination, histopathologic studies are helpful in making a definitive diagnosis. The differential diagnosis of IGH is presented in the Table.

Histopathology of IGH lesions usually reveals slight atrophy of the epidermis with flattening of rete ridges and concomitant hyperkeratosis. A thickened stratum granulosum also has been noted in lesions of IGH.² The diminished number of melanocytes and melanin pigment granules along with hyperkeratosis both appear to contribute to the hypopigmentation noted in IGH.⁷ Ultrastructural studies of lesions of IGH can confirm melanocytic degeneration and a decreased number of melanosomes in melanocytes and keratinocytes.^2,8

There is no uniformly effective treatment of IGH. Topical application of tacrolimus and tretinoin have shown efficacy in repigmenting IGH lesions.^8,9 Short-exposure cryotherapy with a duration of 3 to 
5 seconds, localized chemical peels, and/or local dermabrasion can be helpful.^10-12 CO₂ lasers also have demonstrated promising results.¹³

Syringoid eccrine carcinoma is a rare malignant adnexal tumor with eccrine differentiation that histologically resembles a syringoma.¹ Originally described as eccrine epithelioma by Freeman and Winklemann² in 1969, syringoid eccrine carcinoma has been reported in the literature as eccrine carcinoma, eccrine syringomatous carcinoma, and sclerosing sweat duct carcinoma.³ Clinically, syringoid eccrine carcinoma most 
commonly presents as a tender plaque or nodule on the scalp, and histologic examination generally reveals a dermal-based lesion that rarely shows epidermal connection. It demonstrates 
syringomalike tadpole morphology (epithelial strands 
with lumen formation) composed of basaloid epithelium with uniform hyperchromatic nuclei 
(Figure 1). There usually is an infiltrative growth pattern to the subcutis (Figure 2 [left]) or skeletal muscle as well as remarkable perineural invasion 
(Figure 2 [right]). Mitotic activity is minimal to absent. The tumor cells of syringoid eccrine 
carcinoma typically show positive immuno-staining for high- and low-molecular-weight cytokeratin, while the lumina are highlighted 
by epithelial membrane antigen and carcinoembryonic antigen.⁴ However, immunohistochemistry 
often is not contributory in diagnosing primary eccrine carcinomas.

Figure 1. Dermal infiltrate with tadpole morphology (arrow) characteristic of syringoid eccrine carcinoma (left)(H&E, original magnification ×40). High-power view shows an epithelial infiltrate and tadpole morphology (arrow)(right)(H&E, original magnification ×400).

Figure 2. Syringoid eccrine carcinoma extending to the junction of the reticular dermis and subcutaneous fat (left) (H&E, original magnification ×100). Nerve with adjacent and invasive basaloid nests of syringoid carcinoma (right)(H&E, original magnification ×100). The tumor consists of monomorphic cells with oval hyperchromatic nuclei.

The differential diagnosis of syringoid eccrine carcinoma includes cutaneous adenoid cystic carcinoma, metastatic adenocarcinoma, sclerosing basal cell carcinoma, and syringoma. Cutaneous adenoid cystic carcinoma is a rare, slow-growing, 
flesh-colored tumor that consists of lobules, islands, and cords of basaloid cells with prominent cystic cribriforming (Figure 3). The tumor cells typically are small, cuboidal, and monomorphic. Metastatic adenoid cystic carcinoma, such as from a primary tumor of the salivary glands or breasts, must be excluded before rendering a diagnosis of primary cutaneous disease.

Figure 3. Striking cribriform architecture of cutaneous adenoid cystic carcinoma (H&E, original magnification ×40). The tumor is well circumscribed and consists of multiple cystic spaces lined by flattened to cuboidal basaloid epithelium.

Metastatic adenocarcinoma of the skin usually presents in patients with a clinical history of preexisting disease. The breasts, colon, stomach, and ovaries are common origins of metastases. The histopathologic and immunohistochemical findings depend on the particular site of origin of the metastasis. Compared with primary eccrine carcinomas, metastatic adenocarcinomas of the skin generally are high-grade lesions with prominent atypia, mitosis, and necrosis (Figure 4).

Figure 4. Metastatic adenocarcinoma of the skin with dermal infiltrating glands (H&E, original magnification ×100). The nuclei are highly atypical. The tumor cells are cytokeratin 7 positive, cytokeratin 20 negative, estrogen-receptor positive, and gross cystic disease fluid protein positive, which is consistent with metastasis from a primary carcinoma of the breast (not shown).

Sclerosing basal cell carcinoma shows basaloid tumor cells with deep infiltration. Unlike syringoid eccrine carcinoma, basal cell carcinoma is an epidermal tumor that does not have true lumen formation. Furthermore, other variants of basal cell carcinoma, including nodular, micronodular, or superficial multicentric tumors, often coexist with the sclerosing variant in the same lesion and constitute a useful diagnostic clue (Figure 5). Staining for epithelial membrane antigen may be useful in identifying the absence of lumen formation, and Ber-EP4 highlights the epidermal origin of the lesion.⁵

Figure 5. Deeply invasive tumor with multiple architectures (sclerosing and micronodular) in a case of sclerosing basal cell carcinoma (H&E, original magnification ×40). Basaloid nests without true lumen formation invade subcutaneous adipose tissue.

Syringomas most commonly present as multiple small flesh-colored papules on the eyelids. On histology, syringomas present as small superficial dermal lesions composed of small ducts that may form tadpolelike structures in a fibrotic stroma (Figure 6). The ducts are lined by benign cuboidal cells. In contrast to syringoid eccrine carcinomas, syringomas usually present as multiple lesions that are microscopically superficial without perineural involvement.

Figure 6. Syringoma is composed of dilated ducts in a fibrotic stroma (H&E, original magnification ×40). Careful microscopic examination would reveal no perineural or deep subcutaneous tumor involvement.

Syringoid eccrine carcinoma is a rare malignant adnexal tumor with eccrine differentiation that histologically resembles a syringoma.¹ Originally described as eccrine epithelioma by Freeman and Winklemann² in 1969, syringoid eccrine carcinoma has been reported in the literature as eccrine carcinoma, eccrine syringomatous carcinoma, and sclerosing sweat duct carcinoma.³ Clinically, syringoid eccrine carcinoma most 
commonly presents as a tender plaque or nodule on the scalp, and histologic examination generally reveals a dermal-based lesion that rarely shows epidermal connection. It demonstrates 
syringomalike tadpole morphology (epithelial strands 
with lumen formation) composed of basaloid epithelium with uniform hyperchromatic nuclei 
(Figure 1). There usually is an infiltrative growth pattern to the subcutis (Figure 2 [left]) or skeletal muscle as well as remarkable perineural invasion 
(Figure 2 [right]). Mitotic activity is minimal to absent. The tumor cells of syringoid eccrine 
carcinoma typically show positive immuno-staining for high- and low-molecular-weight cytokeratin, while the lumina are highlighted 
by epithelial membrane antigen and carcinoembryonic antigen.⁴ However, immunohistochemistry 
often is not contributory in diagnosing primary eccrine carcinomas.

Figure 1. Dermal infiltrate with tadpole morphology (arrow) characteristic of syringoid eccrine carcinoma (left)(H&E, original magnification ×40). High-power view shows an epithelial infiltrate and tadpole morphology (arrow)(right)(H&E, original magnification ×400).

Figure 2. Syringoid eccrine carcinoma extending to the junction of the reticular dermis and subcutaneous fat (left) (H&E, original magnification ×100). Nerve with adjacent and invasive basaloid nests of syringoid carcinoma (right)(H&E, original magnification ×100). The tumor consists of monomorphic cells with oval hyperchromatic nuclei.

The differential diagnosis of syringoid eccrine carcinoma includes cutaneous adenoid cystic carcinoma, metastatic adenocarcinoma, sclerosing basal cell carcinoma, and syringoma. Cutaneous adenoid cystic carcinoma is a rare, slow-growing, 
flesh-colored tumor that consists of lobules, islands, and cords of basaloid cells with prominent cystic cribriforming (Figure 3). The tumor cells typically are small, cuboidal, and monomorphic. Metastatic adenoid cystic carcinoma, such as from a primary tumor of the salivary glands or breasts, must be excluded before rendering a diagnosis of primary cutaneous disease.

Figure 3. Striking cribriform architecture of cutaneous adenoid cystic carcinoma (H&E, original magnification ×40). The tumor is well circumscribed and consists of multiple cystic spaces lined by flattened to cuboidal basaloid epithelium.

Metastatic adenocarcinoma of the skin usually presents in patients with a clinical history of preexisting disease. The breasts, colon, stomach, and ovaries are common origins of metastases. The histopathologic and immunohistochemical findings depend on the particular site of origin of the metastasis. Compared with primary eccrine carcinomas, metastatic adenocarcinomas of the skin generally are high-grade lesions with prominent atypia, mitosis, and necrosis (Figure 4).

Figure 4. Metastatic adenocarcinoma of the skin with dermal infiltrating glands (H&E, original magnification ×100). The nuclei are highly atypical. The tumor cells are cytokeratin 7 positive, cytokeratin 20 negative, estrogen-receptor positive, and gross cystic disease fluid protein positive, which is consistent with metastasis from a primary carcinoma of the breast (not shown).

Sclerosing basal cell carcinoma shows basaloid tumor cells with deep infiltration. Unlike syringoid eccrine carcinoma, basal cell carcinoma is an epidermal tumor that does not have true lumen formation. Furthermore, other variants of basal cell carcinoma, including nodular, micronodular, or superficial multicentric tumors, often coexist with the sclerosing variant in the same lesion and constitute a useful diagnostic clue (Figure 5). Staining for epithelial membrane antigen may be useful in identifying the absence of lumen formation, and Ber-EP4 highlights the epidermal origin of the lesion.⁵

Figure 5. Deeply invasive tumor with multiple architectures (sclerosing and micronodular) in a case of sclerosing basal cell carcinoma (H&E, original magnification ×40). Basaloid nests without true lumen formation invade subcutaneous adipose tissue.

Syringomas most commonly present as multiple small flesh-colored papules on the eyelids. On histology, syringomas present as small superficial dermal lesions composed of small ducts that may form tadpolelike structures in a fibrotic stroma (Figure 6). The ducts are lined by benign cuboidal cells. In contrast to syringoid eccrine carcinomas, syringomas usually present as multiple lesions that are microscopically superficial without perineural involvement.

Figure 6. Syringoma is composed of dilated ducts in a fibrotic stroma (H&E, original magnification ×40). Careful microscopic examination would reveal no perineural or deep subcutaneous tumor involvement.

Syringoid eccrine carcinoma is a rare malignant adnexal tumor with eccrine differentiation that histologically resembles a syringoma.¹ Originally described as eccrine epithelioma by Freeman and Winklemann² in 1969, syringoid eccrine carcinoma has been reported in the literature as eccrine carcinoma, eccrine syringomatous carcinoma, and sclerosing sweat duct carcinoma.³ Clinically, syringoid eccrine carcinoma most 
commonly presents as a tender plaque or nodule on the scalp, and histologic examination generally reveals a dermal-based lesion that rarely shows epidermal connection. It demonstrates 
syringomalike tadpole morphology (epithelial strands 
with lumen formation) composed of basaloid epithelium with uniform hyperchromatic nuclei 
(Figure 1). There usually is an infiltrative growth pattern to the subcutis (Figure 2 [left]) or skeletal muscle as well as remarkable perineural invasion 
(Figure 2 [right]). Mitotic activity is minimal to absent. The tumor cells of syringoid eccrine 
carcinoma typically show positive immuno-staining for high- and low-molecular-weight cytokeratin, while the lumina are highlighted 
by epithelial membrane antigen and carcinoembryonic antigen.⁴ However, immunohistochemistry 
often is not contributory in diagnosing primary eccrine carcinomas.

Figure 1. Dermal infiltrate with tadpole morphology (arrow) characteristic of syringoid eccrine carcinoma (left)(H&E, original magnification ×40). High-power view shows an epithelial infiltrate and tadpole morphology (arrow)(right)(H&E, original magnification ×400).

Figure 2. Syringoid eccrine carcinoma extending to the junction of the reticular dermis and subcutaneous fat (left) (H&E, original magnification ×100). Nerve with adjacent and invasive basaloid nests of syringoid carcinoma (right)(H&E, original magnification ×100). The tumor consists of monomorphic cells with oval hyperchromatic nuclei.

The differential diagnosis of syringoid eccrine carcinoma includes cutaneous adenoid cystic carcinoma, metastatic adenocarcinoma, sclerosing basal cell carcinoma, and syringoma. Cutaneous adenoid cystic carcinoma is a rare, slow-growing, 
flesh-colored tumor that consists of lobules, islands, and cords of basaloid cells with prominent cystic cribriforming (Figure 3). The tumor cells typically are small, cuboidal, and monomorphic. Metastatic adenoid cystic carcinoma, such as from a primary tumor of the salivary glands or breasts, must be excluded before rendering a diagnosis of primary cutaneous disease.

Figure 3. Striking cribriform architecture of cutaneous adenoid cystic carcinoma (H&E, original magnification ×40). The tumor is well circumscribed and consists of multiple cystic spaces lined by flattened to cuboidal basaloid epithelium.

Metastatic adenocarcinoma of the skin usually presents in patients with a clinical history of preexisting disease. The breasts, colon, stomach, and ovaries are common origins of metastases. The histopathologic and immunohistochemical findings depend on the particular site of origin of the metastasis. Compared with primary eccrine carcinomas, metastatic adenocarcinomas of the skin generally are high-grade lesions with prominent atypia, mitosis, and necrosis (Figure 4).

Figure 4. Metastatic adenocarcinoma of the skin with dermal infiltrating glands (H&E, original magnification ×100). The nuclei are highly atypical. The tumor cells are cytokeratin 7 positive, cytokeratin 20 negative, estrogen-receptor positive, and gross cystic disease fluid protein positive, which is consistent with metastasis from a primary carcinoma of the breast (not shown).

Sclerosing basal cell carcinoma shows basaloid tumor cells with deep infiltration. Unlike syringoid eccrine carcinoma, basal cell carcinoma is an epidermal tumor that does not have true lumen formation. Furthermore, other variants of basal cell carcinoma, including nodular, micronodular, or superficial multicentric tumors, often coexist with the sclerosing variant in the same lesion and constitute a useful diagnostic clue (Figure 5). Staining for epithelial membrane antigen may be useful in identifying the absence of lumen formation, and Ber-EP4 highlights the epidermal origin of the lesion.⁵

Figure 5. Deeply invasive tumor with multiple architectures (sclerosing and micronodular) in a case of sclerosing basal cell carcinoma (H&E, original magnification ×40). Basaloid nests without true lumen formation invade subcutaneous adipose tissue.

