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Halting active inflammation key in treating PIH
CHICAGO –
Dr. Desai, clinical assistant professor in the department of dermatology at the University of Texas Southwestern Medical Center, Dallas, spoke at the Pigmentary Disorders Exchange Symposium, provided by MedscapeLive!
Like all dermatologists, he said at the meeting, he sees lots of acne cases. However, PIH is often the presenting reason for the visit in his practice, which focuses predominantly on skin of color.
“Most of my patients come in not even worried about the acne,” he said. “They come in wanting me to fix the dark spots.”
Inflammation persists
Dermatologists, Dr. Desai said, should educate patients with active PIH resulting from acne or other diseases that even though the condition has been labeled post- inflammatory hyperpigmentation, the inflammation continues to be a problem.
He said, while patients may think PIH is “just scars,” the inflammation is still active and the condition needs to be treated from a skin-lightening perspective but, more importantly, with a focus on halting the inflammation. “If you were to biopsy the areas of hyperpigmentation, you would find a high density of active inflammatory behaviors still present in the skin,” he said.
When treating patients, it’s critical to first treat the underlying skin condition aggressively, he said. “Things like topical retinoids and azelaic acid mechanistically actually make a lot more sense for PIH than even hydroquinone, in some cases, because these therapies are actually anti-inflammatory for many of the diseases we treat.”
Dr. Desai noted that, in patients with darker skin tones, even diseases like seborrheic dermatitis and plaque psoriasis can result in PIH, while in patients with lighter skin tones, the same diseases may leave some residual postinflammatory erythema.
“I think it’s very important, particularly when you’re treating a darker skin–toned patient, to arrest the erythema early on to prevent that further worsening of hyperpigmentation,” he said.
Biopsies important
In cases of PIH, determining the best treatment requires finding out where the pigment is and how deep it is, Dr. Desai said.
He noted dermatologists are often worried about doing biopsies, particularly in patients with darker skin, because of the risk of scarring and keloid formation for those more prone to keloids. The preference is also for a therapeutic effect without using invasive procedures.
“But particularly with PIH, in patients who have been therapeutically challenging, I don’t hesitate to do very small biopsies – 2- and 3-mm punch biopsies – particularly if they are from the head and neck area.”
He suggests doing biopsies on part of the ear, lower jaw line, or the neck area, as these areas tend to heal nicely. “You don’t have to be so concerned about the scarring if you counsel appropriately,” he said.
The biopsy can be valuable in determining whether a very expensive treatment will reach the intended target.
Topical retinoids play an important role as anti-inflammatories for PIH, Dr. Desai said.
He gave an example of a patient with Fitzpatrick skin type IV or V with chronic acne and extensive PIH. “Are you going to effectively tell that patient to apply 4% hydroquinone triple-combination compound across 30 different areas of PIH on their face? The answer is that’s really not very efficient or effective.”
That’s why therapies, such as retinoids, that target the pathogenesis of PIH, particularly the inflammatory component, are important, he added.
Psychological burden
PIH comes with significant stigma and loss of quality of life loss that can last many years.
During another presentation at the meeting, Susan C. Taylor, MD, professor and vice chair of diversity, equity and inclusion in the department of dermatology, at the University of Pennsylvania, Philadelphia, pointed out that in a 2016 study of 324 patients in seven Asian countries, acne-related PIH lasted longer than 1 year in 65.2% of patients and 5 years or longer in 22.3%, significantly affecting their quality of life.
Dr. Desai added that, in a paper recently published in the British Journal of Dermatology, on the impact of postacne hyperpigmentation in patients, the authors pointed out that the reported prevalence of PIH in patients with acne ranges between 45.5% and 87.2%, depending on skin phototype, and that in most cases, PIH takes more than a year to fade.
“Studies have demonstrated that patients with acne and resulting scarring often face stigmatization, leading to quality of life impairment, social withdrawal and body image disorders, which can further contribute to higher risk for depression and social anxiety,” the paper’s authors wrote.
Dr. Desai reported no financial disclosures relevant to his talk.
CHICAGO –
Dr. Desai, clinical assistant professor in the department of dermatology at the University of Texas Southwestern Medical Center, Dallas, spoke at the Pigmentary Disorders Exchange Symposium, provided by MedscapeLive!
Like all dermatologists, he said at the meeting, he sees lots of acne cases. However, PIH is often the presenting reason for the visit in his practice, which focuses predominantly on skin of color.
“Most of my patients come in not even worried about the acne,” he said. “They come in wanting me to fix the dark spots.”
Inflammation persists
Dermatologists, Dr. Desai said, should educate patients with active PIH resulting from acne or other diseases that even though the condition has been labeled post- inflammatory hyperpigmentation, the inflammation continues to be a problem.
He said, while patients may think PIH is “just scars,” the inflammation is still active and the condition needs to be treated from a skin-lightening perspective but, more importantly, with a focus on halting the inflammation. “If you were to biopsy the areas of hyperpigmentation, you would find a high density of active inflammatory behaviors still present in the skin,” he said.
When treating patients, it’s critical to first treat the underlying skin condition aggressively, he said. “Things like topical retinoids and azelaic acid mechanistically actually make a lot more sense for PIH than even hydroquinone, in some cases, because these therapies are actually anti-inflammatory for many of the diseases we treat.”
Dr. Desai noted that, in patients with darker skin tones, even diseases like seborrheic dermatitis and plaque psoriasis can result in PIH, while in patients with lighter skin tones, the same diseases may leave some residual postinflammatory erythema.
“I think it’s very important, particularly when you’re treating a darker skin–toned patient, to arrest the erythema early on to prevent that further worsening of hyperpigmentation,” he said.
Biopsies important
In cases of PIH, determining the best treatment requires finding out where the pigment is and how deep it is, Dr. Desai said.
He noted dermatologists are often worried about doing biopsies, particularly in patients with darker skin, because of the risk of scarring and keloid formation for those more prone to keloids. The preference is also for a therapeutic effect without using invasive procedures.
“But particularly with PIH, in patients who have been therapeutically challenging, I don’t hesitate to do very small biopsies – 2- and 3-mm punch biopsies – particularly if they are from the head and neck area.”
He suggests doing biopsies on part of the ear, lower jaw line, or the neck area, as these areas tend to heal nicely. “You don’t have to be so concerned about the scarring if you counsel appropriately,” he said.
The biopsy can be valuable in determining whether a very expensive treatment will reach the intended target.
Topical retinoids play an important role as anti-inflammatories for PIH, Dr. Desai said.
He gave an example of a patient with Fitzpatrick skin type IV or V with chronic acne and extensive PIH. “Are you going to effectively tell that patient to apply 4% hydroquinone triple-combination compound across 30 different areas of PIH on their face? The answer is that’s really not very efficient or effective.”
That’s why therapies, such as retinoids, that target the pathogenesis of PIH, particularly the inflammatory component, are important, he added.
Psychological burden
PIH comes with significant stigma and loss of quality of life loss that can last many years.
During another presentation at the meeting, Susan C. Taylor, MD, professor and vice chair of diversity, equity and inclusion in the department of dermatology, at the University of Pennsylvania, Philadelphia, pointed out that in a 2016 study of 324 patients in seven Asian countries, acne-related PIH lasted longer than 1 year in 65.2% of patients and 5 years or longer in 22.3%, significantly affecting their quality of life.
Dr. Desai added that, in a paper recently published in the British Journal of Dermatology, on the impact of postacne hyperpigmentation in patients, the authors pointed out that the reported prevalence of PIH in patients with acne ranges between 45.5% and 87.2%, depending on skin phototype, and that in most cases, PIH takes more than a year to fade.
“Studies have demonstrated that patients with acne and resulting scarring often face stigmatization, leading to quality of life impairment, social withdrawal and body image disorders, which can further contribute to higher risk for depression and social anxiety,” the paper’s authors wrote.
Dr. Desai reported no financial disclosures relevant to his talk.
CHICAGO –
Dr. Desai, clinical assistant professor in the department of dermatology at the University of Texas Southwestern Medical Center, Dallas, spoke at the Pigmentary Disorders Exchange Symposium, provided by MedscapeLive!
Like all dermatologists, he said at the meeting, he sees lots of acne cases. However, PIH is often the presenting reason for the visit in his practice, which focuses predominantly on skin of color.
“Most of my patients come in not even worried about the acne,” he said. “They come in wanting me to fix the dark spots.”
Inflammation persists
Dermatologists, Dr. Desai said, should educate patients with active PIH resulting from acne or other diseases that even though the condition has been labeled post- inflammatory hyperpigmentation, the inflammation continues to be a problem.
He said, while patients may think PIH is “just scars,” the inflammation is still active and the condition needs to be treated from a skin-lightening perspective but, more importantly, with a focus on halting the inflammation. “If you were to biopsy the areas of hyperpigmentation, you would find a high density of active inflammatory behaviors still present in the skin,” he said.