Syringomas most commonly present as multiple small flesh-colored papules on the eyelids. On histology, syringomas present as small superficial dermal lesions composed of small ducts that may form tadpolelike structures in a fibrotic stroma (Figure 6). The ducts are lined by benign cuboidal cells. In contrast to syringoid eccrine carcinomas, syringomas usually present as multiple lesions that are microscopically superficial without perineural involvement.

Figure 6. Syringoma is composed of dilated ducts in a fibrotic stroma (H&E, original magnification ×40). Careful microscopic examination would reveal no perineural or deep subcutaneous tumor involvement.

Actinic keratosis (AK), also referred to as solar keratosis or senile keratosis, is an intraepidermal proliferation of dysplastic keratinocytes that develops in response to chronic exposure to UV radiation. Actinic keratoses are among the most commonly encountered lesions seen by dermatologists, and it has been estimated that 60% of predisposed individuals older than 40 years have at least one AK.^1,2 Prevalence is notably higher in light-skinned individuals and increases with age, presumably from higher cumulative sun exposure and decreased effectiveness of the immune system.^1,3 It remains a point of contention as to whether or not AKs actually represent squamous cell carcinoma (SCC) in situ, but the potential for progression to invasive disease has been well demonstrated, as the majority of SCCs develop from preexisting AKs.^4-6 The risk for progression to invasive disease for an individual AK has been estimated to range from 0.025% to 16% per year, with an average of approximately 8% in immunocompetent patients.⁷

The clinical morphology of AK can vary widely, but the most common presentation is an erythematous scaly macule, papule, or plaque on sun-exposed skin. The skin surrounding AKs typically shows evidence of solar damage with deep wrinkling, mottled pigmentation, scattered telangiectases, purpura, or xerosis (Figure). A variety of clinical variants with unique presentations exist, including atrophic, hypertrophic, acantholytic, lichenoid, bowenoid, and pigmented subtypes. Because more than 80% of AKs occur on highly visible areas such as the head, neck, back of the hands, and forearms, AKs can have an obvious detrimental effect on cosmetic appearance. Studies also have shown a strong association between AKs and decreased overall quality of life (QOL).^3,8,9

Patient with numerous actinic keratoses, scattered plaques suspicious for squamous cell carcinoma, and numerous scars from prior squamous cell carcinoma treatments.

Topical Treatments

5-Fluorouracil

5-Fluorouracil (5-FU) is a US Food and Drug Administration (FDA)–approved, topically applied pyrimidine analogue that inhibits thymidylate synthase. The resulting suppression of DNA and RNA synthesis induces cell death with a preference for mitotically active cells.¹⁰ 5-Fluorouracil has been used for more than 
50 years as a treatment of AK and its efficacy is well established. A systematic review of 5 randomized controlled studies of topical 5-FU reported an average of 49% of 423 patients achieving complete lesion clearance with 5-FU cream 5% applied once or twice daily for up to 7 weeks.¹¹ Some notable drawbacks of 5-FU, however, are application-site erythema, blistering, pruritus, necrosis, erosion, and pain. These effects often lead to premature cessation of therapy, but newer formulations of 5-FU cream 0.5% have shown good efficacy with better tolerability.¹² A randomized, double-blind, multicenter, parallel-group study of 177 patients using 5-FU cream 0.5% once daily for either 1, 2, or 4 weeks demonstrated significant (P<.001) efficacy over vehicle gel in all treatment arms.¹³ The most effective therapy was 
4 weeks of treatment, which achieved a mean 91.7% reduction in lesion count as assessed 1 month after cessation of therapy. The primary adverse effect (AE) reported in this trial was mild to moderate facial irritation, which generally resolved within 
18 to 21 days after treatment cessation.¹³ Overall, 5-FU is a highly effective therapy for treating AKs that also can improve signs of photoaging, but patients should be aware of cosmetically unappealing effects that generally occur throughout therapy and during the immediate posttreatment period.¹⁴

Chemical Peels

Chemical peels traditionally employ acidic compounds to strip away outer layers of skin to variable depths depending on the concentration of the agent being applied. For treatment of AK, trichloroacetic acid (TCA) is a commonly employed cauterant that has shown efficacy comparable to topical 5-FU as well as ablative CO₂ laser resurfacing.¹⁵ Trichloroacetic acid peels also are a convenient therapy, as good results can be achieved after a single treatment session. A split-face study of 15 patients treated with either a single application of 35% TCA and Jessner solution or twice-daily application of 5-FU cream 5% for 3 weeks demonstrated a reduction in 75% of visible AKs in both treatment arms over a 1-year follow-up period.¹⁶ Although 80% of patients self-reported considerable cosmetic improvement with both therapies, patient preference was reported to be in favor of the TCA peel, given its quick results and relatively mild side effects as compared to 5-FU. Treatment with chemical peels will result in temporary erythema and mild desquamation that usually resolves within 2 weeks; however, there are cases in which erythema has been reported to persist for several months.¹⁶ Adverse effects such as permanent scarring or pigmentation changes rarely are seen with TCA concentrations less than 45%.¹⁷ Caution should be used in patients with a history of herpes simplex virus, keloids, postinflammatory hyperpigmentation, radiation exposure, immunosuppression, and those unable or unwilling to use sunscreen and avoid sun exposure in the immediate posttreatment period.

Diclofenac Sodium

Diclofenac sodium (DFS) is an FDA-approved topical, nonsteroidal, 
anti-inflammatory drug whose mechanism of action in the treatment of AK is thought to involve inhibition of the cyclooxygenase 2 enzyme.¹⁸ The resulting reduction of prostaglandins is believed to inhibit tumor angiogenesis, induce apoptosis, and inhibit cell differentiation.^19-22 In a multicenter, double-blind, placebo-controlled study of 195 patients, application of DFS 3% in hyaluronan gel 2.5% twice daily for 60 days showed significant (P<.05) efficacy over placebo in achieving complete resolution of target lesions during a 30-day follow-up period (31% vs 10%). Furthermore, qualitative patient assessment of complete global improvement also was significantly (P<.05) higher in the active treatment group as compared to placebo (31% vs 10%).²³ Additional studies of DFS 3% in hyaluronan gel 2.5% applied twice daily for 90 days have shown even higher rates of success, with complete resolution of target lesions in 40% to 58% of cases.^24,25 This therapy also has been reported to substantially improve QOL following treatment completion.²⁶ The most frequently cited AEs include pruritus, rash, dry skin, erythema, and application-site reactions. Overall, DFS is a 
well-tolerated therapy with efficacy comparable to that of 5-FU but with a lower incidence of AEs 
and higher patient satisfaction as determined in 
2 head-to-head studies.^27,28
ImiquimodImiquimod (IMQ) is an FDA-approved topical agent that functions as an immune response modifier via agonism of toll-like receptor 7.¹⁸ The resulting cytokine production and release enhances the innate and acquired immune responses leading to anticancer activity.²⁹ The efficacy of IMQ for treatment of AK has been demonstrated in numerous well-designed clinical trials. A 
meta-analysis of 5 randomized, double-blind trials including 1293 patients treated with IMQ cream 5% 
2 to 3 times per week for 12 to 16 weeks reported complete clearance of AKs in 50% of patients treated with IMQ as compared to 5% of patients treated with vehicle.³⁰ The most frequently reported AEs with this therapy include erythema, scabbing, flaking, and erosion. These effects generally resolve following cessation of treatment, and therapy is considered to be well tolerated; however, there are case reports of IMQ triggering or exacerbating existing inflammatory conditions.³¹ Imiquimod cream also is approved at 2.5% and 3.75% concentrations, which have demonstrated significant (P<.001) efficacy over placebo and a reduced incidence of AEs; complete clearance rates have been reported as 30.6% and 35.6%, respectively.³² Notably, a study comparing 75 patients randomized to either IMQ cream 5% 
3 times per week for 4 weeks, 1 or 2 courses of cryosurgery, or 5-FU ointment 5% twice daily for 4 weeks reported that IMQ achieved significantly (P<.01) superior sustained clearance rates during a 12-month follow-up period over cryosurgery and 5-FU 
(73% vs 4% vs 33%).³³ Additionally, cosmetic outcomes as determined by both participants and investigators were reported as excellent at 12 months posttreatment in more than 80% of participants treated with IMQ. These excellent, long-lasting cosmetic outcomes also were determined to be significantly (P<.0001) superior to the cosmetic outcomes of 5-FU and cryotherapy, which both reported excellent outcomes in less than 10% of cases.³³
Ingenol MebutateIngenol mebutate (IM) is a macrocyclic diterpene ester derived from the Euphorbia peplus plant that is FDA approved for the treatment of AK.¹ Ingenol mebutate’s mechanism of action is thought to involve induction of cell death via disruption of the plasma membrane and mitochondria in addition to production of an inflammatory response, which produces tumor-specific antibodies and a large influx of neutrophils.^34,35 The overall evidence for the efficacy of IM is strong. A combined analysis of 4 multicenter, randomized, double-blind studies of 1005 participants reported that IM gel 0.015% applied once daily for 3 days to the face or scalp was significantly superior (P<.001) to placebo in achieving complete clearance as assessed 54 days after completion of therapy (42.2% vs 3.7%) and that IM gel 0.05% applied once daily for 2 days to the trunk or extremities also was significantly superior (P<.001) to placebo in achieving complete clearance as determined 55 days after completion of therapy (34.1% vs 4.7%).³⁶ A follow-up report to this study indicated that IM also appears to achieve long-lasting effects with an overall 87% decrease in total AKs at 12 months follow-up in both trial groups.³⁷ Additionally, it has been recently reported that treatment with IM in these trials was associated with significantly higher overall treatment satisfaction (P<.001) and improved QOL (P<.001) as compared to vehicle.³⁸ Cosmetic outcomes of IM therapy have been assessed in a trial analyzing the efficacy of IM gel 0.025% for 3 days or IM gel 0.05% for 2 or 3 days on nonfacial AKs. This study reported significantly (P<.0001) higher patient satisfaction with the cosmetic outcome at 8 weeks after therapy as compared to vehicle.³⁴ Studies performed in mice have demonstrated that IM is able to promote collagen matrix turnover and impose dermal elasticity, which may contribute to these good cosmetic outcomes.³⁹ The most common AEs of IM therapy are erythema, crusting, and flaking; these effects generally occur 3 to 8 days after starting treatment. These effects, however, generally are short lived and resolve within 2 weeks of treatment cessation when IM is applied to the face or scalp or 4 weeks when applied to the trunk or extremities.⁴⁰ Overall, IM is a useful therapeutic option given its relatively short treatment course as compared to other topically applied agents, as well as its lasting efficacy, mild AEs, and good cosmetic outcomes.

Procedural Modalities

Surgical Procedures

Surgical approaches for the treatment of AK include excision, curettage with or without electrodesiccation, and dermabrasion. In the past, these modalities were used with greater frequency, but the advent of effective topical medications with lower risks of AEs has largely reduced their use.⁴¹ Excision may still be indicated in cases where SCC is suspected, and curettage can be used for treatment of thicker hypertrophic AKs.⁴² Although these approaches have not been evaluated in clinical trials, they are generally effective but require the use of local anesthetics and come with substantial risk for infection, permanent scarring, and hypopigmentation. Dermabrasion employs the use of a motorized device equipped with an abrasive material to physically remove superficial layers of the skin. Studies are limited, but this method has been reported as an effective treatment in a retrospective review of 23 participants in which 96% remained free of AKs at 1 year, 83% at 2 years, 64% at 4 years, and 54% at 5 years posttherapy.⁴³ Notably, one split-face study of 40 participants treated with dermabrasion followed by 25% TCA on one side and either Jessner solution and 35% TCA or dermabrasion alone on the other side reported that the combination of dermabrasion with 25% TCA consistently produced excellent cosmetic results with nearly complete eradication of AKs.⁴⁴ In general, however, cosmetic outcomes with dermabrasion are variable, as the technique is highly operator dependent and treatment is associated with notable discomfort as well as risk for scarring and permanent pigmentation alteration.