When treating patients, it’s critical to first treat the underlying skin condition aggressively, he said. “Things like topical retinoids and azelaic acid mechanistically actually make a lot more sense for PIH than even hydroquinone, in some cases, because these therapies are actually anti-inflammatory for many of the diseases we treat.”
Dr. Desai noted that, in patients with darker skin tones, even diseases like seborrheic dermatitis and plaque psoriasis can result in PIH, while in patients with lighter skin tones, the same diseases may leave some residual postinflammatory erythema.
“I think it’s very important, particularly when you’re treating a darker skin–toned patient, to arrest the erythema early on to prevent that further worsening of hyperpigmentation,” he said.
Biopsies important
In cases of PIH, determining the best treatment requires finding out where the pigment is and how deep it is, Dr. Desai said.
He noted dermatologists are often worried about doing biopsies, particularly in patients with darker skin, because of the risk of scarring and keloid formation for those more prone to keloids. The preference is also for a therapeutic effect without using invasive procedures.
“But particularly with PIH, in patients who have been therapeutically challenging, I don’t hesitate to do very small biopsies – 2- and 3-mm punch biopsies – particularly if they are from the head and neck area.”
He suggests doing biopsies on part of the ear, lower jaw line, or the neck area, as these areas tend to heal nicely. “You don’t have to be so concerned about the scarring if you counsel appropriately,” he said.
The biopsy can be valuable in determining whether a very expensive treatment will reach the intended target.
Topical retinoids play an important role as anti-inflammatories for PIH, Dr. Desai said.
He gave an example of a patient with Fitzpatrick skin type IV or V with chronic acne and extensive PIH. “Are you going to effectively tell that patient to apply 4% hydroquinone triple-combination compound across 30 different areas of PIH on their face? The answer is that’s really not very efficient or effective.”
That’s why therapies, such as retinoids, that target the pathogenesis of PIH, particularly the inflammatory component, are important, he added.
Psychological burden
PIH comes with significant stigma and loss of quality of life loss that can last many years.
During another presentation at the meeting, Susan C. Taylor, MD, professor and vice chair of diversity, equity and inclusion in the department of dermatology, at the University of Pennsylvania, Philadelphia, pointed out that in a 2016 study of 324 patients in seven Asian countries, acne-related PIH lasted longer than 1 year in 65.2% of patients and 5 years or longer in 22.3%, significantly affecting their quality of life.
Dr. Desai added that, in a paper recently published in the British Journal of Dermatology, on the impact of postacne hyperpigmentation in patients, the authors pointed out that the reported prevalence of PIH in patients with acne ranges between 45.5% and 87.2%, depending on skin phototype, and that in most cases, PIH takes more than a year to fade.
“Studies have demonstrated that patients with acne and resulting scarring often face stigmatization, leading to quality of life impairment, social withdrawal and body image disorders, which can further contribute to higher risk for depression and social anxiety,” the paper’s authors wrote.
Dr. Desai reported no financial disclosures relevant to his talk.
AT THE MEDSCAPELIVE! PIGMENTARY DISORDERS SYMPOSIUM
Macular dermal hyperpigmentation: Treatment tips from an expert
CHICAGO – based on cases she has treated in her practice.
Heather Woolery-Lloyd, MD, director of the skin of color division in the dermatology department at University of Miami, provided three general pointers.
- When in doubt, biopsy.
- For inflammatory disorders, always treat the inflammation in addition to the hyperpigmentation.
- Avoid long-term hydroquinone use in these patients.
Dr. Woolery-Lloyd also reviewed examples of what she has found successful in treating her patients with these conditions.
Lichen planus pigmentosus (LPP)
“It’s one of the hardest things that we treat,” said Dr. Woolery-Lloyd, who often sees cases of LPP in patients in their 30s, 40s, and 50s.
Lesions first appear as small, ill-defined oval-to-round macules, which later become confluent and form large areas of pigmentation. In different patients, the pigment on the face and neck, and sometimes on the forearms can be slate gray or brownish black.
In 2013, dermatologist N.C. Dlova, MD, at the University of KwaZulu‐Natal, Durban, South Africa, reported a link between frontal fibrosing alopecia and LPP in the British Journal of Dermatology. “I definitely see this connection in my practice,” said Dr. Woolery-Lloyd, noting that “both conditions often result in the loss of both eyebrows.”
She recommends always using a topical anti-inflammatory that is safe for the face. One combination she uses is azelaic acid 20% plus hydrocortisone 2.5%.
“We do use a lot of azelaic acid in my practice because it’s affordable,” she said, at the meeting, provided by MedscapeLive! She added that the hardest area to treat in women is around the chin.
Two other conditions, ashy dermatosis and erythema dyschromicum perstans (EDP), are similar. Ashy dermatosis mimics LPP but occurs more prominently on the trunk and extremities. EDP often has a preceding ring of erythema.
Dr. Woolery-Lloyd said the term EDP is often used to cover both EDP and ashy dermatosis in North America because “ashy” can have a negative connotation.
She noted there is no consensus on effective therapy for LPP, ashy dermatosis, or EDP.
A review of the literature on EDP, which included 16 studies on treatment outcomes, found the following:
- Narrow-band ultraviolet B and tacrolimus were effective treatments with minimal side effects.
- Clofazimine was effective, but had side effects, which, ironically, included pigmentary changes.
- Griseofulvin, isotretinoin, and dapsone were comparatively ineffective as lesions recurred after discontinuation.
- Lasers were largely ineffective and can also result in postinflammatory hyperpigmentation and fibrosis.
Ochronosis
Dr. Woolery-Lloyd said she may see one to two patients a year with ochronosis, which is characterized by paradoxical darkening of the skin with long-term hydroquinone use. It usually starts with redness followed by blue-black patches on the face where hydroquinone is applied. In severe cases, blue-black papules and nodules can occur.
“When I give a patient hydroquinone, I always say: ‘I don’t want to see any redness,’” Dr. Woolery-Lloyd said. “If you have any redness, please stop because ochronosis is typically preceded by this redness.”
But, she noted, “people will come in actively using hydroquinone, will have the dark brown or deep black papules or macules on their face, and then this background of redness because they are so inflamed.”
She said that ochronosis can occur in any skin type, not just in patients with darker skin tones. Dr. Woolery-Lloyd advised: “Do not hesitate to biopsy the face if ochronosis is suspected. I always biopsy ochronosis.”
There are two reasons for doing so, she explained. It can help with the diagnosis but it will also provide the patient with an incentive to stop using hydroquinone. “People who are using hydroquinone are addicted to it. They love it. They don’t want to stop. They keep using it despite the fact that their face is getting darker.” When they see a biopsy report, they may be convinced to stop.
Dr. Woolery-Lloyd said she does a 2-mm punch biopsy in the crow’s feet area because there’s almost always ochronosis in that area and it does not leave an obvious scar.
Eventually, she said, if the person stops using hydroquinone, it will clear up, “but it will take years.” Again, here she has had success with her “special formula” of azelaic acid 20% plus hydrocortisone 2.5%
“Don’t tell patients there’s no treatment. That’s the take-home,” she said.
Drug-induced facial hyperpigmentation
“I see this all the time in my African American patients,” Dr. Woolery-Lloyd said. The condition usually is characterized by dark brown hyperpigmentation on the face.
In this situation, the first question to ask is whether the patient is taking medication for hypertension, and the second question is whether it is “HCTZ.” It’s important to use the abbreviation for hydrochlorothiazide – the most common cause of drug-induced facial hyperpigmentation – because that’s what a patient sees on the bottle.
If they are taking HCTZ or another blood pressure medication associated with photosensitivity, they need to switch to a nonphotosensitizing antihypertensive agent (there are several options) and they should start treatment with a topical anti-inflammatory, Dr. Woolery-Lloyd said. Then, she suggests introducing hydrocortisone 2.5% cream and a hydroquinone-free skin brightener (azelaic acid, for example).
Importantly, with any of these conditions, Dr Woolery-Lloyd said, dermatologists should talk with patients about realistic expectations. “It takes a long time for dermal pigment to clear,” she emphasized.
Dr. Woolery-Lloyd has been a speaker for Ortho Dermatologics, L’Oreal, and EPI; has done research for Pfizer, Galderma, Allergan, Arcutis, Vyne, Merz, and Eirion; and has been on advisory boards for L’Oreal, Allergan, Ortho Dermatologics, Pfizer, and Merz.
CHICAGO – based on cases she has treated in her practice.
Heather Woolery-Lloyd, MD, director of the skin of color division in the dermatology department at University of Miami, provided three general pointers.
- When in doubt, biopsy.
- For inflammatory disorders, always treat the inflammation in addition to the hyperpigmentation.
- Avoid long-term hydroquinone use in these patients.
Dr. Woolery-Lloyd also reviewed examples of what she has found successful in treating her patients with these conditions.