Cryotherapy

Cryotherapy remains one of the most commonly utilized treatments of AK and involves the delivery of liquid nitrogen via a spray device or a cotton tip applicator to rapidly freeze cells, thus causing cellular destruction via ice crystal formation and protein denaturation.⁴⁵ Efficacy with this technique has been reported to be as high as 98.8% at 12 months follow-up, but more recent studies cite lower rates of success.⁴⁶ A prospective multicenter study of 90 participants with 421 AKs on the face or scalp treated with a single freeze-thaw cycle of liquid nitrogen reported an overall complete response rate of 67.2% at 3 months posttherapy. Additionally, higher complete response rates were associated with longer freeze times, and cosmetic outcomes were reported as good to excellent in 94% of complete response lesions.⁴⁷ Similar results were reported in an open-label, prospective, randomized, controlled clinical trial of 200 participants with 
543 AKs, which compared a single freeze-thaw cycle with liquid nitrogen to a single session of CO₂ laser ablation in the treatment of isolated AKs of the face and scalp.⁴⁸ At 3 months posttherapy, complete clearance was observed in 71.6% of participants treated with cryotherapy and in 65.3% of participants treated with laser ablation (P=.532). At 
12 months posttherapy, participants who originally showed complete response at 3 months were assessed for relapse. Complete clearance was preserved in 72.6% of participants treated with cryotherapy versus 21.9% of participants treated with laser ablation (P<.0001), and cosmetic outcomes were reported by participants as good or excellent at 3 months follow-up in more than 93% of participants for both treatment arms.⁴⁸ Possible AEs of cryotherapy include pain during treatment, blister formation with possible hemorrhage, infection, scarring, and permanent pigmentary changes.^47,48 Notably, the risk for hypopigmentation increases with longer freezing times, thus requiring clinicians to consider the balance between improved efficacy and reduced cosmetic outcomes.⁴⁷

Light-Based Therapies

Laser Therapy

Ablative laser resurfacing with either the CO₂ or erbium-doped:YAG (Er:YAG) laser utilizes light of specific wavelengths to selectively induce thermolysis and destruction of the epidermal layer. Both lasers have been studied as treatments of AK, but there is a lack of large, well-designed studies. In one small study of 14 participants treated with 
1 to 2 passes of the CO₂ laser, complete clearance was reported in all cases without any recurrences during a follow-up period of 6 to 24 months. Additionally, all participants in this study reported satisfaction with the cosmetic outcome.⁴⁹ The CO₂ laser also has demonstrated efficacy comparable to that of the TCA peel and 5-FU therapy in a prospective randomized trial of 34 patients with facial or scalp AKs who received either CO₂ laser with 2 passes, 30% TCA peel, or 5-FU cream 5% twice daily for 
3 weeks.¹⁵ Reduction in mean AK counts at 3 months posttherapy was significantly (P<.03) higher in all treatment arms as compared to the control group (92% for CO₂ laser, 89% for TCA peel, and 83% for 5-FU cream). No significant (P=.31) difference in outcomes was noted among the different treatment arms.¹⁵ Similar results were reported for the Er:YAG laser in a small prospective study of 5 participants treated with 2 to 3 passes with the Er:YAG laser in which reduction in mean AK counts was reported as ranging from 86% to 96% at 3 months posttherapy.⁵⁰ The Er:YAG laser in combination with the CO₂ laser has shown notable long-term efficacy in achieving higher lesion clearance rates and sustained complete clearance rates over treatment with topical 5-FU.⁵¹ In a prospective randomized study of 55 par-ticipants with multiple AKs on the face or scalp, participants were assigned to receive either combination laser ablation with the Er:YAG and CO₂ lasers down to the level of the papillary dermis or 
5-FU cream 5% applied twice daily for 2 to 7 weeks until an appropriate clinical inflammatory response was achieved. At 12 months follow-up, the laser treatment group achieved significantly (P=.048) higher mean lesion clearance rates (91.1%) as compared to the 5-FU arm (76.6%) and significantly (P=.003) higher sustained complete clearance rates (59.3%) as compared to 5-FU (29.2%). The proportion of participants with an improvement in photoaging score at 12 months follow-up approached statistical significance (P=.07), with 74% of the laser-treated group showing improvement as compared to 43% of the 5-FU–treated group. Long-term, cosmetically unappealing side effects such as erythema and hypopigmentation occurred notably more often in the laser-treated group as compared to the 5-FU group.⁵¹ In summary, ablative lasers appear to be a highly effective therapy for AK but at the cost of increased risk for AEs such as permanent pigmentary changes, prolonged erythema lasting up to several months, and scarring.^50,52-55

Fractional photothermolysis is a relatively new advancement in the field of laser therapy that has received FDA approval for the treatment of AK.⁵⁶ This treatment works by creating multiple noncontiguous microscopic columns of thermal injury while sparing adjacent zones of viable tissue.⁵⁷ Although there are limited studies involving the use of such lasers in the treatment of AK, initial findings suggest that 1927-nm thulium lasers may be more effective than 1550-nm erbium lasers in achieving lesion clearance. A trial of 14 participants who received 5 laser treatments with a 1550-nm fractionated erbium-doped fiber laser reported an average reduction in AK counts of 66.2% at 3 months follow-up and a 55.6% reduction at 6 months follow-up. A participant-determined marked or very significant improvement of lesions was reported in 83% of participants at 1 month posttreatment but only in 44% of participants at 6 months posttreatment.⁵⁸ A similar trial of 24 participants treated with up to 4 treatment sessions of the fractionated 1927-nm thulium laser reported an 87.3% reduction in number of AKs at 3 months follow-up and an 86.6% reduction at 
6 months follow-up.⁵⁶ The primary advantage of fractional laser therapy is a faster recovery period generally lasting only 2 or 3 days as compared to 
2 weeks or more with traditional ablative lasers, thus limiting the amount of time a patient must tolerate cosmetically unappealing erythema.^59,60 The quick recovery time has been attributed to the fractional laser’s ability to preserve the stratum corneum and skin barrier, which also helps reduce the risk for other AEs such as scarring and infection.^56,59-61 Additional studies are needed to better assess the true efficacy of fractional laser therapy, but treatment with the fractional 1927-nm thulium laser appears to be a promising and well-tolerated therapeutic option for treatment of AK with similar efficacy to traditional ablative lasers but with a lower risk of AEs.

Photodynamic TherapyPhotodynamic therapy (PDT) is an FDA-approved treatment that involves the use of a topical photosensitizing agent such as 5-aminolevulinic acid (ALA) or methyl aminovulinate (MAL) before exposure to an activating light source to generate reactive oxygen species that lead to cell death.^62-65 Multiple PDT regimens with varying combinations of photosensitizers, incubation time, and light sources have been studied, but a 
2012 Cochrane review determined that treatment with conventional formulations of MAL and ALA with either blue- or red-light PDT were similarly efficacious for treatment of individual AKs as compared to vehicle with blue- or red-light PDT. One exception was that longer incubation time (ie, 4 hours) with ALA resulted in better results than shorter incubation times (ie, 0.5, 1, 2 hours) with ALA.⁶⁶

Standard PDT treatment with MAL also has consistently demonstrated superior efficacy in achieving complete clearance rates in addition to superior cosmetic outcomes over treatment with either cryotherapy, DFS, or 5-FU.^67-73 Three studies in particular noted an excellent or good investigator-determined cosmetic outcome in 96% to 98% of participants treated with MAL-PDT.^69,71,74 Photodynamic therapy with ALA also has been reported as superior over CO2 laser ablation for AK reduction as well as both patient and investigator overall satisfaction.⁷⁵

More recently, several methods of improving photosensitizer delivery have been studied, which have demonstrated remarkable efficacy at achieving lesion clearance over standard cream formulations or application routines. One such method involves the use of gentle heating to increase photosensitizer uptake. In a split-extremity study of 20 participants who were treated with 20% ALA under occlusion for 1 hour with one side heated to 38.8°C, the heated side demonstrated significant (P<.0001) efficacy at achieving higher median clearance rates over control when evaluated at 2 and 6 months posttherapy.⁷⁶ Notably, occlusion of ALA in itself during the incubation period also has been demonstrated to significantly (P<.0001) improve clearance rates.⁷⁷ Another method involves the use of a new nanoemulsion-based formulation of 
ALA gel, known as BF-200 ALA, which has demonstrated remarkable efficacy over standard 
MAL cream and placebo in a long-term follow-up 
analysis of 2 prospective, randomized, controlled trials.⁷⁸ In a similar vein, 3 prospective randomized trials with a minimum follow-up time of 3 months demonstrated that MAL-PDT in combination with fractional ablative laser pretreatment has significant (P<.02 in all trials) efficacy over MAL-PDT without pretreatment in achieving complete AK clearance. Although the cosmetic outcomes were good or excellent in 87% to 100% of patients, they were not significantly different from stand-alone 
MAL-PDT treatment in any of the trials.^79-81 However, pretreatment with microneedling in MAL-PDT has been shown to achieve superior cosmetic outcomes over 
MAL-PDT without microneedling, according to one small split-face study of 10 participants.⁸²

Overall, PDT is an excellent therapeutic option that is able to provide efficacious clearance of AKs as well as superior cosmetic outcomes. Common AEs of PDT include burning, itching, and stinging during therapy, but pain intensity decreases dramatically upon termination of illumination, with cessation of most symptoms by 12 hours posttherapy.⁷³ Permanent pigmentation changes have been reported to occasionally occur following PDT therapy.⁸¹

Conclusion

When determining which therapy to use in a patient, clinicians must take into account a variety of factors such as patient preference, cost of treatment, availability, tolerance for AEs, and the need for field therapy. Although all therapies discussed within this article are effective and reasonable treatment choices, patients who are particularly concerned about cosmetic outcomes would most likely benefit from either IMQ or PDT, as the data for cosmetic outcomes with these therapies are the strongest. Combination or sequential treatments may be required in some cases and all patients should be monitored for lesion recurrence regardless of treatment choice. A summary of the therapies and key studies discussed here is available in the PDF.

Actinic keratosis (AK), also referred to as solar keratosis or senile keratosis, is an intraepidermal proliferation of dysplastic keratinocytes that develops in response to chronic exposure to UV radiation. Actinic keratoses are among the most commonly encountered lesions seen by dermatologists, and it has been estimated that 60% of predisposed individuals older than 40 years have at least one AK.^1,2 Prevalence is notably higher in light-skinned individuals and increases with age, presumably from higher cumulative sun exposure and decreased effectiveness of the immune system.^1,3 It remains a point of contention as to whether or not AKs actually represent squamous cell carcinoma (SCC) in situ, but the potential for progression to invasive disease has been well demonstrated, as the majority of SCCs develop from preexisting AKs.^4-6 The risk for progression to invasive disease for an individual AK has been estimated to range from 0.025% to 16% per year, with an average of approximately 8% in immunocompetent patients.⁷

The clinical morphology of AK can vary widely, but the most common presentation is an erythematous scaly macule, papule, or plaque on sun-exposed skin. The skin surrounding AKs typically shows evidence of solar damage with deep wrinkling, mottled pigmentation, scattered telangiectases, purpura, or xerosis (Figure). A variety of clinical variants with unique presentations exist, including atrophic, hypertrophic, acantholytic, lichenoid, bowenoid, and pigmented subtypes. Because more than 80% of AKs occur on highly visible areas such as the head, neck, back of the hands, and forearms, AKs can have an obvious detrimental effect on cosmetic appearance. Studies also have shown a strong association between AKs and decreased overall quality of life (QOL).^3,8,9

Patient with numerous actinic keratoses, scattered plaques suspicious for squamous cell carcinoma, and numerous scars from prior squamous cell carcinoma treatments.

Topical Treatments

5-Fluorouracil

5-Fluorouracil (5-FU) is a US Food and Drug Administration (FDA)–approved, topically applied pyrimidine analogue that inhibits thymidylate synthase. The resulting suppression of DNA and RNA synthesis induces cell death with a preference for mitotically active cells.¹⁰ 5-Fluorouracil has been used for more than 
50 years as a treatment of AK and its efficacy is well established. A systematic review of 5 randomized controlled studies of topical 5-FU reported an average of 49% of 423 patients achieving complete lesion clearance with 5-FU cream 5% applied once or twice daily for up to 7 weeks.¹¹ Some notable drawbacks of 5-FU, however, are application-site erythema, blistering, pruritus, necrosis, erosion, and pain. These effects often lead to premature cessation of therapy, but newer formulations of 5-FU cream 0.5% have shown good efficacy with better tolerability.¹² A randomized, double-blind, multicenter, parallel-group study of 177 patients using 5-FU cream 0.5% once daily for either 1, 2, or 4 weeks demonstrated significant (P<.001) efficacy over vehicle gel in all treatment arms.¹³ The most effective therapy was 
4 weeks of treatment, which achieved a mean 91.7% reduction in lesion count as assessed 1 month after cessation of therapy. The primary adverse effect (AE) reported in this trial was mild to moderate facial irritation, which generally resolved within 
18 to 21 days after treatment cessation.¹³ Overall, 5-FU is a highly effective therapy for treating AKs that also can improve signs of photoaging, but patients should be aware of cosmetically unappealing effects that generally occur throughout therapy and during the immediate posttreatment period.¹⁴

Chemical Peels

Chemical peels traditionally employ acidic compounds to strip away outer layers of skin to variable depths depending on the concentration of the agent being applied. For treatment of AK, trichloroacetic acid (TCA) is a commonly employed cauterant that has shown efficacy comparable to topical 5-FU as well as ablative CO₂ laser resurfacing.¹⁵ Trichloroacetic acid peels also are a convenient therapy, as good results can be achieved after a single treatment session. A split-face study of 15 patients treated with either a single application of 35% TCA and Jessner solution or twice-daily application of 5-FU cream 5% for 3 weeks demonstrated a reduction in 75% of visible AKs in both treatment arms over a 1-year follow-up period.¹⁶ Although 80% of patients self-reported considerable cosmetic improvement with both therapies, patient preference was reported to be in favor of the TCA peel, given its quick results and relatively mild side effects as compared to 5-FU. Treatment with chemical peels will result in temporary erythema and mild desquamation that usually resolves within 2 weeks; however, there are cases in which erythema has been reported to persist for several months.¹⁶ Adverse effects such as permanent scarring or pigmentation changes rarely are seen with TCA concentrations less than 45%.¹⁷ Caution should be used in patients with a history of herpes simplex virus, keloids, postinflammatory hyperpigmentation, radiation exposure, immunosuppression, and those unable or unwilling to use sunscreen and avoid sun exposure in the immediate posttreatment period.