Lichen planus pigmentosus (LPP)
“It’s one of the hardest things that we treat,” said Dr. Woolery-Lloyd, who often sees cases of LPP in patients in their 30s, 40s, and 50s.
Lesions first appear as small, ill-defined oval-to-round macules, which later become confluent and form large areas of pigmentation. In different patients, the pigment on the face and neck, and sometimes on the forearms can be slate gray or brownish black.
In 2013, dermatologist N.C. Dlova, MD, at the University of KwaZulu‐Natal, Durban, South Africa, reported a link between frontal fibrosing alopecia and LPP in the British Journal of Dermatology. “I definitely see this connection in my practice,” said Dr. Woolery-Lloyd, noting that “both conditions often result in the loss of both eyebrows.”
She recommends always using a topical anti-inflammatory that is safe for the face. One combination she uses is azelaic acid 20% plus hydrocortisone 2.5%.
“We do use a lot of azelaic acid in my practice because it’s affordable,” she said, at the meeting, provided by MedscapeLive! She added that the hardest area to treat in women is around the chin.
Two other conditions, ashy dermatosis and erythema dyschromicum perstans (EDP), are similar. Ashy dermatosis mimics LPP but occurs more prominently on the trunk and extremities. EDP often has a preceding ring of erythema.
Dr. Woolery-Lloyd said the term EDP is often used to cover both EDP and ashy dermatosis in North America because “ashy” can have a negative connotation.
She noted there is no consensus on effective therapy for LPP, ashy dermatosis, or EDP.
A review of the literature on EDP, which included 16 studies on treatment outcomes, found the following:
- Narrow-band ultraviolet B and tacrolimus were effective treatments with minimal side effects.
- Clofazimine was effective, but had side effects, which, ironically, included pigmentary changes.
- Griseofulvin, isotretinoin, and dapsone were comparatively ineffective as lesions recurred after discontinuation.
- Lasers were largely ineffective and can also result in postinflammatory hyperpigmentation and fibrosis.
Ochronosis
Dr. Woolery-Lloyd said she may see one to two patients a year with ochronosis, which is characterized by paradoxical darkening of the skin with long-term hydroquinone use. It usually starts with redness followed by blue-black patches on the face where hydroquinone is applied. In severe cases, blue-black papules and nodules can occur.
“When I give a patient hydroquinone, I always say: ‘I don’t want to see any redness,’” Dr. Woolery-Lloyd said. “If you have any redness, please stop because ochronosis is typically preceded by this redness.”
But, she noted, “people will come in actively using hydroquinone, will have the dark brown or deep black papules or macules on their face, and then this background of redness because they are so inflamed.”
She said that ochronosis can occur in any skin type, not just in patients with darker skin tones. Dr. Woolery-Lloyd advised: “Do not hesitate to biopsy the face if ochronosis is suspected. I always biopsy ochronosis.”
There are two reasons for doing so, she explained. It can help with the diagnosis but it will also provide the patient with an incentive to stop using hydroquinone. “People who are using hydroquinone are addicted to it. They love it. They don’t want to stop. They keep using it despite the fact that their face is getting darker.” When they see a biopsy report, they may be convinced to stop.
Dr. Woolery-Lloyd said she does a 2-mm punch biopsy in the crow’s feet area because there’s almost always ochronosis in that area and it does not leave an obvious scar.
Eventually, she said, if the person stops using hydroquinone, it will clear up, “but it will take years.” Again, here she has had success with her “special formula” of azelaic acid 20% plus hydrocortisone 2.5%
“Don’t tell patients there’s no treatment. That’s the take-home,” she said.
Drug-induced facial hyperpigmentation
“I see this all the time in my African American patients,” Dr. Woolery-Lloyd said. The condition usually is characterized by dark brown hyperpigmentation on the face.
In this situation, the first question to ask is whether the patient is taking medication for hypertension, and the second question is whether it is “HCTZ.” It’s important to use the abbreviation for hydrochlorothiazide – the most common cause of drug-induced facial hyperpigmentation – because that’s what a patient sees on the bottle.
If they are taking HCTZ or another blood pressure medication associated with photosensitivity, they need to switch to a nonphotosensitizing antihypertensive agent (there are several options) and they should start treatment with a topical anti-inflammatory, Dr. Woolery-Lloyd said. Then, she suggests introducing hydrocortisone 2.5% cream and a hydroquinone-free skin brightener (azelaic acid, for example).
Importantly, with any of these conditions, Dr Woolery-Lloyd said, dermatologists should talk with patients about realistic expectations. “It takes a long time for dermal pigment to clear,” she emphasized.
Dr. Woolery-Lloyd has been a speaker for Ortho Dermatologics, L’Oreal, and EPI; has done research for Pfizer, Galderma, Allergan, Arcutis, Vyne, Merz, and Eirion; and has been on advisory boards for L’Oreal, Allergan, Ortho Dermatologics, Pfizer, and Merz.
CHICAGO – based on cases she has treated in her practice.
Heather Woolery-Lloyd, MD, director of the skin of color division in the dermatology department at University of Miami, provided three general pointers.
- When in doubt, biopsy.
- For inflammatory disorders, always treat the inflammation in addition to the hyperpigmentation.
- Avoid long-term hydroquinone use in these patients.
Dr. Woolery-Lloyd also reviewed examples of what she has found successful in treating her patients with these conditions.
Lichen planus pigmentosus (LPP)
“It’s one of the hardest things that we treat,” said Dr. Woolery-Lloyd, who often sees cases of LPP in patients in their 30s, 40s, and 50s.
Lesions first appear as small, ill-defined oval-to-round macules, which later become confluent and form large areas of pigmentation. In different patients, the pigment on the face and neck, and sometimes on the forearms can be slate gray or brownish black.
In 2013, dermatologist N.C. Dlova, MD, at the University of KwaZulu‐Natal, Durban, South Africa, reported a link between frontal fibrosing alopecia and LPP in the British Journal of Dermatology. “I definitely see this connection in my practice,” said Dr. Woolery-Lloyd, noting that “both conditions often result in the loss of both eyebrows.”
She recommends always using a topical anti-inflammatory that is safe for the face. One combination she uses is azelaic acid 20% plus hydrocortisone 2.5%.
“We do use a lot of azelaic acid in my practice because it’s affordable,” she said, at the meeting, provided by MedscapeLive! She added that the hardest area to treat in women is around the chin.
Two other conditions, ashy dermatosis and erythema dyschromicum perstans (EDP), are similar. Ashy dermatosis mimics LPP but occurs more prominently on the trunk and extremities. EDP often has a preceding ring of erythema.
Dr. Woolery-Lloyd said the term EDP is often used to cover both EDP and ashy dermatosis in North America because “ashy” can have a negative connotation.
She noted there is no consensus on effective therapy for LPP, ashy dermatosis, or EDP.
A review of the literature on EDP, which included 16 studies on treatment outcomes, found the following:
- Narrow-band ultraviolet B and tacrolimus were effective treatments with minimal side effects.
- Clofazimine was effective, but had side effects, which, ironically, included pigmentary changes.
- Griseofulvin, isotretinoin, and dapsone were comparatively ineffective as lesions recurred after discontinuation.
- Lasers were largely ineffective and can also result in postinflammatory hyperpigmentation and fibrosis.
Ochronosis
Dr. Woolery-Lloyd said she may see one to two patients a year with ochronosis, which is characterized by paradoxical darkening of the skin with long-term hydroquinone use. It usually starts with redness followed by blue-black patches on the face where hydroquinone is applied. In severe cases, blue-black papules and nodules can occur.
“When I give a patient hydroquinone, I always say: ‘I don’t want to see any redness,’” Dr. Woolery-Lloyd said. “If you have any redness, please stop because ochronosis is typically preceded by this redness.”
But, she noted, “people will come in actively using hydroquinone, will have the dark brown or deep black papules or macules on their face, and then this background of redness because they are so inflamed.”
She said that ochronosis can occur in any skin type, not just in patients with darker skin tones. Dr. Woolery-Lloyd advised: “Do not hesitate to biopsy the face if ochronosis is suspected. I always biopsy ochronosis.”
There are two reasons for doing so, she explained. It can help with the diagnosis but it will also provide the patient with an incentive to stop using hydroquinone. “People who are using hydroquinone are addicted to it. They love it. They don’t want to stop. They keep using it despite the fact that their face is getting darker.” When they see a biopsy report, they may be convinced to stop.
Dr. Woolery-Lloyd said she does a 2-mm punch biopsy in the crow’s feet area because there’s almost always ochronosis in that area and it does not leave an obvious scar.
Eventually, she said, if the person stops using hydroquinone, it will clear up, “but it will take years.” Again, here she has had success with her “special formula” of azelaic acid 20% plus hydrocortisone 2.5%
“Don’t tell patients there’s no treatment. That’s the take-home,” she said.