Diclofenac Sodium

Diclofenac sodium (DFS) is an FDA-approved topical, nonsteroidal, 
anti-inflammatory drug whose mechanism of action in the treatment of AK is thought to involve inhibition of the cyclooxygenase 2 enzyme.¹⁸ The resulting reduction of prostaglandins is believed to inhibit tumor angiogenesis, induce apoptosis, and inhibit cell differentiation.^19-22 In a multicenter, double-blind, placebo-controlled study of 195 patients, application of DFS 3% in hyaluronan gel 2.5% twice daily for 60 days showed significant (P<.05) efficacy over placebo in achieving complete resolution of target lesions during a 30-day follow-up period (31% vs 10%). Furthermore, qualitative patient assessment of complete global improvement also was significantly (P<.05) higher in the active treatment group as compared to placebo (31% vs 10%).²³ Additional studies of DFS 3% in hyaluronan gel 2.5% applied twice daily for 90 days have shown even higher rates of success, with complete resolution of target lesions in 40% to 58% of cases.^24,25 This therapy also has been reported to substantially improve QOL following treatment completion.²⁶ The most frequently cited AEs include pruritus, rash, dry skin, erythema, and application-site reactions. Overall, DFS is a 
well-tolerated therapy with efficacy comparable to that of 5-FU but with a lower incidence of AEs 
and higher patient satisfaction as determined in 
2 head-to-head studies.^27,28
ImiquimodImiquimod (IMQ) is an FDA-approved topical agent that functions as an immune response modifier via agonism of toll-like receptor 7.¹⁸ The resulting cytokine production and release enhances the innate and acquired immune responses leading to anticancer activity.²⁹ The efficacy of IMQ for treatment of AK has been demonstrated in numerous well-designed clinical trials. A 
meta-analysis of 5 randomized, double-blind trials including 1293 patients treated with IMQ cream 5% 
2 to 3 times per week for 12 to 16 weeks reported complete clearance of AKs in 50% of patients treated with IMQ as compared to 5% of patients treated with vehicle.³⁰ The most frequently reported AEs with this therapy include erythema, scabbing, flaking, and erosion. These effects generally resolve following cessation of treatment, and therapy is considered to be well tolerated; however, there are case reports of IMQ triggering or exacerbating existing inflammatory conditions.³¹ Imiquimod cream also is approved at 2.5% and 3.75% concentrations, which have demonstrated significant (P<.001) efficacy over placebo and a reduced incidence of AEs; complete clearance rates have been reported as 30.6% and 35.6%, respectively.³² Notably, a study comparing 75 patients randomized to either IMQ cream 5% 
3 times per week for 4 weeks, 1 or 2 courses of cryosurgery, or 5-FU ointment 5% twice daily for 4 weeks reported that IMQ achieved significantly (P<.01) superior sustained clearance rates during a 12-month follow-up period over cryosurgery and 5-FU 
(73% vs 4% vs 33%).³³ Additionally, cosmetic outcomes as determined by both participants and investigators were reported as excellent at 12 months posttreatment in more than 80% of participants treated with IMQ. These excellent, long-lasting cosmetic outcomes also were determined to be significantly (P<.0001) superior to the cosmetic outcomes of 5-FU and cryotherapy, which both reported excellent outcomes in less than 10% of cases.³³
Ingenol MebutateIngenol mebutate (IM) is a macrocyclic diterpene ester derived from the Euphorbia peplus plant that is FDA approved for the treatment of AK.¹ Ingenol mebutate’s mechanism of action is thought to involve induction of cell death via disruption of the plasma membrane and mitochondria in addition to production of an inflammatory response, which produces tumor-specific antibodies and a large influx of neutrophils.^34,35 The overall evidence for the efficacy of IM is strong. A combined analysis of 4 multicenter, randomized, double-blind studies of 1005 participants reported that IM gel 0.015% applied once daily for 3 days to the face or scalp was significantly superior (P<.001) to placebo in achieving complete clearance as assessed 54 days after completion of therapy (42.2% vs 3.7%) and that IM gel 0.05% applied once daily for 2 days to the trunk or extremities also was significantly superior (P<.001) to placebo in achieving complete clearance as determined 55 days after completion of therapy (34.1% vs 4.7%).³⁶ A follow-up report to this study indicated that IM also appears to achieve long-lasting effects with an overall 87% decrease in total AKs at 12 months follow-up in both trial groups.³⁷ Additionally, it has been recently reported that treatment with IM in these trials was associated with significantly higher overall treatment satisfaction (P<.001) and improved QOL (P<.001) as compared to vehicle.³⁸ Cosmetic outcomes of IM therapy have been assessed in a trial analyzing the efficacy of IM gel 0.025% for 3 days or IM gel 0.05% for 2 or 3 days on nonfacial AKs. This study reported significantly (P<.0001) higher patient satisfaction with the cosmetic outcome at 8 weeks after therapy as compared to vehicle.³⁴ Studies performed in mice have demonstrated that IM is able to promote collagen matrix turnover and impose dermal elasticity, which may contribute to these good cosmetic outcomes.³⁹ The most common AEs of IM therapy are erythema, crusting, and flaking; these effects generally occur 3 to 8 days after starting treatment. These effects, however, generally are short lived and resolve within 2 weeks of treatment cessation when IM is applied to the face or scalp or 4 weeks when applied to the trunk or extremities.⁴⁰ Overall, IM is a useful therapeutic option given its relatively short treatment course as compared to other topically applied agents, as well as its lasting efficacy, mild AEs, and good cosmetic outcomes.

Procedural Modalities

Surgical Procedures

Surgical approaches for the treatment of AK include excision, curettage with or without electrodesiccation, and dermabrasion. In the past, these modalities were used with greater frequency, but the advent of effective topical medications with lower risks of AEs has largely reduced their use.⁴¹ Excision may still be indicated in cases where SCC is suspected, and curettage can be used for treatment of thicker hypertrophic AKs.⁴² Although these approaches have not been evaluated in clinical trials, they are generally effective but require the use of local anesthetics and come with substantial risk for infection, permanent scarring, and hypopigmentation. Dermabrasion employs the use of a motorized device equipped with an abrasive material to physically remove superficial layers of the skin. Studies are limited, but this method has been reported as an effective treatment in a retrospective review of 23 participants in which 96% remained free of AKs at 1 year, 83% at 2 years, 64% at 4 years, and 54% at 5 years posttherapy.⁴³ Notably, one split-face study of 40 participants treated with dermabrasion followed by 25% TCA on one side and either Jessner solution and 35% TCA or dermabrasion alone on the other side reported that the combination of dermabrasion with 25% TCA consistently produced excellent cosmetic results with nearly complete eradication of AKs.⁴⁴ In general, however, cosmetic outcomes with dermabrasion are variable, as the technique is highly operator dependent and treatment is associated with notable discomfort as well as risk for scarring and permanent pigmentation alteration.

Cryotherapy

Cryotherapy remains one of the most commonly utilized treatments of AK and involves the delivery of liquid nitrogen via a spray device or a cotton tip applicator to rapidly freeze cells, thus causing cellular destruction via ice crystal formation and protein denaturation.⁴⁵ Efficacy with this technique has been reported to be as high as 98.8% at 12 months follow-up, but more recent studies cite lower rates of success.⁴⁶ A prospective multicenter study of 90 participants with 421 AKs on the face or scalp treated with a single freeze-thaw cycle of liquid nitrogen reported an overall complete response rate of 67.2% at 3 months posttherapy. Additionally, higher complete response rates were associated with longer freeze times, and cosmetic outcomes were reported as good to excellent in 94% of complete response lesions.⁴⁷ Similar results were reported in an open-label, prospective, randomized, controlled clinical trial of 200 participants with 
543 AKs, which compared a single freeze-thaw cycle with liquid nitrogen to a single session of CO₂ laser ablation in the treatment of isolated AKs of the face and scalp.⁴⁸ At 3 months posttherapy, complete clearance was observed in 71.6% of participants treated with cryotherapy and in 65.3% of participants treated with laser ablation (P=.532). At 
12 months posttherapy, participants who originally showed complete response at 3 months were assessed for relapse. Complete clearance was preserved in 72.6% of participants treated with cryotherapy versus 21.9% of participants treated with laser ablation (P<.0001), and cosmetic outcomes were reported by participants as good or excellent at 3 months follow-up in more than 93% of participants for both treatment arms.⁴⁸ Possible AEs of cryotherapy include pain during treatment, blister formation with possible hemorrhage, infection, scarring, and permanent pigmentary changes.^47,48 Notably, the risk for hypopigmentation increases with longer freezing times, thus requiring clinicians to consider the balance between improved efficacy and reduced cosmetic outcomes.⁴⁷

Light-Based Therapies

Laser Therapy

Ablative laser resurfacing with either the CO₂ or erbium-doped:YAG (Er:YAG) laser utilizes light of specific wavelengths to selectively induce thermolysis and destruction of the epidermal layer. Both lasers have been studied as treatments of AK, but there is a lack of large, well-designed studies. In one small study of 14 participants treated with 
1 to 2 passes of the CO₂ laser, complete clearance was reported in all cases without any recurrences during a follow-up period of 6 to 24 months. Additionally, all participants in this study reported satisfaction with the cosmetic outcome.⁴⁹ The CO₂ laser also has demonstrated efficacy comparable to that of the TCA peel and 5-FU therapy in a prospective randomized trial of 34 patients with facial or scalp AKs who received either CO₂ laser with 2 passes, 30% TCA peel, or 5-FU cream 5% twice daily for 
3 weeks.¹⁵ Reduction in mean AK counts at 3 months posttherapy was significantly (P<.03) higher in all treatment arms as compared to the control group (92% for CO₂ laser, 89% for TCA peel, and 83% for 5-FU cream). No significant (P=.31) difference in outcomes was noted among the different treatment arms.¹⁵ Similar results were reported for the Er:YAG laser in a small prospective study of 5 participants treated with 2 to 3 passes with the Er:YAG laser in which reduction in mean AK counts was reported as ranging from 86% to 96% at 3 months posttherapy.⁵⁰ The Er:YAG laser in combination with the CO₂ laser has shown notable long-term efficacy in achieving higher lesion clearance rates and sustained complete clearance rates over treatment with topical 5-FU.⁵¹ In a prospective randomized study of 55 par-ticipants with multiple AKs on the face or scalp, participants were assigned to receive either combination laser ablation with the Er:YAG and CO₂ lasers down to the level of the papillary dermis or 
5-FU cream 5% applied twice daily for 2 to 7 weeks until an appropriate clinical inflammatory response was achieved. At 12 months follow-up, the laser treatment group achieved significantly (P=.048) higher mean lesion clearance rates (91.1%) as compared to the 5-FU arm (76.6%) and significantly (P=.003) higher sustained complete clearance rates (59.3%) as compared to 5-FU (29.2%). The proportion of participants with an improvement in photoaging score at 12 months follow-up approached statistical significance (P=.07), with 74% of the laser-treated group showing improvement as compared to 43% of the 5-FU–treated group. Long-term, cosmetically unappealing side effects such as erythema and hypopigmentation occurred notably more often in the laser-treated group as compared to the 5-FU group.⁵¹ In summary, ablative lasers appear to be a highly effective therapy for AK but at the cost of increased risk for AEs such as permanent pigmentary changes, prolonged erythema lasting up to several months, and scarring.^50,52-55

Fractional photothermolysis is a relatively new advancement in the field of laser therapy that has received FDA approval for the treatment of AK.⁵⁶ This treatment works by creating multiple noncontiguous microscopic columns of thermal injury while sparing adjacent zones of viable tissue.⁵⁷ Although there are limited studies involving the use of such lasers in the treatment of AK, initial findings suggest that 1927-nm thulium lasers may be more effective than 1550-nm erbium lasers in achieving lesion clearance. A trial of 14 participants who received 5 laser treatments with a 1550-nm fractionated erbium-doped fiber laser reported an average reduction in AK counts of 66.2% at 3 months follow-up and a 55.6% reduction at 6 months follow-up. A participant-determined marked or very significant improvement of lesions was reported in 83% of participants at 1 month posttreatment but only in 44% of participants at 6 months posttreatment.⁵⁸ A similar trial of 24 participants treated with up to 4 treatment sessions of the fractionated 1927-nm thulium laser reported an 87.3% reduction in number of AKs at 3 months follow-up and an 86.6% reduction at 
6 months follow-up.⁵⁶ The primary advantage of fractional laser therapy is a faster recovery period generally lasting only 2 or 3 days as compared to 
2 weeks or more with traditional ablative lasers, thus limiting the amount of time a patient must tolerate cosmetically unappealing erythema.^59,60 The quick recovery time has been attributed to the fractional laser’s ability to preserve the stratum corneum and skin barrier, which also helps reduce the risk for other AEs such as scarring and infection.^56,59-61 Additional studies are needed to better assess the true efficacy of fractional laser therapy, but treatment with the fractional 1927-nm thulium laser appears to be a promising and well-tolerated therapeutic option for treatment of AK with similar efficacy to traditional ablative lasers but with a lower risk of AEs.

Photodynamic TherapyPhotodynamic therapy (PDT) is an FDA-approved treatment that involves the use of a topical photosensitizing agent such as 5-aminolevulinic acid (ALA) or methyl aminovulinate (MAL) before exposure to an activating light source to generate reactive oxygen species that lead to cell death.^62-65 Multiple PDT regimens with varying combinations of photosensitizers, incubation time, and light sources have been studied, but a 
2012 Cochrane review determined that treatment with conventional formulations of MAL and ALA with either blue- or red-light PDT were similarly efficacious for treatment of individual AKs as compared to vehicle with blue- or red-light PDT. One exception was that longer incubation time (ie, 4 hours) with ALA resulted in better results than shorter incubation times (ie, 0.5, 1, 2 hours) with ALA.⁶⁶

Standard PDT treatment with MAL also has consistently demonstrated superior efficacy in achieving complete clearance rates in addition to superior cosmetic outcomes over treatment with either cryotherapy, DFS, or 5-FU.^67-73 Three studies in particular noted an excellent or good investigator-determined cosmetic outcome in 96% to 98% of participants treated with MAL-PDT.^69,71,74 Photodynamic therapy with ALA also has been reported as superior over CO2 laser ablation for AK reduction as well as both patient and investigator overall satisfaction.⁷⁵

More recently, several methods of improving photosensitizer delivery have been studied, which have demonstrated remarkable efficacy at achieving lesion clearance over standard cream formulations or application routines. One such method involves the use of gentle heating to increase photosensitizer uptake. In a split-extremity study of 20 participants who were treated with 20% ALA under occlusion for 1 hour with one side heated to 38.8°C, the heated side demonstrated significant (P<.0001) efficacy at achieving higher median clearance rates over control when evaluated at 2 and 6 months posttherapy.⁷⁶ Notably, occlusion of ALA in itself during the incubation period also has been demonstrated to significantly (P<.0001) improve clearance rates.⁷⁷ Another method involves the use of a new nanoemulsion-based formulation of 
ALA gel, known as BF-200 ALA, which has demonstrated remarkable efficacy over standard 
MAL cream and placebo in a long-term follow-up 
analysis of 2 prospective, randomized, controlled trials.⁷⁸ In a similar vein, 3 prospective randomized trials with a minimum follow-up time of 3 months demonstrated that MAL-PDT in combination with fractional ablative laser pretreatment has significant (P<.02 in all trials) efficacy over MAL-PDT without pretreatment in achieving complete AK clearance. Although the cosmetic outcomes were good or excellent in 87% to 100% of patients, they were not significantly different from stand-alone 
MAL-PDT treatment in any of the trials.^79-81 However, pretreatment with microneedling in MAL-PDT has been shown to achieve superior cosmetic outcomes over 
MAL-PDT without microneedling, according to one small split-face study of 10 participants.⁸²

Overall, PDT is an excellent therapeutic option that is able to provide efficacious clearance of AKs as well as superior cosmetic outcomes. Common AEs of PDT include burning, itching, and stinging during therapy, but pain intensity decreases dramatically upon termination of illumination, with cessation of most symptoms by 12 hours posttherapy.⁷³ Permanent pigmentation changes have been reported to occasionally occur following PDT therapy.⁸¹

Conclusion

When determining which therapy to use in a patient, clinicians must take into account a variety of factors such as patient preference, cost of treatment, availability, tolerance for AEs, and the need for field therapy. Although all therapies discussed within this article are effective and reasonable treatment choices, patients who are particularly concerned about cosmetic outcomes would most likely benefit from either IMQ or PDT, as the data for cosmetic outcomes with these therapies are the strongest. Combination or sequential treatments may be required in some cases and all patients should be monitored for lesion recurrence regardless of treatment choice. A summary of the therapies and key studies discussed here is available in the PDF.