Drug-induced facial hyperpigmentation
“I see this all the time in my African American patients,” Dr. Woolery-Lloyd said. The condition usually is characterized by dark brown hyperpigmentation on the face.
In this situation, the first question to ask is whether the patient is taking medication for hypertension, and the second question is whether it is “HCTZ.” It’s important to use the abbreviation for hydrochlorothiazide – the most common cause of drug-induced facial hyperpigmentation – because that’s what a patient sees on the bottle.
If they are taking HCTZ or another blood pressure medication associated with photosensitivity, they need to switch to a nonphotosensitizing antihypertensive agent (there are several options) and they should start treatment with a topical anti-inflammatory, Dr. Woolery-Lloyd said. Then, she suggests introducing hydrocortisone 2.5% cream and a hydroquinone-free skin brightener (azelaic acid, for example).
Importantly, with any of these conditions, Dr Woolery-Lloyd said, dermatologists should talk with patients about realistic expectations. “It takes a long time for dermal pigment to clear,” she emphasized.
Dr. Woolery-Lloyd has been a speaker for Ortho Dermatologics, L’Oreal, and EPI; has done research for Pfizer, Galderma, Allergan, Arcutis, Vyne, Merz, and Eirion; and has been on advisory boards for L’Oreal, Allergan, Ortho Dermatologics, Pfizer, and Merz.
AT THE MEDSCAPELIVE! PIGMENTARY DISORDERS SYMPOSIUM
Tips, contraindications for superficial chemical peels reviewed
CHICAGO – Heather Woolery-Lloyd, MD, says she’s generally “risk averse,” but when it comes to superficial chemical peels, she’s in her comfort zone.
Superficial peeling is “one of the most common cosmetic procedures that I do,” Dr. Woolery-Lloyd, director of the skin of color division in the dermatology department at the University of Miami, said at the Pigmentary Disorders Exchange Symposium.
In her practice, .
Contraindications are an active bacterial infection, open wounds, and active herpes simplex virus. “If someone looks like they even have a remnant of a cold sore, I tell them to come back,” she said.
Setting expectations for patients is critical, Dr. Woolery-Lloyd said, as a series of superficial peels is needed before the desired results are evident.
The peel she uses most is salicylic acid, a beta-hydroxy acid, at a strength of 20%-30%. “It’s very effective on our acne patients,” she said at the meeting, provided by MedscapeLIVE! “If you’re just starting with peels, I think this is a very safe one. You don’t have to time it, and you don’t have to neutralize it,” and at lower concentrations, is “very safe.”
Dr. Woolery-Lloyd provided these other tips during her presentation:
- Even superficial peels can be uncomfortable, she noted, so she keeps a fan nearby to use when needed to help with discomfort.
- Find the peel you’re comfortable with, master that peel, and don’t jump from peel to peel. Get familiar with the side effects and how to predict results.
- Stop retinoids up to 7 days before a peel. Consider placing the patient on hydroquinone before the chemical peel to decrease the risk of hyperpigmentation.
- Before the procedure, prep the skin with acetone or alcohol. Applying petrolatum helps protect around the eyes, alar crease, and other sensitive areas, “or anywhere you’re concerned about the depth of the peel.”
- Application with rough gauze helps avoid the waste that comes with makeup sponges soaking up the product. It also helps add exfoliation.
- Have everything ready before starting the procedure, including (depending on the peel), a neutralizer or soapless cleanser. Although peels are generally safe, you want to be able to remove one quickly, if needed, without having to leave the room.
- Start with the lowest concentration (salicylic acid or glycolic acid) then titrate up. Ask patients about any reactions they experienced with the previous peel before making the decision on the next concentration.
- For a peel to treat hyperpigmentation, she recommends one peel about every 4 weeks for a series of 5-6 peels.
- After a peel, the patient should use a mineral sunscreen; chemical sunscreens will sting.
Know your comfort zone
Conference chair Pearl Grimes, MD, director of The Vitiligo & Pigmentation Institute of Southern California in Los Angeles, said superficial peels are best for dermatologists new to peeling until they gain comfort with experience.
Superficial and medium-depth peels work well for mild to moderate photoaging, she said at the meeting.
“We know that in darker skin we have more intrinsic aging rather than photoaging. We have more textural changes, hyperpigmentation,” Dr. Grimes said.
For Fitzpatrick skin types I-III, she said, “you can do superficial, medium, and deep peels.” For darker skin types, “I typically stay in the superficial, medium range.”
She said that she uses retinoids to exfoliate before a superficial peel but added, “you’ve got to stop them early because retinoids can make a superficial peel a medium-depth peel.”
Taking photos is important before any procedure, she said, as is spending time with patients clarifying their outcome expectations.
“I love peeling,” Dr. Grimes said. “And it’s cost effective. If you don’t want to spend a ton of money, it’s amazing what you can achieve with chemical peeling.”
When asked by a member of the audience whether they avoid superficial peels in women who are pregnant or breastfeeding, both Dr. Woolery-Lloyd and Dr. Grimes said they do avoid them in those patients.
Dr. Grimes said she tells her patients, especially in the first trimester, “I am the most conservative woman on the planet. I do nothing during the first trimester.”
Dr. Woolery-Lloyd has been a speaker for Ortho Dermatologics, Loreal and EPI, and has done research for Pfizer, Galderma, Allergan, Arcutis, Vyne, Merz, and Eirion. She has been on advisory boards for Loreal, Allergan, Ortho Dermatologics, Pfize,r and Merz. Dr. Grimes reports grant/research Support from Clinuvel Pharmaceuticals, Incyte, Johnson & Johnson, LASEROPTEK, L’Oréal USA, Pfizer, Procter & Gamble, skinbetter science, and Versicolor Technologies, and is on the speakers bureau/receives honoraria for non-CME for Incyte and Procter & Gamble; and is a consultant or is on the advisory board for L’Oréal USA and Procter & Gamble. She has stock options in Versicolor Technologies.
CHICAGO – Heather Woolery-Lloyd, MD, says she’s generally “risk averse,” but when it comes to superficial chemical peels, she’s in her comfort zone.
Superficial peeling is “one of the most common cosmetic procedures that I do,” Dr. Woolery-Lloyd, director of the skin of color division in the dermatology department at the University of Miami, said at the Pigmentary Disorders Exchange Symposium.
In her practice, .
Contraindications are an active bacterial infection, open wounds, and active herpes simplex virus. “If someone looks like they even have a remnant of a cold sore, I tell them to come back,” she said.
Setting expectations for patients is critical, Dr. Woolery-Lloyd said, as a series of superficial peels is needed before the desired results are evident.
The peel she uses most is salicylic acid, a beta-hydroxy acid, at a strength of 20%-30%. “It’s very effective on our acne patients,” she said at the meeting, provided by MedscapeLIVE! “If you’re just starting with peels, I think this is a very safe one. You don’t have to time it, and you don’t have to neutralize it,” and at lower concentrations, is “very safe.”
Dr. Woolery-Lloyd provided these other tips during her presentation:
- Even superficial peels can be uncomfortable, she noted, so she keeps a fan nearby to use when needed to help with discomfort.
- Find the peel you’re comfortable with, master that peel, and don’t jump from peel to peel. Get familiar with the side effects and how to predict results.
- Stop retinoids up to 7 days before a peel. Consider placing the patient on hydroquinone before the chemical peel to decrease the risk of hyperpigmentation.
- Before the procedure, prep the skin with acetone or alcohol. Applying petrolatum helps protect around the eyes, alar crease, and other sensitive areas, “or anywhere you’re concerned about the depth of the peel.”
- Application with rough gauze helps avoid the waste that comes with makeup sponges soaking up the product. It also helps add exfoliation.
- Have everything ready before starting the procedure, including (depending on the peel), a neutralizer or soapless cleanser. Although peels are generally safe, you want to be able to remove one quickly, if needed, without having to leave the room.
- Start with the lowest concentration (salicylic acid or glycolic acid) then titrate up. Ask patients about any reactions they experienced with the previous peel before making the decision on the next concentration.
- For a peel to treat hyperpigmentation, she recommends one peel about every 4 weeks for a series of 5-6 peels.
- After a peel, the patient should use a mineral sunscreen; chemical sunscreens will sting.
Know your comfort zone
Conference chair Pearl Grimes, MD, director of The Vitiligo & Pigmentation Institute of Southern California in Los Angeles, said superficial peels are best for dermatologists new to peeling until they gain comfort with experience.
Superficial and medium-depth peels work well for mild to moderate photoaging, she said at the meeting.
“We know that in darker skin we have more intrinsic aging rather than photoaging. We have more textural changes, hyperpigmentation,” Dr. Grimes said.
For Fitzpatrick skin types I-III, she said, “you can do superficial, medium, and deep peels.” For darker skin types, “I typically stay in the superficial, medium range.”