Actinic keratosis (AK), also referred to as solar keratosis or senile keratosis, is an intraepidermal proliferation of dysplastic keratinocytes that develops in response to chronic exposure to UV radiation. Actinic keratoses are among the most commonly encountered lesions seen by dermatologists, and it has been estimated that 60% of predisposed individuals older than 40 years have at least one AK.^1,2 Prevalence is notably higher in light-skinned individuals and increases with age, presumably from higher cumulative sun exposure and decreased effectiveness of the immune system.^1,3 It remains a point of contention as to whether or not AKs actually represent squamous cell carcinoma (SCC) in situ, but the potential for progression to invasive disease has been well demonstrated, as the majority of SCCs develop from preexisting AKs.^4-6 The risk for progression to invasive disease for an individual AK has been estimated to range from 0.025% to 16% per year, with an average of approximately 8% in immunocompetent patients.⁷

The clinical morphology of AK can vary widely, but the most common presentation is an erythematous scaly macule, papule, or plaque on sun-exposed skin. The skin surrounding AKs typically shows evidence of solar damage with deep wrinkling, mottled pigmentation, scattered telangiectases, purpura, or xerosis (Figure). A variety of clinical variants with unique presentations exist, including atrophic, hypertrophic, acantholytic, lichenoid, bowenoid, and pigmented subtypes. Because more than 80% of AKs occur on highly visible areas such as the head, neck, back of the hands, and forearms, AKs can have an obvious detrimental effect on cosmetic appearance. Studies also have shown a strong association between AKs and decreased overall quality of life (QOL).^3,8,9

Patient with numerous actinic keratoses, scattered plaques suspicious for squamous cell carcinoma, and numerous scars from prior squamous cell carcinoma treatments.

Topical Treatments

5-Fluorouracil

5-Fluorouracil (5-FU) is a US Food and Drug Administration (FDA)–approved, topically applied pyrimidine analogue that inhibits thymidylate synthase. The resulting suppression of DNA and RNA synthesis induces cell death with a preference for mitotically active cells.¹⁰ 5-Fluorouracil has been used for more than 
50 years as a treatment of AK and its efficacy is well established. A systematic review of 5 randomized controlled studies of topical 5-FU reported an average of 49% of 423 patients achieving complete lesion clearance with 5-FU cream 5% applied once or twice daily for up to 7 weeks.¹¹ Some notable drawbacks of 5-FU, however, are application-site erythema, blistering, pruritus, necrosis, erosion, and pain. These effects often lead to premature cessation of therapy, but newer formulations of 5-FU cream 0.5% have shown good efficacy with better tolerability.¹² A randomized, double-blind, multicenter, parallel-group study of 177 patients using 5-FU cream 0.5% once daily for either 1, 2, or 4 weeks demonstrated significant (P<.001) efficacy over vehicle gel in all treatment arms.¹³ The most effective therapy was 
4 weeks of treatment, which achieved a mean 91.7% reduction in lesion count as assessed 1 month after cessation of therapy. The primary adverse effect (AE) reported in this trial was mild to moderate facial irritation, which generally resolved within 
18 to 21 days after treatment cessation.¹³ Overall, 5-FU is a highly effective therapy for treating AKs that also can improve signs of photoaging, but patients should be aware of cosmetically unappealing effects that generally occur throughout therapy and during the immediate posttreatment period.¹⁴

Chemical Peels

Chemical peels traditionally employ acidic compounds to strip away outer layers of skin to variable depths depending on the concentration of the agent being applied. For treatment of AK, trichloroacetic acid (TCA) is a commonly employed cauterant that has shown efficacy comparable to topical 5-FU as well as ablative CO₂ laser resurfacing.¹⁵ Trichloroacetic acid peels also are a convenient therapy, as good results can be achieved after a single treatment session. A split-face study of 15 patients treated with either a single application of 35% TCA and Jessner solution or twice-daily application of 5-FU cream 5% for 3 weeks demonstrated a reduction in 75% of visible AKs in both treatment arms over a 1-year follow-up period.¹⁶ Although 80% of patients self-reported considerable cosmetic improvement with both therapies, patient preference was reported to be in favor of the TCA peel, given its quick results and relatively mild side effects as compared to 5-FU. Treatment with chemical peels will result in temporary erythema and mild desquamation that usually resolves within 2 weeks; however, there are cases in which erythema has been reported to persist for several months.¹⁶ Adverse effects such as permanent scarring or pigmentation changes rarely are seen with TCA concentrations less than 45%.¹⁷ Caution should be used in patients with a history of herpes simplex virus, keloids, postinflammatory hyperpigmentation, radiation exposure, immunosuppression, and those unable or unwilling to use sunscreen and avoid sun exposure in the immediate posttreatment period.

Diclofenac Sodium

Diclofenac sodium (DFS) is an FDA-approved topical, nonsteroidal, 
anti-inflammatory drug whose mechanism of action in the treatment of AK is thought to involve inhibition of the cyclooxygenase 2 enzyme.¹⁸ The resulting reduction of prostaglandins is believed to inhibit tumor angiogenesis, induce apoptosis, and inhibit cell differentiation.^19-22 In a multicenter, double-blind, placebo-controlled study of 195 patients, application of DFS 3% in hyaluronan gel 2.5% twice daily for 60 days showed significant (P<.05) efficacy over placebo in achieving complete resolution of target lesions during a 30-day follow-up period (31% vs 10%). Furthermore, qualitative patient assessment of complete global improvement also was significantly (P<.05) higher in the active treatment group as compared to placebo (31% vs 10%).²³ Additional studies of DFS 3% in hyaluronan gel 2.5% applied twice daily for 90 days have shown even higher rates of success, with complete resolution of target lesions in 40% to 58% of cases.^24,25 This therapy also has been reported to substantially improve QOL following treatment completion.²⁶ The most frequently cited AEs include pruritus, rash, dry skin, erythema, and application-site reactions. Overall, DFS is a 
well-tolerated therapy with efficacy comparable to that of 5-FU but with a lower incidence of AEs 
and higher patient satisfaction as determined in 
2 head-to-head studies.^27,28
ImiquimodImiquimod (IMQ) is an FDA-approved topical agent that functions as an immune response modifier via agonism of toll-like receptor 7.¹⁸ The resulting cytokine production and release enhances the innate and acquired immune responses leading to anticancer activity.²⁹ The efficacy of IMQ for treatment of AK has been demonstrated in numerous well-designed clinical trials. A 
meta-analysis of 5 randomized, double-blind trials including 1293 patients treated with IMQ cream 5% 
2 to 3 times per week for 12 to 16 weeks reported complete clearance of AKs in 50% of patients treated with IMQ as compared to 5% of patients treated with vehicle.³⁰ The most frequently reported AEs with this therapy include erythema, scabbing, flaking, and erosion. These effects generally resolve following cessation of treatment, and therapy is considered to be well tolerated; however, there are case reports of IMQ triggering or exacerbating existing inflammatory conditions.³¹ Imiquimod cream also is approved at 2.5% and 3.75% concentrations, which have demonstrated significant (P<.001) efficacy over placebo and a reduced incidence of AEs; complete clearance rates have been reported as 30.6% and 35.6%, respectively.³² Notably, a study comparing 75 patients randomized to either IMQ cream 5% 
3 times per week for 4 weeks, 1 or 2 courses of cryosurgery, or 5-FU ointment 5% twice daily for 4 weeks reported that IMQ achieved significantly (P<.01) superior sustained clearance rates during a 12-month follow-up period over cryosurgery and 5-FU 
(73% vs 4% vs 33%).³³ Additionally, cosmetic outcomes as determined by both participants and investigators were reported as excellent at 12 months posttreatment in more than 80% of participants treated with IMQ. These excellent, long-lasting cosmetic outcomes also were determined to be significantly (P<.0001) superior to the cosmetic outcomes of 5-FU and cryotherapy, which both reported excellent outcomes in less than 10% of cases.³³
Ingenol MebutateIngenol mebutate (IM) is a macrocyclic diterpene ester derived from the Euphorbia peplus plant that is FDA approved for the treatment of AK.¹ Ingenol mebutate’s mechanism of action is thought to involve induction of cell death via disruption of the plasma membrane and mitochondria in addition to production of an inflammatory response, which produces tumor-specific antibodies and a large influx of neutrophils.^34,35 The overall evidence for the efficacy of IM is strong. A combined analysis of 4 multicenter, randomized, double-blind studies of 1005 participants reported that IM gel 0.015% applied once daily for 3 days to the face or scalp was significantly superior (P<.001) to placebo in achieving complete clearance as assessed 54 days after completion of therapy (42.2% vs 3.7%) and that IM gel 0.05% applied once daily for 2 days to the trunk or extremities also was significantly superior (P<.001) to placebo in achieving complete clearance as determined 55 days after completion of therapy (34.1% vs 4.7%).³⁶ A follow-up report to this study indicated that IM also appears to achieve long-lasting effects with an overall 87% decrease in total AKs at 12 months follow-up in both trial groups.³⁷ Additionally, it has been recently reported that treatment with IM in these trials was associated with significantly higher overall treatment satisfaction (P<.001) and improved QOL (P<.001) as compared to vehicle.³⁸ Cosmetic outcomes of IM therapy have been assessed in a trial analyzing the efficacy of IM gel 0.025% for 3 days or IM gel 0.05% for 2 or 3 days on nonfacial AKs. This study reported significantly (P<.0001) higher patient satisfaction with the cosmetic outcome at 8 weeks after therapy as compared to vehicle.³⁴ Studies performed in mice have demonstrated that IM is able to promote collagen matrix turnover and impose dermal elasticity, which may contribute to these good cosmetic outcomes.³⁹ The most common AEs of IM therapy are erythema, crusting, and flaking; these effects generally occur 3 to 8 days after starting treatment. These effects, however, generally are short lived and resolve within 2 weeks of treatment cessation when IM is applied to the face or scalp or 4 weeks when applied to the trunk or extremities.⁴⁰ Overall, IM is a useful therapeutic option given its relatively short treatment course as compared to other topically applied agents, as well as its lasting efficacy, mild AEs, and good cosmetic outcomes.

Procedural Modalities

Surgical Procedures

Surgical approaches for the treatment of AK include excision, curettage with or without electrodesiccation, and dermabrasion. In the past, these modalities were used with greater frequency, but the advent of effective topical medications with lower risks of AEs has largely reduced their use.⁴¹ Excision may still be indicated in cases where SCC is suspected, and curettage can be used for treatment of thicker hypertrophic AKs.⁴² Although these approaches have not been evaluated in clinical trials, they are generally effective but require the use of local anesthetics and come with substantial risk for infection, permanent scarring, and hypopigmentation. Dermabrasion employs the use of a motorized device equipped with an abrasive material to physically remove superficial layers of the skin. Studies are limited, but this method has been reported as an effective treatment in a retrospective review of 23 participants in which 96% remained free of AKs at 1 year, 83% at 2 years, 64% at 4 years, and 54% at 5 years posttherapy.⁴³ Notably, one split-face study of 40 participants treated with dermabrasion followed by 25% TCA on one side and either Jessner solution and 35% TCA or dermabrasion alone on the other side reported that the combination of dermabrasion with 25% TCA consistently produced excellent cosmetic results with nearly complete eradication of AKs.⁴⁴ In general, however, cosmetic outcomes with dermabrasion are variable, as the technique is highly operator dependent and treatment is associated with notable discomfort as well as risk for scarring and permanent pigmentation alteration.

Cryotherapy

Cryotherapy remains one of the most commonly utilized treatments of AK and involves the delivery of liquid nitrogen via a spray device or a cotton tip applicator to rapidly freeze cells, thus causing cellular destruction via ice crystal formation and protein denaturation.⁴⁵ Efficacy with this technique has been reported to be as high as 98.8% at 12 months follow-up, but more recent studies cite lower rates of success.⁴⁶ A prospective multicenter study of 90 participants with 421 AKs on the face or scalp treated with a single freeze-thaw cycle of liquid nitrogen reported an overall complete response rate of 67.2% at 3 months posttherapy. Additionally, higher complete response rates were associated with longer freeze times, and cosmetic outcomes were reported as good to excellent in 94% of complete response lesions.⁴⁷ Similar results were reported in an open-label, prospective, randomized, controlled clinical trial of 200 participants with 
543 AKs, which compared a single freeze-thaw cycle with liquid nitrogen to a single session of CO₂ laser ablation in the treatment of isolated AKs of the face and scalp.⁴⁸ At 3 months posttherapy, complete clearance was observed in 71.6% of participants treated with cryotherapy and in 65.3% of participants treated with laser ablation (P=.532). At 
12 months posttherapy, participants who originally showed complete response at 3 months were assessed for relapse. Complete clearance was preserved in 72.6% of participants treated with cryotherapy versus 21.9% of participants treated with laser ablation (P<.0001), and cosmetic outcomes were reported by participants as good or excellent at 3 months follow-up in more than 93% of participants for both treatment arms.⁴⁸ Possible AEs of cryotherapy include pain during treatment, blister formation with possible hemorrhage, infection, scarring, and permanent pigmentary changes.^47,48 Notably, the risk for hypopigmentation increases with longer freezing times, thus requiring clinicians to consider the balance between improved efficacy and reduced cosmetic outcomes.⁴⁷

Light-Based Therapies

Laser Therapy

Ablative laser resurfacing with either the CO₂ or erbium-doped:YAG (Er:YAG) laser utilizes light of specific wavelengths to selectively induce thermolysis and destruction of the epidermal layer. Both lasers have been studied as treatments of AK, but there is a lack of large, well-designed studies. In one small study of 14 participants treated with 
1 to 2 passes of the CO₂ laser, complete clearance was reported in all cases without any recurrences during a follow-up period of 6 to 24 months. Additionally, all participants in this study reported satisfaction with the cosmetic outcome.⁴⁹ The CO₂ laser also has demonstrated efficacy comparable to that of the TCA peel and 5-FU therapy in a prospective randomized trial of 34 patients with facial or scalp AKs who received either CO₂ laser with 2 passes, 30% TCA peel, or 5-FU cream 5% twice daily for 
3 weeks.¹⁵ Reduction in mean AK counts at 3 months posttherapy was significantly (P<.03) higher in all treatment arms as compared to the control group (92% for CO₂ laser, 89% for TCA peel, and 83% for 5-FU cream). No significant (P=.31) difference in outcomes was noted among the different treatment arms.¹⁵ Similar results were reported for the Er:YAG laser in a small prospective study of 5 participants treated with 2 to 3 passes with the Er:YAG laser in which reduction in mean AK counts was reported as ranging from 86% to 96% at 3 months posttherapy.⁵⁰ The Er:YAG laser in combination with the CO₂ laser has shown notable long-term efficacy in achieving higher lesion clearance rates and sustained complete clearance rates over treatment with topical 5-FU.⁵¹ In a prospective randomized study of 55 par-ticipants with multiple AKs on the face or scalp, participants were assigned to receive either combination laser ablation with the Er:YAG and CO₂ lasers down to the level of the papillary dermis or 
5-FU cream 5% applied twice daily for 2 to 7 weeks until an appropriate clinical inflammatory response was achieved. At 12 months follow-up, the laser treatment group achieved significantly (P=.048) higher mean lesion clearance rates (91.1%) as compared to the 5-FU arm (76.6%) and significantly (P=.003) higher sustained complete clearance rates (59.3%) as compared to 5-FU (29.2%). The proportion of participants with an improvement in photoaging score at 12 months follow-up approached statistical significance (P=.07), with 74% of the laser-treated group showing improvement as compared to 43% of the 5-FU–treated group. Long-term, cosmetically unappealing side effects such as erythema and hypopigmentation occurred notably more often in the laser-treated group as compared to the 5-FU group.⁵¹ In summary, ablative lasers appear to be a highly effective therapy for AK but at the cost of increased risk for AEs such as permanent pigmentary changes, prolonged erythema lasting up to several months, and scarring.^50,52-55

Fractional photothermolysis is a relatively new advancement in the field of laser therapy that has received FDA approval for the treatment of AK.⁵⁶ This treatment works by creating multiple noncontiguous microscopic columns of thermal injury while sparing adjacent zones of viable tissue.⁵⁷ Although there are limited studies involving the use of such lasers in the treatment of AK, initial findings suggest that 1927-nm thulium lasers may be more effective than 1550-nm erbium lasers in achieving lesion clearance. A trial of 14 participants who received 5 laser treatments with a 1550-nm fractionated erbium-doped fiber laser reported an average reduction in AK counts of 66.2% at 3 months follow-up and a 55.6% reduction at 6 months follow-up. A participant-determined marked or very significant improvement of lesions was reported in 83% of participants at 1 month posttreatment but only in 44% of participants at 6 months posttreatment.⁵⁸ A similar trial of 24 participants treated with up to 4 treatment sessions of the fractionated 1927-nm thulium laser reported an 87.3% reduction in number of AKs at 3 months follow-up and an 86.6% reduction at 
6 months follow-up.⁵⁶ The primary advantage of fractional laser therapy is a faster recovery period generally lasting only 2 or 3 days as compared to 
2 weeks or more with traditional ablative lasers, thus limiting the amount of time a patient must tolerate cosmetically unappealing erythema.^59,60 The quick recovery time has been attributed to the fractional laser’s ability to preserve the stratum corneum and skin barrier, which also helps reduce the risk for other AEs such as scarring and infection.^56,59-61 Additional studies are needed to better assess the true efficacy of fractional laser therapy, but treatment with the fractional 1927-nm thulium laser appears to be a promising and well-tolerated therapeutic option for treatment of AK with similar efficacy to traditional ablative lasers but with a lower risk of AEs.

Photodynamic TherapyPhotodynamic therapy (PDT) is an FDA-approved treatment that involves the use of a topical photosensitizing agent such as 5-aminolevulinic acid (ALA) or methyl aminovulinate (MAL) before exposure to an activating light source to generate reactive oxygen species that lead to cell death.^62-65 Multiple PDT regimens with varying combinations of photosensitizers, incubation time, and light sources have been studied, but a 
2012 Cochrane review determined that treatment with conventional formulations of MAL and ALA with either blue- or red-light PDT were similarly efficacious for treatment of individual AKs as compared to vehicle with blue- or red-light PDT. One exception was that longer incubation time (ie, 4 hours) with ALA resulted in better results than shorter incubation times (ie, 0.5, 1, 2 hours) with ALA.⁶⁶

Standard PDT treatment with MAL also has consistently demonstrated superior efficacy in achieving complete clearance rates in addition to superior cosmetic outcomes over treatment with either cryotherapy, DFS, or 5-FU.^67-73 Three studies in particular noted an excellent or good investigator-determined cosmetic outcome in 96% to 98% of participants treated with MAL-PDT.^69,71,74 Photodynamic therapy with ALA also has been reported as superior over CO2 laser ablation for AK reduction as well as both patient and investigator overall satisfaction.⁷⁵

More recently, several methods of improving photosensitizer delivery have been studied, which have demonstrated remarkable efficacy at achieving lesion clearance over standard cream formulations or application routines. One such method involves the use of gentle heating to increase photosensitizer uptake. In a split-extremity study of 20 participants who were treated with 20% ALA under occlusion for 1 hour with one side heated to 38.8°C, the heated side demonstrated significant (P<.0001) efficacy at achieving higher median clearance rates over control when evaluated at 2 and 6 months posttherapy.⁷⁶ Notably, occlusion of ALA in itself during the incubation period also has been demonstrated to significantly (P<.0001) improve clearance rates.⁷⁷ Another method involves the use of a new nanoemulsion-based formulation of 
ALA gel, known as BF-200 ALA, which has demonstrated remarkable efficacy over standard 
MAL cream and placebo in a long-term follow-up 
analysis of 2 prospective, randomized, controlled trials.⁷⁸ In a similar vein, 3 prospective randomized trials with a minimum follow-up time of 3 months demonstrated that MAL-PDT in combination with fractional ablative laser pretreatment has significant (P<.02 in all trials) efficacy over MAL-PDT without pretreatment in achieving complete AK clearance. Although the cosmetic outcomes were good or excellent in 87% to 100% of patients, they were not significantly different from stand-alone 
MAL-PDT treatment in any of the trials.^79-81 However, pretreatment with microneedling in MAL-PDT has been shown to achieve superior cosmetic outcomes over 
MAL-PDT without microneedling, according to one small split-face study of 10 participants.⁸²

Overall, PDT is an excellent therapeutic option that is able to provide efficacious clearance of AKs as well as superior cosmetic outcomes. Common AEs of PDT include burning, itching, and stinging during therapy, but pain intensity decreases dramatically upon termination of illumination, with cessation of most symptoms by 12 hours posttherapy.⁷³ Permanent pigmentation changes have been reported to occasionally occur following PDT therapy.⁸¹

Conclusion

When determining which therapy to use in a patient, clinicians must take into account a variety of factors such as patient preference, cost of treatment, availability, tolerance for AEs, and the need for field therapy. Although all therapies discussed within this article are effective and reasonable treatment choices, patients who are particularly concerned about cosmetic outcomes would most likely benefit from either IMQ or PDT, as the data for cosmetic outcomes with these therapies are the strongest. Combination or sequential treatments may be required in some cases and all patients should be monitored for lesion recurrence regardless of treatment choice. A summary of the therapies and key studies discussed here is available in the PDF.

Medically Unlikely Edits (MUEs) are benchmarks recognized by the Centers for Medicare & Medicaid Services (CMS) that are designed to prevent incorrect or excessive coding. Specifically, an MUE is an edit that tests medical claims for services billed in excess of the maximum number of units of service permitted for a single beneficiary on the same date of service from the same provider (eg, multiples of the same Healthcare Common Procedure Coding System [HCPCS] code listed on different claim lines).¹

The MUE System

If the number of units of service billed by the same physician for the same patient on the same day exceeds the maximum number permitted by the CMS, the Medicare Administrative Contractor (MAC) will deny the code or return the claim to the provider for correction (return to provider [RTP]). Units of service billed in excess of the MUE will not be paid, but other services billed on the same claim form may still be paid. In the case of an MUE-associated RTP, the provider should resubmit a corrected claim, not an appeal; however, an appeal is possible in the case of an MUE-associated denial. An MUE-associated denial is a coding denial, not a medical necessity denial; therefore, the provider cannot use an Advance Beneficiary Notice to transfer liability for claim payment to the patient.

MUE Adjudication Indicators

In 2013, the CMS modified the MUE process to include 3 different MUE adjudication indicators (MAIs) with a value of 1, 2, or 3 so that some MUE values would be date of service edits rather than claim line edits.² Medically Unlikely Edits for HCPCS codes with an MAI of 1 are identical to the prior claim line edits. If a provider needs to report excess units of service with an MAI of 1, appropriate modifiers should be used to report them on separate lines of a claim. Current Procedural Terminology (CPT) modifiers such as -76 (repeat procedure or service by the same physician) and -91 (repeat clinical diagnostic laboratory test) as well as anatomic modifiers (eg, RT, LT, F1, F2) may be used, with modifier -59 (distinct procedural service) used only if no other modifier suffices. An example of an 
MUE with an MAI of 1 is CPT code 17264 (destruction, malignant lesion [eg, laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement], trunk, arms or legs; lesion 
diameter 3.1–4.0 cm), for which the MUE threshold is 3, meaning no more than 3 destructions can be submitted per claim line without triggering an 
edit-based rejection or RTP.

An MAI of 2 denotes absolute date of service edits, or so-called “per day edits based on policy.” Such edits are in place because units of service billed in excess of the MUE value on the same date of service are considered to be impossible by the CMS based on regulatory guidance or anatomic considerations.² For instance, although the same physician may destroy multiple actinic keratoses in a single patient on the same date of service, it would not be possible to code more than one unit of service as 
CPT code 17000, which specifically and exclusively 
refers to the first lesion destroyed. Similarly, 
CPT code 13101 (repair, complex, trunk; lesion diameter 2.6–7.5 cm) could only be reported once that day, as all complex repairs at that anatomic site must be summed and smaller or larger totals would be reported with another code.

Anatomic limitations are sometimes obvious and do not require specific coding rules. For example, only 1 gallbladder can be removed per patient. Although Qualified Independent Contractors and Administrative Law Judges are not bound by MAIs, they do give particular deference to an MAI of 
2 given its definitive nature.² Because ambulatory surgical center providers (Medicare specialty code 49) cannot report modifier -50 for bilateral 
procedures, the MUE value used for editing is doubled for HCPCS codes with an MAI of 2 or 3 if the bilateral surgery indicator for the HCPCS code is 1.³

An MAI of 3 describes less strict date of service edits, so-called “per day edits based on clinical benchmarks.”² Similar to MAIs of 1, MUEs for MAIs of 3 are based on medically likely daily frequencies of services provided in most settings. To determine if an MUE with an MAI of 3 has been reached, the MAC sums the units of service billed on all claim lines of the current claim as well as all prior paid claims for the same patient billed by the same provider on the same date of service. If the total units of service obtained in this manner exceeds the MUE value, then all claim lines with the relevant code for the current claim will be denied, but prior paid claims will not be adjusted. Denials based on MUEs for codes with an MAI of 3 can be appealed to the local MAC. Successful appeals require documentation that the units of service in excess of the MUE value were actually delivered and demonstration of medical necessity.² An example of a CPT code with an MAI of 3 is 40490 (biopsy of lip) for which the MUE value is 3.

Complications With MUE and MAI

Because MUEs are based on current coding guidelines as well as current clinical practice, they are only applicable for the time period in which they are in effect. A change made to an MUE value for a particular code is not retroactive; however, in exceptional circumstances when a retroactive effective date is applied, MACs are not directed to examine prior claims but only “claims that are brought to their attention.”²

It also is important to realize that not all 
MUEs are publicly available and many are confidential. When claim denials occur, particularly in the context of multiple units of a particular code, 
automated MUE edits should be among the issues that are suspected. Physicians may resubmit RTP claims on separate lines if a claim line edit 
(MAI of 1) is operative. An MAI of 2 suggests a coding error that needs to be corrected, as these coding approaches are generally impossible based on definitional issues or anatomy. If an MUE with an 
MAI of 3 is the reason for denial, an appeal is possible, provided there is documentation to show that the service was actually provided and that it was medically necessary.

Final Thoughts

Dermatologists should be vigilant for unexpected payment denials, which may coincide with the implementation of new MUE values. When such denials occur and MUE values are publicly available, dermatologists should consider filing an appeal if the relevant MUEs were associated with an MAI of 
1 or 3. Overall, dermatologists should be aware that many MUEs that were formerly claim line edits 
(MAI of 1) have been recently transitioned to date of service edits (MAI of 3), which are more restrictive.

Medically Unlikely Edits (MUEs) are benchmarks recognized by the Centers for Medicare & Medicaid Services (CMS) that are designed to prevent incorrect or excessive coding. Specifically, an MUE is an edit that tests medical claims for services billed in excess of the maximum number of units of service permitted for a single beneficiary on the same date of service from the same provider (eg, multiples of the same Healthcare Common Procedure Coding System [HCPCS] code listed on different claim lines).¹

The MUE System

If the number of units of service billed by the same physician for the same patient on the same day exceeds the maximum number permitted by the CMS, the Medicare Administrative Contractor (MAC) will deny the code or return the claim to the provider for correction (return to provider [RTP]). Units of service billed in excess of the MUE will not be paid, but other services billed on the same claim form may still be paid. In the case of an MUE-associated RTP, the provider should resubmit a corrected claim, not an appeal; however, an appeal is possible in the case of an MUE-associated denial. An MUE-associated denial is a coding denial, not a medical necessity denial; therefore, the provider cannot use an Advance Beneficiary Notice to transfer liability for claim payment to the patient.