She said that she uses retinoids to exfoliate before a superficial peel but added, “you’ve got to stop them early because retinoids can make a superficial peel a medium-depth peel.”
Taking photos is important before any procedure, she said, as is spending time with patients clarifying their outcome expectations.
“I love peeling,” Dr. Grimes said. “And it’s cost effective. If you don’t want to spend a ton of money, it’s amazing what you can achieve with chemical peeling.”
When asked by a member of the audience whether they avoid superficial peels in women who are pregnant or breastfeeding, both Dr. Woolery-Lloyd and Dr. Grimes said they do avoid them in those patients.
Dr. Grimes said she tells her patients, especially in the first trimester, “I am the most conservative woman on the planet. I do nothing during the first trimester.”
Dr. Woolery-Lloyd has been a speaker for Ortho Dermatologics, Loreal and EPI, and has done research for Pfizer, Galderma, Allergan, Arcutis, Vyne, Merz, and Eirion. She has been on advisory boards for Loreal, Allergan, Ortho Dermatologics, Pfize,r and Merz. Dr. Grimes reports grant/research Support from Clinuvel Pharmaceuticals, Incyte, Johnson & Johnson, LASEROPTEK, L’Oréal USA, Pfizer, Procter & Gamble, skinbetter science, and Versicolor Technologies, and is on the speakers bureau/receives honoraria for non-CME for Incyte and Procter & Gamble; and is a consultant or is on the advisory board for L’Oréal USA and Procter & Gamble. She has stock options in Versicolor Technologies.
CHICAGO – Heather Woolery-Lloyd, MD, says she’s generally “risk averse,” but when it comes to superficial chemical peels, she’s in her comfort zone.
Superficial peeling is “one of the most common cosmetic procedures that I do,” Dr. Woolery-Lloyd, director of the skin of color division in the dermatology department at the University of Miami, said at the Pigmentary Disorders Exchange Symposium.
In her practice, .
Contraindications are an active bacterial infection, open wounds, and active herpes simplex virus. “If someone looks like they even have a remnant of a cold sore, I tell them to come back,” she said.
Setting expectations for patients is critical, Dr. Woolery-Lloyd said, as a series of superficial peels is needed before the desired results are evident.
The peel she uses most is salicylic acid, a beta-hydroxy acid, at a strength of 20%-30%. “It’s very effective on our acne patients,” she said at the meeting, provided by MedscapeLIVE! “If you’re just starting with peels, I think this is a very safe one. You don’t have to time it, and you don’t have to neutralize it,” and at lower concentrations, is “very safe.”
Dr. Woolery-Lloyd provided these other tips during her presentation:
- Even superficial peels can be uncomfortable, she noted, so she keeps a fan nearby to use when needed to help with discomfort.
- Find the peel you’re comfortable with, master that peel, and don’t jump from peel to peel. Get familiar with the side effects and how to predict results.
- Stop retinoids up to 7 days before a peel. Consider placing the patient on hydroquinone before the chemical peel to decrease the risk of hyperpigmentation.
- Before the procedure, prep the skin with acetone or alcohol. Applying petrolatum helps protect around the eyes, alar crease, and other sensitive areas, “or anywhere you’re concerned about the depth of the peel.”
- Application with rough gauze helps avoid the waste that comes with makeup sponges soaking up the product. It also helps add exfoliation.
- Have everything ready before starting the procedure, including (depending on the peel), a neutralizer or soapless cleanser. Although peels are generally safe, you want to be able to remove one quickly, if needed, without having to leave the room.
- Start with the lowest concentration (salicylic acid or glycolic acid) then titrate up. Ask patients about any reactions they experienced with the previous peel before making the decision on the next concentration.
- For a peel to treat hyperpigmentation, she recommends one peel about every 4 weeks for a series of 5-6 peels.
- After a peel, the patient should use a mineral sunscreen; chemical sunscreens will sting.
Know your comfort zone
Conference chair Pearl Grimes, MD, director of The Vitiligo & Pigmentation Institute of Southern California in Los Angeles, said superficial peels are best for dermatologists new to peeling until they gain comfort with experience.
Superficial and medium-depth peels work well for mild to moderate photoaging, she said at the meeting.
“We know that in darker skin we have more intrinsic aging rather than photoaging. We have more textural changes, hyperpigmentation,” Dr. Grimes said.
For Fitzpatrick skin types I-III, she said, “you can do superficial, medium, and deep peels.” For darker skin types, “I typically stay in the superficial, medium range.”
She said that she uses retinoids to exfoliate before a superficial peel but added, “you’ve got to stop them early because retinoids can make a superficial peel a medium-depth peel.”
Taking photos is important before any procedure, she said, as is spending time with patients clarifying their outcome expectations.
“I love peeling,” Dr. Grimes said. “And it’s cost effective. If you don’t want to spend a ton of money, it’s amazing what you can achieve with chemical peeling.”
When asked by a member of the audience whether they avoid superficial peels in women who are pregnant or breastfeeding, both Dr. Woolery-Lloyd and Dr. Grimes said they do avoid them in those patients.
Dr. Grimes said she tells her patients, especially in the first trimester, “I am the most conservative woman on the planet. I do nothing during the first trimester.”
Dr. Woolery-Lloyd has been a speaker for Ortho Dermatologics, Loreal and EPI, and has done research for Pfizer, Galderma, Allergan, Arcutis, Vyne, Merz, and Eirion. She has been on advisory boards for Loreal, Allergan, Ortho Dermatologics, Pfize,r and Merz. Dr. Grimes reports grant/research Support from Clinuvel Pharmaceuticals, Incyte, Johnson & Johnson, LASEROPTEK, L’Oréal USA, Pfizer, Procter & Gamble, skinbetter science, and Versicolor Technologies, and is on the speakers bureau/receives honoraria for non-CME for Incyte and Procter & Gamble; and is a consultant or is on the advisory board for L’Oréal USA and Procter & Gamble. She has stock options in Versicolor Technologies.
AT THE MEDSCAPE LIVE! PIGMENTARY DISORDERS SYMPOSIUM
SPF is only the start when recommending sunscreens
CHICAGO – at the inaugural Pigmentary Disorders Exchange Symposium.
Among the first factors physicians should consider before recommending sunscreen are a patient’s Fitzpatrick skin type, risks for burning or tanning, underlying skin disorders, and medications the patient is taking, Dr. Taylor, professor of dermatology at the University of Pennsylvania, Philadelphia, said at the meeting, provided by MedscapeLIVE! If patients are on hypertensives, for example, medications can make them more photosensitive.
Consider skin type
Dr. Taylor said she was dismayed by the results of a recent study, which found that 43% of dermatologists who responded to a survey reported that they never, rarely, or only sometimes took a patient’s skin type into account when making sunscreen recommendations. The article is referenced in a 2022 expert panel consensus paper she coauthored on photoprotection “for skin of all color.” But she pointed out that considering skin type alone is inadequate.
Questions for patients in joint decision-making should include lifestyle and work choices such as whether they work inside or outside, and how much sun exposure they get in a typical day. Heat and humidity levels should also be considered as should a patient’s susceptibility to dyspigmentation. “That could be overall darkening of the skin, mottled hyperpigmentation, actinic dyspigmentation, and, of course, propensity for skin cancer,” she said.
Use differs by race
Dr. Taylor, who is also vice chair for diversity, equity and inclusion in the department of dermatology at the University of Pennsylvania, pointed out that sunscreen use differs considerably by race.
In study of 8,952 adults in the United States who reported that they were sun sensitive found that a subset of adults with skin of color were significantly less likely to use sunscreen when compared with non-Hispanic White adults: Non-Hispanic Black (adjusted odds ratio, 0.43); non-Hispanic Asian (aOR. 0.54); and Hispanic (aOR, 0.70) adults.
In the study, non-Hispanic Black and Hispanic adults were significantly less likely to use sunscreens with an SPF greater than 15. In addition, non-Hispanic Black, non-Hispanic Asian, and Hispanic adults were significantly more likely than non-Hispanic Whites to wear long sleeves when outside. Such differences are important to keep in mind when advising patients about sunscreens, she said.
Protection for lighter-colored skin
Dr. Taylor said that, for patients with lighter skin tones, “we really want to protect against ultraviolet B as well as ultraviolet A, particularly ultraviolet A2. Ultraviolet radiation is going to cause DNA damage.” Patients with Fitzpatrick skin types I, II, or III are most susceptible to the effects of UVB with sunburn inflammation, which will cause erythema and tanning, and immunosuppression.
“For those who are I, II, and III, we do want to recommend a broad-spectrum, photostable sunscreen with a critical wavelength of 370 nanometers, which is going to protect from both UVB and UVA2,” she said.
Sunscreen recommendations are meant to be paired with advice to avoid midday sun from 10 a.m. to 2 p.m., wearing protective clothing and accessories, and seeking shade, she noted.
Dr. Taylor said, for those patients with lighter skin who are more susceptible to photodamage and premature aging, physicians should recommend sunscreens that contain DNA repair enzymes such as photolyases and sunscreens that contain antioxidants that can prevent or reverse DNA damage. “The exogenous form of these lyases have been manufactured and added to sunscreens,” Dr. Taylor said. “They’re readily available in the United States. That is something to consider for patients with significant photodamage.”
Retinoids can also help alleviate or reverse photodamage, she added.
Protection for darker-colored skin
“Many people of color do not believe they need sunscreen,” Dr. Taylor said. But studies show that, although there may be more intrinsic protection, sunscreen is still needed.
Over 30 years ago, Halder and colleagues reported that melanin in skin of color can filter two to five times more UV radiation, and in a paper on the photoprotective role of melanin, Kaidbey and colleagues found that skin types V and VI had an intrinsic SPF of 13 when compared with those who have lighter complexions, which had an SPF of 3.
Sunburns seem to occur less frequently in people with skin of color, but that may be because erythema is less apparent in people with darker skin tones or because of differences in personal definitions of sunburn, Dr. Taylor said.
“Skin of color can and does sustain sunburns and sunscreen will help prevent that,” she said, adding that a recommendation of an SPF 30 is likely sufficient for these patients. Dr. Taylor noted that sunscreens for patients with darker skin often cost substantially more than those for lighter skin, and that should be considered in recommendations.
Tinted sunscreens
Dr. Taylor said that, while broad-spectrum photostable sunscreens protect against UVB and UVA 2, they don’t protect from visible light and UVA1. Two methods to add that protection are using inorganic tinted sunscreens that contain iron oxide or pigmentary titanium dioxide. Dr. Taylor was a coauthor of a practical guide to tinted sunscreens published in 2022.
“For iron oxide, we want a concentration of 3% or greater,” she said, adding that the percentage often is not known because if it is contained in a sunscreen, it is listed as an inactive ingredient.
Another method to address visible light and UVA1 is the use of antioxidant-containing sunscreens with vitamin E, vitamin C, or licochalcone A, Dr. Taylor said.
During the question-and-answer period following her presentation, Amit Pandya, MD, adjunct professor of dermatology at University of Texas Southwestern Medical Center, Dallas, asked why “every makeup, every sunscreen, just says iron oxide,” since it is known that visible light will cause pigmentation, especially in those with darker skin tones.
He urged pushing for a law that would require listing the percentage of iron oxide on products to assure it is sufficient, according to what the literature recommends.
Conference Chair Pearl Grimes, MD, director of the Vitiligo and Pigmentation Institute of Southern California, Los Angeles, said that she recommends tinted sunscreens almost exclusively for her patients, but those with darker skin colors struggle to match color.
Dr. Taylor referred to an analysis published in 2022 of 58 over-the counter sunscreens, which found that only 38% of tinted sunscreens was available in more than one shade, “which is a problem for many of our patients.” She said that providing samples with different hues and tactile sensations may help patients find the right product.
Dr. Taylor disclosed being on the advisory boards for AbbVie, Avita Medical, Beiersdorf, Biorez, Eli Lily, EPI Health, Evolus, Galderma, Hugel America, Johnson and Johnson, L’Oreal USA, MedScape, Pfizer, Scientis US, UCB, Vichy Laboratories. She is a consultant for Arcutis Biothermapeutics, Beiersdorf, Bristol-Myers Squibb, Cara Therapeutics, Dior, and Sanofi. She has done contracted research for Allergan Aesthetics, Concert Pharmaceuticals, Croma-Pharma, Eli Lilly, and Pfizer, and has an ownership interest in Armis Scientific, GloGetter, and Piction Health.
Medscape and this news organization are owned by the same parent company.
CHICAGO – at the inaugural Pigmentary Disorders Exchange Symposium.
Among the first factors physicians should consider before recommending sunscreen are a patient’s Fitzpatrick skin type, risks for burning or tanning, underlying skin disorders, and medications the patient is taking, Dr. Taylor, professor of dermatology at the University of Pennsylvania, Philadelphia, said at the meeting, provided by MedscapeLIVE! If patients are on hypertensives, for example, medications can make them more photosensitive.
Consider skin type
Dr. Taylor said she was dismayed by the results of a recent study, which found that 43% of dermatologists who responded to a survey reported that they never, rarely, or only sometimes took a patient’s skin type into account when making sunscreen recommendations. The article is referenced in a 2022 expert panel consensus paper she coauthored on photoprotection “for skin of all color.” But she pointed out that considering skin type alone is inadequate.
Questions for patients in joint decision-making should include lifestyle and work choices such as whether they work inside or outside, and how much sun exposure they get in a typical day. Heat and humidity levels should also be considered as should a patient’s susceptibility to dyspigmentation. “That could be overall darkening of the skin, mottled hyperpigmentation, actinic dyspigmentation, and, of course, propensity for skin cancer,” she said.
Use differs by race
Dr. Taylor, who is also vice chair for diversity, equity and inclusion in the department of dermatology at the University of Pennsylvania, pointed out that sunscreen use differs considerably by race.
In study of 8,952 adults in the United States who reported that they were sun sensitive found that a subset of adults with skin of color were significantly less likely to use sunscreen when compared with non-Hispanic White adults: Non-Hispanic Black (adjusted odds ratio, 0.43); non-Hispanic Asian (aOR. 0.54); and Hispanic (aOR, 0.70) adults.
In the study, non-Hispanic Black and Hispanic adults were significantly less likely to use sunscreens with an SPF greater than 15. In addition, non-Hispanic Black, non-Hispanic Asian, and Hispanic adults were significantly more likely than non-Hispanic Whites to wear long sleeves when outside. Such differences are important to keep in mind when advising patients about sunscreens, she said.
Protection for lighter-colored skin
Dr. Taylor said that, for patients with lighter skin tones, “we really want to protect against ultraviolet B as well as ultraviolet A, particularly ultraviolet A2. Ultraviolet radiation is going to cause DNA damage.” Patients with Fitzpatrick skin types I, II, or III are most susceptible to the effects of UVB with sunburn inflammation, which will cause erythema and tanning, and immunosuppression.
“For those who are I, II, and III, we do want to recommend a broad-spectrum, photostable sunscreen with a critical wavelength of 370 nanometers, which is going to protect from both UVB and UVA2,” she said.
Sunscreen recommendations are meant to be paired with advice to avoid midday sun from 10 a.m. to 2 p.m., wearing protective clothing and accessories, and seeking shade, she noted.
Dr. Taylor said, for those patients with lighter skin who are more susceptible to photodamage and premature aging, physicians should recommend sunscreens that contain DNA repair enzymes such as photolyases and sunscreens that contain antioxidants that can prevent or reverse DNA damage. “The exogenous form of these lyases have been manufactured and added to sunscreens,” Dr. Taylor said. “They’re readily available in the United States. That is something to consider for patients with significant photodamage.”
Retinoids can also help alleviate or reverse photodamage, she added.
Protection for darker-colored skin
“Many people of color do not believe they need sunscreen,” Dr. Taylor said. But studies show that, although there may be more intrinsic protection, sunscreen is still needed.
Over 30 years ago, Halder and colleagues reported that melanin in skin of color can filter two to five times more UV radiation, and in a paper on the photoprotective role of melanin, Kaidbey and colleagues found that skin types V and VI had an intrinsic SPF of 13 when compared with those who have lighter complexions, which had an SPF of 3.
Sunburns seem to occur less frequently in people with skin of color, but that may be because erythema is less apparent in people with darker skin tones or because of differences in personal definitions of sunburn, Dr. Taylor said.
“Skin of color can and does sustain sunburns and sunscreen will help prevent that,” she said, adding that a recommendation of an SPF 30 is likely sufficient for these patients. Dr. Taylor noted that sunscreens for patients with darker skin often cost substantially more than those for lighter skin, and that should be considered in recommendations.
Tinted sunscreens
Dr. Taylor said that, while broad-spectrum photostable sunscreens protect against UVB and UVA 2, they don’t protect from visible light and UVA1. Two methods to add that protection are using inorganic tinted sunscreens that contain iron oxide or pigmentary titanium dioxide. Dr. Taylor was a coauthor of a practical guide to tinted sunscreens published in 2022.
“For iron oxide, we want a concentration of 3% or greater,” she said, adding that the percentage often is not known because if it is contained in a sunscreen, it is listed as an inactive ingredient.
Another method to address visible light and UVA1 is the use of antioxidant-containing sunscreens with vitamin E, vitamin C, or licochalcone A, Dr. Taylor said.
During the question-and-answer period following her presentation, Amit Pandya, MD, adjunct professor of dermatology at University of Texas Southwestern Medical Center, Dallas, asked why “every makeup, every sunscreen, just says iron oxide,” since it is known that visible light will cause pigmentation, especially in those with darker skin tones.