MUE Adjudication Indicators

In 2013, the CMS modified the MUE process to include 3 different MUE adjudication indicators (MAIs) with a value of 1, 2, or 3 so that some MUE values would be date of service edits rather than claim line edits.² Medically Unlikely Edits for HCPCS codes with an MAI of 1 are identical to the prior claim line edits. If a provider needs to report excess units of service with an MAI of 1, appropriate modifiers should be used to report them on separate lines of a claim. Current Procedural Terminology (CPT) modifiers such as -76 (repeat procedure or service by the same physician) and -91 (repeat clinical diagnostic laboratory test) as well as anatomic modifiers (eg, RT, LT, F1, F2) may be used, with modifier -59 (distinct procedural service) used only if no other modifier suffices. An example of an 
MUE with an MAI of 1 is CPT code 17264 (destruction, malignant lesion [eg, laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement], trunk, arms or legs; lesion 
diameter 3.1–4.0 cm), for which the MUE threshold is 3, meaning no more than 3 destructions can be submitted per claim line without triggering an 
edit-based rejection or RTP.

An MAI of 2 denotes absolute date of service edits, or so-called “per day edits based on policy.” Such edits are in place because units of service billed in excess of the MUE value on the same date of service are considered to be impossible by the CMS based on regulatory guidance or anatomic considerations.² For instance, although the same physician may destroy multiple actinic keratoses in a single patient on the same date of service, it would not be possible to code more than one unit of service as 
CPT code 17000, which specifically and exclusively 
refers to the first lesion destroyed. Similarly, 
CPT code 13101 (repair, complex, trunk; lesion diameter 2.6–7.5 cm) could only be reported once that day, as all complex repairs at that anatomic site must be summed and smaller or larger totals would be reported with another code.

Anatomic limitations are sometimes obvious and do not require specific coding rules. For example, only 1 gallbladder can be removed per patient. Although Qualified Independent Contractors and Administrative Law Judges are not bound by MAIs, they do give particular deference to an MAI of 
2 given its definitive nature.² Because ambulatory surgical center providers (Medicare specialty code 49) cannot report modifier -50 for bilateral 
procedures, the MUE value used for editing is doubled for HCPCS codes with an MAI of 2 or 3 if the bilateral surgery indicator for the HCPCS code is 1.³

An MAI of 3 describes less strict date of service edits, so-called “per day edits based on clinical benchmarks.”² Similar to MAIs of 1, MUEs for MAIs of 3 are based on medically likely daily frequencies of services provided in most settings. To determine if an MUE with an MAI of 3 has been reached, the MAC sums the units of service billed on all claim lines of the current claim as well as all prior paid claims for the same patient billed by the same provider on the same date of service. If the total units of service obtained in this manner exceeds the MUE value, then all claim lines with the relevant code for the current claim will be denied, but prior paid claims will not be adjusted. Denials based on MUEs for codes with an MAI of 3 can be appealed to the local MAC. Successful appeals require documentation that the units of service in excess of the MUE value were actually delivered and demonstration of medical necessity.² An example of a CPT code with an MAI of 3 is 40490 (biopsy of lip) for which the MUE value is 3.

Complications With MUE and MAI

Because MUEs are based on current coding guidelines as well as current clinical practice, they are only applicable for the time period in which they are in effect. A change made to an MUE value for a particular code is not retroactive; however, in exceptional circumstances when a retroactive effective date is applied, MACs are not directed to examine prior claims but only “claims that are brought to their attention.”²

It also is important to realize that not all 
MUEs are publicly available and many are confidential. When claim denials occur, particularly in the context of multiple units of a particular code, 
automated MUE edits should be among the issues that are suspected. Physicians may resubmit RTP claims on separate lines if a claim line edit 
(MAI of 1) is operative. An MAI of 2 suggests a coding error that needs to be corrected, as these coding approaches are generally impossible based on definitional issues or anatomy. If an MUE with an 
MAI of 3 is the reason for denial, an appeal is possible, provided there is documentation to show that the service was actually provided and that it was medically necessary.

Final Thoughts

Dermatologists should be vigilant for unexpected payment denials, which may coincide with the implementation of new MUE values. When such denials occur and MUE values are publicly available, dermatologists should consider filing an appeal if the relevant MUEs were associated with an MAI of 
1 or 3. Overall, dermatologists should be aware that many MUEs that were formerly claim line edits 
(MAI of 1) have been recently transitioned to date of service edits (MAI of 3), which are more restrictive.

Medically Unlikely Edits (MUEs) are benchmarks recognized by the Centers for Medicare & Medicaid Services (CMS) that are designed to prevent incorrect or excessive coding. Specifically, an MUE is an edit that tests medical claims for services billed in excess of the maximum number of units of service permitted for a single beneficiary on the same date of service from the same provider (eg, multiples of the same Healthcare Common Procedure Coding System [HCPCS] code listed on different claim lines).¹

The MUE System

If the number of units of service billed by the same physician for the same patient on the same day exceeds the maximum number permitted by the CMS, the Medicare Administrative Contractor (MAC) will deny the code or return the claim to the provider for correction (return to provider [RTP]). Units of service billed in excess of the MUE will not be paid, but other services billed on the same claim form may still be paid. In the case of an MUE-associated RTP, the provider should resubmit a corrected claim, not an appeal; however, an appeal is possible in the case of an MUE-associated denial. An MUE-associated denial is a coding denial, not a medical necessity denial; therefore, the provider cannot use an Advance Beneficiary Notice to transfer liability for claim payment to the patient.

MUE Adjudication Indicators

In 2013, the CMS modified the MUE process to include 3 different MUE adjudication indicators (MAIs) with a value of 1, 2, or 3 so that some MUE values would be date of service edits rather than claim line edits.² Medically Unlikely Edits for HCPCS codes with an MAI of 1 are identical to the prior claim line edits. If a provider needs to report excess units of service with an MAI of 1, appropriate modifiers should be used to report them on separate lines of a claim. Current Procedural Terminology (CPT) modifiers such as -76 (repeat procedure or service by the same physician) and -91 (repeat clinical diagnostic laboratory test) as well as anatomic modifiers (eg, RT, LT, F1, F2) may be used, with modifier -59 (distinct procedural service) used only if no other modifier suffices. An example of an 
MUE with an MAI of 1 is CPT code 17264 (destruction, malignant lesion [eg, laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement], trunk, arms or legs; lesion 
diameter 3.1–4.0 cm), for which the MUE threshold is 3, meaning no more than 3 destructions can be submitted per claim line without triggering an 
edit-based rejection or RTP.

An MAI of 2 denotes absolute date of service edits, or so-called “per day edits based on policy.” Such edits are in place because units of service billed in excess of the MUE value on the same date of service are considered to be impossible by the CMS based on regulatory guidance or anatomic considerations.² For instance, although the same physician may destroy multiple actinic keratoses in a single patient on the same date of service, it would not be possible to code more than one unit of service as 
CPT code 17000, which specifically and exclusively 
refers to the first lesion destroyed. Similarly, 
CPT code 13101 (repair, complex, trunk; lesion diameter 2.6–7.5 cm) could only be reported once that day, as all complex repairs at that anatomic site must be summed and smaller or larger totals would be reported with another code.

Anatomic limitations are sometimes obvious and do not require specific coding rules. For example, only 1 gallbladder can be removed per patient. Although Qualified Independent Contractors and Administrative Law Judges are not bound by MAIs, they do give particular deference to an MAI of 
2 given its definitive nature.² Because ambulatory surgical center providers (Medicare specialty code 49) cannot report modifier -50 for bilateral 
procedures, the MUE value used for editing is doubled for HCPCS codes with an MAI of 2 or 3 if the bilateral surgery indicator for the HCPCS code is 1.³

An MAI of 3 describes less strict date of service edits, so-called “per day edits based on clinical benchmarks.”² Similar to MAIs of 1, MUEs for MAIs of 3 are based on medically likely daily frequencies of services provided in most settings. To determine if an MUE with an MAI of 3 has been reached, the MAC sums the units of service billed on all claim lines of the current claim as well as all prior paid claims for the same patient billed by the same provider on the same date of service. If the total units of service obtained in this manner exceeds the MUE value, then all claim lines with the relevant code for the current claim will be denied, but prior paid claims will not be adjusted. Denials based on MUEs for codes with an MAI of 3 can be appealed to the local MAC. Successful appeals require documentation that the units of service in excess of the MUE value were actually delivered and demonstration of medical necessity.² An example of a CPT code with an MAI of 3 is 40490 (biopsy of lip) for which the MUE value is 3.

Complications With MUE and MAI

Because MUEs are based on current coding guidelines as well as current clinical practice, they are only applicable for the time period in which they are in effect. A change made to an MUE value for a particular code is not retroactive; however, in exceptional circumstances when a retroactive effective date is applied, MACs are not directed to examine prior claims but only “claims that are brought to their attention.”²

It also is important to realize that not all 
MUEs are publicly available and many are confidential. When claim denials occur, particularly in the context of multiple units of a particular code, 
automated MUE edits should be among the issues that are suspected. Physicians may resubmit RTP claims on separate lines if a claim line edit 
(MAI of 1) is operative. An MAI of 2 suggests a coding error that needs to be corrected, as these coding approaches are generally impossible based on definitional issues or anatomy. If an MUE with an 
MAI of 3 is the reason for denial, an appeal is possible, provided there is documentation to show that the service was actually provided and that it was medically necessary.

Final Thoughts

Dermatologists should be vigilant for unexpected payment denials, which may coincide with the implementation of new MUE values. When such denials occur and MUE values are publicly available, dermatologists should consider filing an appeal if the relevant MUEs were associated with an MAI of 
1 or 3. Overall, dermatologists should be aware that many MUEs that were formerly claim line edits 
(MAI of 1) have been recently transitioned to date of service edits (MAI of 3), which are more restrictive.

The introduction of high-density radiation electronic brachytherapy (eBX) for the treatment of nonmelanoma skin cancers has induced great angst within the dermatology community.¹ The Current Procedural Terminology (CPT) code 0182T (high dose rate eBX) reimburses at an extraordinarily high rate, which has drawn a substantial amount of attention. Some critics see it as another case of overutilization, of sucking more money out of a bleeding Medicare system. The financial opportunity afforded by eBX has even led some entrepreneurs to purchase dermatology clinics so that skin cancer patients can be treated via this modality instead of more traditional and less costly techniques (personal communication, 2014).

Among radiation oncologists, high-density radiation eBX is considered to be an important treatment option for select patients who have skin cancers staged as T1 or T2 tumors that are 4 cm or smaller in diameter and 5 mm or less in depth.² Additionally, ideal candidates for nonsurgical treatment options such as eBX include patients with lesions in cosmetically challenging areas (eg, ears, nose), those who may experience problematic wound healing due to tumor location (eg, lower extremities) or medical conditions (eg, diabetes mellitus, peripheral vascular disease), those with medical comorbidities that may preclude them from surgery, those currently taking anticoagulants, and those who are not interested in undergoing surgery.

A common criticism of eBX is that there is little data on long-term treatment outcomes, which will soon be addressed by a 5-year multicenter, prospective, randomized study of 720 patients with basal cell carcinoma and squamous cell carcinoma led by the University of California, Irvine, and the University of California, San Diego (study protocol currently with institutional review board). Another criticism is that some manufacturers of eBX devices gained the less rigorous US Food and Drug Administration Premarket Notification 510(k) certification; however, this certification is quite commonplace in the United States, and an examination of the data actually shows a lower recall rate with this method when compared to the longer premarket approval application process.³ A more important criticism of eBX might be that radiation therapy is associated with a substantial increase in skin cancers that may occur decades later in irradiated areas; however, there remains a paucity of studies examining the safety data on eBX during the posttreatment period when such effects would be expected.

In practice, the forces for good and evil are not only limited to those who utilize eBX. It is widely known that CPT codes for Mohs micrographic surgery also have been abused—that is, the procedure has been used in circumstances where it was not absolutely necessary⁴—which led to an effort by dermatologic surgery organizations to agree on appropriate use criteria for Mohs surgery.⁵ These criteria are not perfect but should help curb the misuse of a valuable technique, which is one that is recognized as being optimal for the treatment of complex skin cancers. One might suggest forming similar appropriate use criteria for eBX and limiting this treatment to patients who either are older than 65 years, have serious medical issues, are currently taking anticoagulants, are immobile, or simply cannot handle further dermatologic surgeries.

The American Medical Association has developed new Category III CPT codes for treatment of the skin with eBX that will become effective January 2016.⁶ These codes take into consideration the need for a radiation oncologist and a physicist to be present for planning, dosimetry, simulation, and selection of parameters for the appropriate depth. Although I do not know the reimbursement rates for these new codes yet, they will likely be substantially less than the current payment for treatment with eBX. That said, the gravy train has left the station, and those who have invested in the devices for eBX will either see the benefit of continued treatment for their patients or divest themselves of eBX now that the reimbursement will be more modest.

Some of my dermatology colleagues, who also are some of my very good friends, have a visceral and absolute objection to the use of any form of radiation therapy, and I respect their opinions. However, eBX does play a role in treating cutaneous malignancies, and our radiation oncology colleagues—many who treat patients with extensive, aggressive, and recurrent skin cancers—also have a place at the table.

Speaking as a fellowship-trained dermatologic surgeon and a department chair, I am very aware that the teaching we provide today for our dermatology residents and fellows is likely to be their modus operandi for the future, a future in which the Patient Protection and Affordable Care Act will force physicians to carefully choose quality of care over personal gain and where financial rewards will be based on appropriate utilization and measurable outcomes. Electronic brachytherapy is one tool amongst many. I have a plethora of patients in their 70s and 80s who have given up on surgery for skin cancer and who would prefer painless treatment with eBX, which allows for the appropriate use of such a controversial therapy.

Acknowledgments—I would like to thank Janellen Smith, MD (Irvine, California), Joshua Spanogle, MD (Saint Augustine, Florida), and Jordan 
V. Wang, MBE (Philadelphia, Pennsylvania), for their constructive comments.

The introduction of high-density radiation electronic brachytherapy (eBX) for the treatment of nonmelanoma skin cancers has induced great angst within the dermatology community.¹ The Current Procedural Terminology (CPT) code 0182T (high dose rate eBX) reimburses at an extraordinarily high rate, which has drawn a substantial amount of attention. Some critics see it as another case of overutilization, of sucking more money out of a bleeding Medicare system. The financial opportunity afforded by eBX has even led some entrepreneurs to purchase dermatology clinics so that skin cancer patients can be treated via this modality instead of more traditional and less costly techniques (personal communication, 2014).