He urged pushing for a law that would require listing the percentage of iron oxide on products to assure it is sufficient, according to what the literature recommends.
Conference Chair Pearl Grimes, MD, director of the Vitiligo and Pigmentation Institute of Southern California, Los Angeles, said that she recommends tinted sunscreens almost exclusively for her patients, but those with darker skin colors struggle to match color.
Dr. Taylor referred to an analysis published in 2022 of 58 over-the counter sunscreens, which found that only 38% of tinted sunscreens was available in more than one shade, “which is a problem for many of our patients.” She said that providing samples with different hues and tactile sensations may help patients find the right product.
Dr. Taylor disclosed being on the advisory boards for AbbVie, Avita Medical, Beiersdorf, Biorez, Eli Lily, EPI Health, Evolus, Galderma, Hugel America, Johnson and Johnson, L’Oreal USA, MedScape, Pfizer, Scientis US, UCB, Vichy Laboratories. She is a consultant for Arcutis Biothermapeutics, Beiersdorf, Bristol-Myers Squibb, Cara Therapeutics, Dior, and Sanofi. She has done contracted research for Allergan Aesthetics, Concert Pharmaceuticals, Croma-Pharma, Eli Lilly, and Pfizer, and has an ownership interest in Armis Scientific, GloGetter, and Piction Health.
Medscape and this news organization are owned by the same parent company.
CHICAGO – at the inaugural Pigmentary Disorders Exchange Symposium.
Among the first factors physicians should consider before recommending sunscreen are a patient’s Fitzpatrick skin type, risks for burning or tanning, underlying skin disorders, and medications the patient is taking, Dr. Taylor, professor of dermatology at the University of Pennsylvania, Philadelphia, said at the meeting, provided by MedscapeLIVE! If patients are on hypertensives, for example, medications can make them more photosensitive.
Consider skin type
Dr. Taylor said she was dismayed by the results of a recent study, which found that 43% of dermatologists who responded to a survey reported that they never, rarely, or only sometimes took a patient’s skin type into account when making sunscreen recommendations. The article is referenced in a 2022 expert panel consensus paper she coauthored on photoprotection “for skin of all color.” But she pointed out that considering skin type alone is inadequate.
Questions for patients in joint decision-making should include lifestyle and work choices such as whether they work inside or outside, and how much sun exposure they get in a typical day. Heat and humidity levels should also be considered as should a patient’s susceptibility to dyspigmentation. “That could be overall darkening of the skin, mottled hyperpigmentation, actinic dyspigmentation, and, of course, propensity for skin cancer,” she said.
Use differs by race
Dr. Taylor, who is also vice chair for diversity, equity and inclusion in the department of dermatology at the University of Pennsylvania, pointed out that sunscreen use differs considerably by race.
In study of 8,952 adults in the United States who reported that they were sun sensitive found that a subset of adults with skin of color were significantly less likely to use sunscreen when compared with non-Hispanic White adults: Non-Hispanic Black (adjusted odds ratio, 0.43); non-Hispanic Asian (aOR. 0.54); and Hispanic (aOR, 0.70) adults.
In the study, non-Hispanic Black and Hispanic adults were significantly less likely to use sunscreens with an SPF greater than 15. In addition, non-Hispanic Black, non-Hispanic Asian, and Hispanic adults were significantly more likely than non-Hispanic Whites to wear long sleeves when outside. Such differences are important to keep in mind when advising patients about sunscreens, she said.
Protection for lighter-colored skin
Dr. Taylor said that, for patients with lighter skin tones, “we really want to protect against ultraviolet B as well as ultraviolet A, particularly ultraviolet A2. Ultraviolet radiation is going to cause DNA damage.” Patients with Fitzpatrick skin types I, II, or III are most susceptible to the effects of UVB with sunburn inflammation, which will cause erythema and tanning, and immunosuppression.
“For those who are I, II, and III, we do want to recommend a broad-spectrum, photostable sunscreen with a critical wavelength of 370 nanometers, which is going to protect from both UVB and UVA2,” she said.
Sunscreen recommendations are meant to be paired with advice to avoid midday sun from 10 a.m. to 2 p.m., wearing protective clothing and accessories, and seeking shade, she noted.
Dr. Taylor said, for those patients with lighter skin who are more susceptible to photodamage and premature aging, physicians should recommend sunscreens that contain DNA repair enzymes such as photolyases and sunscreens that contain antioxidants that can prevent or reverse DNA damage. “The exogenous form of these lyases have been manufactured and added to sunscreens,” Dr. Taylor said. “They’re readily available in the United States. That is something to consider for patients with significant photodamage.”
Retinoids can also help alleviate or reverse photodamage, she added.
Protection for darker-colored skin
“Many people of color do not believe they need sunscreen,” Dr. Taylor said. But studies show that, although there may be more intrinsic protection, sunscreen is still needed.
Over 30 years ago, Halder and colleagues reported that melanin in skin of color can filter two to five times more UV radiation, and in a paper on the photoprotective role of melanin, Kaidbey and colleagues found that skin types V and VI had an intrinsic SPF of 13 when compared with those who have lighter complexions, which had an SPF of 3.
Sunburns seem to occur less frequently in people with skin of color, but that may be because erythema is less apparent in people with darker skin tones or because of differences in personal definitions of sunburn, Dr. Taylor said.
“Skin of color can and does sustain sunburns and sunscreen will help prevent that,” she said, adding that a recommendation of an SPF 30 is likely sufficient for these patients. Dr. Taylor noted that sunscreens for patients with darker skin often cost substantially more than those for lighter skin, and that should be considered in recommendations.
Tinted sunscreens
Dr. Taylor said that, while broad-spectrum photostable sunscreens protect against UVB and UVA 2, they don’t protect from visible light and UVA1. Two methods to add that protection are using inorganic tinted sunscreens that contain iron oxide or pigmentary titanium dioxide. Dr. Taylor was a coauthor of a practical guide to tinted sunscreens published in 2022.
“For iron oxide, we want a concentration of 3% or greater,” she said, adding that the percentage often is not known because if it is contained in a sunscreen, it is listed as an inactive ingredient.
Another method to address visible light and UVA1 is the use of antioxidant-containing sunscreens with vitamin E, vitamin C, or licochalcone A, Dr. Taylor said.
During the question-and-answer period following her presentation, Amit Pandya, MD, adjunct professor of dermatology at University of Texas Southwestern Medical Center, Dallas, asked why “every makeup, every sunscreen, just says iron oxide,” since it is known that visible light will cause pigmentation, especially in those with darker skin tones.
He urged pushing for a law that would require listing the percentage of iron oxide on products to assure it is sufficient, according to what the literature recommends.
Conference Chair Pearl Grimes, MD, director of the Vitiligo and Pigmentation Institute of Southern California, Los Angeles, said that she recommends tinted sunscreens almost exclusively for her patients, but those with darker skin colors struggle to match color.
Dr. Taylor referred to an analysis published in 2022 of 58 over-the counter sunscreens, which found that only 38% of tinted sunscreens was available in more than one shade, “which is a problem for many of our patients.” She said that providing samples with different hues and tactile sensations may help patients find the right product.
Dr. Taylor disclosed being on the advisory boards for AbbVie, Avita Medical, Beiersdorf, Biorez, Eli Lily, EPI Health, Evolus, Galderma, Hugel America, Johnson and Johnson, L’Oreal USA, MedScape, Pfizer, Scientis US, UCB, Vichy Laboratories. She is a consultant for Arcutis Biothermapeutics, Beiersdorf, Bristol-Myers Squibb, Cara Therapeutics, Dior, and Sanofi. She has done contracted research for Allergan Aesthetics, Concert Pharmaceuticals, Croma-Pharma, Eli Lilly, and Pfizer, and has an ownership interest in Armis Scientific, GloGetter, and Piction Health.
Medscape and this news organization are owned by the same parent company.
AT THE MEDSCAPELIVE! PIGMENTARY DISORDERS SYMPOSIUM
Nevus Sebaceus With Novel HRAS Sequence Variant Mutation Misdiagnosed as Alopecia Areata
To the Editor:
A 12-year-old girl presented to the dermatology clinic for evaluation of a congenital scalp lesion. The patient was diagnosed with alopecia areata by a dermatologist at 4 years of age, and she was treated with topical corticosteroids and minoxidil, which failed to resolve her condition. Physical examination revealed an 8×10-cm, well-demarcated, yellowish-pink plaque located over the vertex and right parietal scalp (Figure 1A), extending down to the right preauricular cheek (Figure 1B) in a linear configuration with blaschkoid features. The scalp plaque appeared bald and completely lacking in terminal hairs but contained numerous fine vellus hairs (Figure 1A). A 6-mm, oval-appearing, pigmented papule was present in the plaque, and a few smaller, scattered, pigmented papules were noted in the vertex region (Figure 1A).