Among radiation oncologists, high-density radiation eBX is considered to be an important treatment option for select patients who have skin cancers staged as T1 or T2 tumors that are 4 cm or smaller in diameter and 5 mm or less in depth.² Additionally, ideal candidates for nonsurgical treatment options such as eBX include patients with lesions in cosmetically challenging areas (eg, ears, nose), those who may experience problematic wound healing due to tumor location (eg, lower extremities) or medical conditions (eg, diabetes mellitus, peripheral vascular disease), those with medical comorbidities that may preclude them from surgery, those currently taking anticoagulants, and those who are not interested in undergoing surgery.

A common criticism of eBX is that there is little data on long-term treatment outcomes, which will soon be addressed by a 5-year multicenter, prospective, randomized study of 720 patients with basal cell carcinoma and squamous cell carcinoma led by the University of California, Irvine, and the University of California, San Diego (study protocol currently with institutional review board). Another criticism is that some manufacturers of eBX devices gained the less rigorous US Food and Drug Administration Premarket Notification 510(k) certification; however, this certification is quite commonplace in the United States, and an examination of the data actually shows a lower recall rate with this method when compared to the longer premarket approval application process.³ A more important criticism of eBX might be that radiation therapy is associated with a substantial increase in skin cancers that may occur decades later in irradiated areas; however, there remains a paucity of studies examining the safety data on eBX during the posttreatment period when such effects would be expected.

In practice, the forces for good and evil are not only limited to those who utilize eBX. It is widely known that CPT codes for Mohs micrographic surgery also have been abused—that is, the procedure has been used in circumstances where it was not absolutely necessary⁴—which led to an effort by dermatologic surgery organizations to agree on appropriate use criteria for Mohs surgery.⁵ These criteria are not perfect but should help curb the misuse of a valuable technique, which is one that is recognized as being optimal for the treatment of complex skin cancers. One might suggest forming similar appropriate use criteria for eBX and limiting this treatment to patients who either are older than 65 years, have serious medical issues, are currently taking anticoagulants, are immobile, or simply cannot handle further dermatologic surgeries.

The American Medical Association has developed new Category III CPT codes for treatment of the skin with eBX that will become effective January 2016.⁶ These codes take into consideration the need for a radiation oncologist and a physicist to be present for planning, dosimetry, simulation, and selection of parameters for the appropriate depth. Although I do not know the reimbursement rates for these new codes yet, they will likely be substantially less than the current payment for treatment with eBX. That said, the gravy train has left the station, and those who have invested in the devices for eBX will either see the benefit of continued treatment for their patients or divest themselves of eBX now that the reimbursement will be more modest.

Some of my dermatology colleagues, who also are some of my very good friends, have a visceral and absolute objection to the use of any form of radiation therapy, and I respect their opinions. However, eBX does play a role in treating cutaneous malignancies, and our radiation oncology colleagues—many who treat patients with extensive, aggressive, and recurrent skin cancers—also have a place at the table.

Speaking as a fellowship-trained dermatologic surgeon and a department chair, I am very aware that the teaching we provide today for our dermatology residents and fellows is likely to be their modus operandi for the future, a future in which the Patient Protection and Affordable Care Act will force physicians to carefully choose quality of care over personal gain and where financial rewards will be based on appropriate utilization and measurable outcomes. Electronic brachytherapy is one tool amongst many. I have a plethora of patients in their 70s and 80s who have given up on surgery for skin cancer and who would prefer painless treatment with eBX, which allows for the appropriate use of such a controversial therapy.

Acknowledgments—I would like to thank Janellen Smith, MD (Irvine, California), Joshua Spanogle, MD (Saint Augustine, Florida), and Jordan 
V. Wang, MBE (Philadelphia, Pennsylvania), for their constructive comments.

The introduction of high-density radiation electronic brachytherapy (eBX) for the treatment of nonmelanoma skin cancers has induced great angst within the dermatology community.¹ The Current Procedural Terminology (CPT) code 0182T (high dose rate eBX) reimburses at an extraordinarily high rate, which has drawn a substantial amount of attention. Some critics see it as another case of overutilization, of sucking more money out of a bleeding Medicare system. The financial opportunity afforded by eBX has even led some entrepreneurs to purchase dermatology clinics so that skin cancer patients can be treated via this modality instead of more traditional and less costly techniques (personal communication, 2014).

Among radiation oncologists, high-density radiation eBX is considered to be an important treatment option for select patients who have skin cancers staged as T1 or T2 tumors that are 4 cm or smaller in diameter and 5 mm or less in depth.² Additionally, ideal candidates for nonsurgical treatment options such as eBX include patients with lesions in cosmetically challenging areas (eg, ears, nose), those who may experience problematic wound healing due to tumor location (eg, lower extremities) or medical conditions (eg, diabetes mellitus, peripheral vascular disease), those with medical comorbidities that may preclude them from surgery, those currently taking anticoagulants, and those who are not interested in undergoing surgery.

A common criticism of eBX is that there is little data on long-term treatment outcomes, which will soon be addressed by a 5-year multicenter, prospective, randomized study of 720 patients with basal cell carcinoma and squamous cell carcinoma led by the University of California, Irvine, and the University of California, San Diego (study protocol currently with institutional review board). Another criticism is that some manufacturers of eBX devices gained the less rigorous US Food and Drug Administration Premarket Notification 510(k) certification; however, this certification is quite commonplace in the United States, and an examination of the data actually shows a lower recall rate with this method when compared to the longer premarket approval application process.³ A more important criticism of eBX might be that radiation therapy is associated with a substantial increase in skin cancers that may occur decades later in irradiated areas; however, there remains a paucity of studies examining the safety data on eBX during the posttreatment period when such effects would be expected.

In practice, the forces for good and evil are not only limited to those who utilize eBX. It is widely known that CPT codes for Mohs micrographic surgery also have been abused—that is, the procedure has been used in circumstances where it was not absolutely necessary⁴—which led to an effort by dermatologic surgery organizations to agree on appropriate use criteria for Mohs surgery.⁵ These criteria are not perfect but should help curb the misuse of a valuable technique, which is one that is recognized as being optimal for the treatment of complex skin cancers. One might suggest forming similar appropriate use criteria for eBX and limiting this treatment to patients who either are older than 65 years, have serious medical issues, are currently taking anticoagulants, are immobile, or simply cannot handle further dermatologic surgeries.

The American Medical Association has developed new Category III CPT codes for treatment of the skin with eBX that will become effective January 2016.⁶ These codes take into consideration the need for a radiation oncologist and a physicist to be present for planning, dosimetry, simulation, and selection of parameters for the appropriate depth. Although I do not know the reimbursement rates for these new codes yet, they will likely be substantially less than the current payment for treatment with eBX. That said, the gravy train has left the station, and those who have invested in the devices for eBX will either see the benefit of continued treatment for their patients or divest themselves of eBX now that the reimbursement will be more modest.

Some of my dermatology colleagues, who also are some of my very good friends, have a visceral and absolute objection to the use of any form of radiation therapy, and I respect their opinions. However, eBX does play a role in treating cutaneous malignancies, and our radiation oncology colleagues—many who treat patients with extensive, aggressive, and recurrent skin cancers—also have a place at the table.

Speaking as a fellowship-trained dermatologic surgeon and a department chair, I am very aware that the teaching we provide today for our dermatology residents and fellows is likely to be their modus operandi for the future, a future in which the Patient Protection and Affordable Care Act will force physicians to carefully choose quality of care over personal gain and where financial rewards will be based on appropriate utilization and measurable outcomes. Electronic brachytherapy is one tool amongst many. I have a plethora of patients in their 70s and 80s who have given up on surgery for skin cancer and who would prefer painless treatment with eBX, which allows for the appropriate use of such a controversial therapy.

Acknowledgments—I would like to thank Janellen Smith, MD (Irvine, California), Joshua Spanogle, MD (Saint Augustine, Florida), and Jordan 
V. Wang, MBE (Philadelphia, Pennsylvania), for their constructive comments.

The impact of endovascular repair on specialties performing abdominal aortic aneurysm repair.

Klaas H. J. Ultee, BSc,Rob Hurks, MD, PhD, Dominique B. Buck, MD, George S. DaSilva, BS, Peter A. Soden, MD,Joost A. van Herwaarden, MD, PhD, Hence J. M. Verhagen, MD, PhD, and Marc L. Schermerhorn, MD

Due to the increased use of EVAR for both intact and ruptured AAA repair, vascular surgeons are performing an increasing majority of AAA repairs, according to a new study reported in the September edition of Journal of Vascular 
Surgery.

The study examined the years 2001 through 2009 using the Nationwide Inpatient Sample, the largest national administrative database, which is maintained by the Agency for Healthcare Research and Quality as part of the Healthcare Cost and Utilization Project.

After 2009 the surgeon identification variables in the database were discontinued so more recent data were unavailable for the study.

“We do plan to analyze (this same subject) using Medicare data,” according to Dr. Marc L. Schermerhorn, “but our access to it lags several years behind. It will allow better risk adjustment as well.”

The study was interested in AAA repairs by the following types of physicians: vascular surgeons, general surgeons, cardiac surgeons, as well as nonsurgical specialists such as interventional cardiologists and interventional radiologists.

Overall, 108,587 EVARS and 85,080 open AAA repairs were identified. Of all repairs, 61 percent were performed by vascular surgeons, 20 percent by general surgeons, and 16 percent by cardiac surgeons. ICs and IRs performed the remaining 3 percent.

Significantly, the absolute number of vascular surgeons performing AAA repair increased 30 percent during the study period, whereas the number of GS and CS repairs decreased 46 and 30 percent, respectively.

AAA repairs are still done by general surgeons and cardiovascular surgeons; however, in those cases, patients are less likely to receive EVAR.

Researchers also found that whether patients received open or endovascular repair varied with the type of surgeon, but also by the patient’s gender, emergent admission, and race.

Other influencing factors were age of patient, treatment in a teaching hospital, year, and whether or not the hospital was in an urban area.

“The big question,” Schermerhorn noted, “is whether specialty has an influence on outcomes. We chose not to try to analyze this using this database because we did not think we could adequately do risk adjustment. It is difficult to distinguish a pre-existing condition from a post-op complication, for example, renal failure.”

The impact of endovascular repair on specialties performing abdominal aortic aneurysm repair.

Klaas H. J. Ultee, BSc,Rob Hurks, MD, PhD, Dominique B. Buck, MD, George S. DaSilva, BS, Peter A. Soden, MD,Joost A. van Herwaarden, MD, PhD, Hence J. M. Verhagen, MD, PhD, and Marc L. Schermerhorn, MD

Due to the increased use of EVAR for both intact and ruptured AAA repair, vascular surgeons are performing an increasing majority of AAA repairs, according to a new study reported in the September edition of Journal of Vascular 
Surgery.

The study examined the years 2001 through 2009 using the Nationwide Inpatient Sample, the largest national administrative database, which is maintained by the Agency for Healthcare Research and Quality as part of the Healthcare Cost and Utilization Project.

After 2009 the surgeon identification variables in the database were discontinued so more recent data were unavailable for the study.

“We do plan to analyze (this same subject) using Medicare data,” according to Dr. Marc L. Schermerhorn, “but our access to it lags several years behind. It will allow better risk adjustment as well.”

The study was interested in AAA repairs by the following types of physicians: vascular surgeons, general surgeons, cardiac surgeons, as well as nonsurgical specialists such as interventional cardiologists and interventional radiologists.

Overall, 108,587 EVARS and 85,080 open AAA repairs were identified. Of all repairs, 61 percent were performed by vascular surgeons, 20 percent by general surgeons, and 16 percent by cardiac surgeons. ICs and IRs performed the remaining 3 percent.

Significantly, the absolute number of vascular surgeons performing AAA repair increased 30 percent during the study period, whereas the number of GS and CS repairs decreased 46 and 30 percent, respectively.

AAA repairs are still done by general surgeons and cardiovascular surgeons; however, in those cases, patients are less likely to receive EVAR.

Researchers also found that whether patients received open or endovascular repair varied with the type of surgeon, but also by the patient’s gender, emergent admission, and race.

Other influencing factors were age of patient, treatment in a teaching hospital, year, and whether or not the hospital was in an urban area.

“The big question,” Schermerhorn noted, “is whether specialty has an influence on outcomes. We chose not to try to analyze this using this database because we did not think we could adequately do risk adjustment. It is difficult to distinguish a pre-existing condition from a post-op complication, for example, renal failure.”

The impact of endovascular repair on specialties performing abdominal aortic aneurysm repair.

Klaas H. J. Ultee, BSc,Rob Hurks, MD, PhD, Dominique B. Buck, MD, George S. DaSilva, BS, Peter A. Soden, MD,Joost A. van Herwaarden, MD, PhD, Hence J. M. Verhagen, MD, PhD, and Marc L. Schermerhorn, MD

Due to the increased use of EVAR for both intact and ruptured AAA repair, vascular surgeons are performing an increasing majority of AAA repairs, according to a new study reported in the September edition of Journal of Vascular 
Surgery.

The study examined the years 2001 through 2009 using the Nationwide Inpatient Sample, the largest national administrative database, which is maintained by the Agency for Healthcare Research and Quality as part of the Healthcare Cost and Utilization Project.

After 2009 the surgeon identification variables in the database were discontinued so more recent data were unavailable for the study.

“We do plan to analyze (this same subject) using Medicare data,” according to Dr. Marc L. Schermerhorn, “but our access to it lags several years behind. It will allow better risk adjustment as well.”

The study was interested in AAA repairs by the following types of physicians: vascular surgeons, general surgeons, cardiac surgeons, as well as nonsurgical specialists such as interventional cardiologists and interventional radiologists.

Overall, 108,587 EVARS and 85,080 open AAA repairs were identified. Of all repairs, 61 percent were performed by vascular surgeons, 20 percent by general surgeons, and 16 percent by cardiac surgeons. ICs and IRs performed the remaining 3 percent.

Significantly, the absolute number of vascular surgeons performing AAA repair increased 30 percent during the study period, whereas the number of GS and CS repairs decreased 46 and 30 percent, respectively.

AAA repairs are still done by general surgeons and cardiovascular surgeons; however, in those cases, patients are less likely to receive EVAR.

Researchers also found that whether patients received open or endovascular repair varied with the type of surgeon, but also by the patient’s gender, emergent admission, and race.

Other influencing factors were age of patient, treatment in a teaching hospital, year, and whether or not the hospital was in an urban area.

“The big question,” Schermerhorn noted, “is whether specialty has an influence on outcomes. We chose not to try to analyze this using this database because we did not think we could adequately do risk adjustment. It is difficult to distinguish a pre-existing condition from a post-op complication, for example, renal failure.”