The cutaneous examination was otherwise unremarkable. A review of systems was negative, except for a history of attention-deficit/hyperactivity disorder. There was no history of seizures or other neurocognitive developmental abnormalities.
A 4-mm punch biopsy of the vertex scalp included the pigmented lesion but excluded an adnexal neoplasm. Epidermal acanthosis and mild papillomatosis were reported on microscopic examination. Multiple prominent sebaceous glands without associated hair follicles, which emptied directly onto the epidermal surface, were noted in the dermis (Figure 2). Several apocrine glands were observed (Figure 3). Epidermal and dermal melanocytic nests were highlighted with SOX-10 and Melan-A immunohistochemical stains, confirming the presence of a benign compound nevus. The punch biopsy analysis confirmed the diagnosis of a nevus sebaceus (NS) of Jadassohn (organoid nevus) with incidental compound nevus. Additional 4-mm punch biopsies were obtained for genetic testing, performed by the Genomics and Pathology Services at Washington University (St. Louis, Missouri). A missense HRAS p.G12V variant was observed in the tissue. A negative blood test result ruled out a germline mutation. The patient was managed with active observation of the lesion to evaluate for potential formation of neoplasms, as well as continuity of care with the dermatology clinic, considering the extent of the lesions, to monitor the development of any new medical conditions that would be concerning for syndromes associated with NS.
Nevus sebaceus is a benign skin hamartoma caused by a congenital defect in the pilosebaceous follicular unit and consists of epidermal, sebaceous, and apocrine elements.1,2 In dermatology patients, the prevalence of NS ranges from 0.05% to 1%.1 In 90% of cases, NS presents at birth as a 1- to 10-cm, round or linear, yellowish-orange, hairless plaque located on the scalp. It also may appear on the face, neck, trunk, oral mucosa, or labia minora.1,3 Although NS is a benign condition, secondary tumors may form within the lesion.3
The physical and histologic characteristics of NS evolve as the patient ages. In childhood, NS typically appears as a yellow-pink macule or patch with mild to moderate epidermal hyperplasia. Patients exhibit underdeveloped sebaceous glands, immature hair follicles, hyperkeratosis, and acanthosis.1,3,4 The development of early lesions can be quite subtle and can lead to diagnostic uncertainty, as described in our patient. During puberty, lesions thicken due to papillomatous hyperplasia in the epidermis, and the number and size of sebaceous and apocrine glands increase.4 In adults, the risk for secondary tumor formation increases. These physical and histologic transformations, including secondary tumor formation, are thought to be stimulated by the action of postpubertal androgens.1
Nevus sebaceus is associated with both benign and malignant secondary tumor formation; however, fewer than 1% of tumors are malignant.1 In a retrospective analysis, Idriss and Elston5 (N=707) reported that 21.4% of patients with NS had secondary neoplasms; 18.9% of the secondary neoplasms were benign, and 2.5% were malignant. Additionally, this study showed that secondary tumor formation can occur in children, though it typically occurs in adults. Benign neoplasms were reported in 5 children in the subset aged 0 to 10 years and 10 children in the subset aged 11 to 17 years; 1 child developed a malignant neoplasm in the latter subset.5 The most common NS-associated benign neoplasms include trichoblastoma and syringocystadenoma papilliferum. Others include trichilemmoma, apocrine/eccrine adenoma, and sebaceoma.1 Nevus sebaceus–associated malignant neoplasms include basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, carcinosarcoma, and sebaceous carcinoma.3
Our patient was incorrectly diagnosed and treated for alopecia areata before an eventual diagnosis of NS was confirmed by biopsy. Additional genetic studies revealed a novel mutation in the HRAS gene, the most commonly affected gene in NS. The most common mutation location seen in more than 90% of NS lesions is HRAS c.37G>C (p.G13R), while KRAS mutations account for almost all the remaining cases.3 In our patient, a pathogenic missense HRAS p.G12V variant of somatic origin was detected with DNA extraction and sequencing from a fresh tissue sample acquired from two 4-mm punch biopsies performed on the lesion. The following genes were sequenced and found to be uninvolved: BRAF, FGFR1, FGFR2, FGFR3, GNA11, GNAQ, KRAS, MAP3K3, NRAS, PIK3CA, and TEK. The Sanger sequencing method for comparative analysis performed on peripheral blood was negative.
Nevus sebaceus typically is caused by a sporadic mutation, though familial cases have been reported.1 Additionally, germline HRAS mutations can lead to Costello syndrome, an autosomal-dominant disorder characterized by short stature; intellectual disabilities; coarse facial features; facial and perianal papillomata; cardiac defects; loose skin; joint hyperflexibility; and an increased risk for malignant tumors including rhabdomyosarcoma, neuroblastoma, and transitional cell carcinoma of the bladder.6
The diagnosis of NS often can be made clinically but can be difficult to confirm in underdeveloped lesions in young children. The differential diagnosis can include alopecia areata, aplasia cutis congenita, juvenile xanthogranuloma, epidermal nevus, de novo syringocystadenoma papilliferum, and solitary mastocytoma.1 Nevus sebaceus can be associated with 4 additional syndromes: Schimmelpenning syndrome; phacomatosis pigmentokeratotica; didymosis aplasticosebacea; and SCALP (sebaceus nevus, central nervous system malformations, aplasia cutis congenital, limbal dermoid, pigmented nevus) syndrome.1 Approximately 7% of NS cases may be associated with Schimmelpenning-Feuerstein-Mims (SFM) syndrome, a more severe condition that leads to systemic involvement and abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.1,3 Phacomatosis pigmentokeratotica has speckled lentiginous nevi, as well as abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.1 Didymosis aplasticosebacea is the concurrence of NS and aplasia cutis congenita.
The definitive treatment of NS is surgical excision. Alternative therapies include photodynamic therapy, fractional laser resurfacing, and dermabrasion; these are not definitive treatments, and patients must be monitored for the development of secondary neoplasms. Multiple variables must be considered when determining treatment, including patient age, risk potential for malignancy, and surgery-associated risks.1 In our patient, given the extent of the lesions, active observation and follow-up was agreed upon for management.
This case demonstrates the importance of considering NS as an alternative diagnosis when alopecia areata has been diagnosed in a child who is unresponsive to treatments. After the diagnosis of NS is confirmed, more serious associated syndromes should be ruled out, and treatment should be tailored to each case.
- Patel P, Malik K, Khachemoune A. Sebaceus and Becker’s nevus: overview of their presentation, pathogenesis, associations, and treatment. Am J Clin Dermatol. 2015;16:197-204. doi:10.1007/s40257-015-0123-y
- Azzam MJ, Beutler BD, Calame A, et al. Osteoma cutis associated with nevus sebaceus: case report and review of cutaneous osteoma-associated skin tumors (COASTs). Cureus. 2019;11:E4959. doi:10.7759/cureus.4959
- Aslam A, Salam A, Griffiths CEM, et al. Naevus sebaceus: a mosaic RASopathy. Clin Exp Dermatol. 2014;39:1-6. doi:10.1111/ced.12209
- Basu P, Erickson CP, Calame A, et al. Nevus sebaceus with syringocystadenoma papilliferum, prurigo nodularis, apocrine cystadenoma, basaloid follicular proliferation, and sebaceoma: case report and review of nevus sebaceus-associated conditions. Dermatol Online J. 2020;26:13030/qt85k968bk.
- Idriss MH, Elston DM. Secondary neoplasms associated with nevus sebaceus of Jadassohn: a study of 707 cases. J Am Acad Dermatol. 2014;70:332-337. doi:10.1016/j.jaad.2013.10.004
- Gripp KW, Rauen KA. Costello syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 1993-2020. August 29, 2006. Updated August 29, 2019. https://pubmed.ncbi.nlm.nih.gov/20301680
To the Editor:
A 12-year-old girl presented to the dermatology clinic for evaluation of a congenital scalp lesion. The patient was diagnosed with alopecia areata by a dermatologist at 4 years of age, and she was treated with topical corticosteroids and minoxidil, which failed to resolve her condition. Physical examination revealed an 8×10-cm, well-demarcated, yellowish-pink plaque located over the vertex and right parietal scalp (Figure 1A), extending down to the right preauricular cheek (Figure 1B) in a linear configuration with blaschkoid features. The scalp plaque appeared bald and completely lacking in terminal hairs but contained numerous fine vellus hairs (Figure 1A). A 6-mm, oval-appearing, pigmented papule was present in the plaque, and a few smaller, scattered, pigmented papules were noted in the vertex region (Figure 1A).
The cutaneous examination was otherwise unremarkable. A review of systems was negative, except for a history of attention-deficit/hyperactivity disorder. There was no history of seizures or other neurocognitive developmental abnormalities.
A 4-mm punch biopsy of the vertex scalp included the pigmented lesion but excluded an adnexal neoplasm. Epidermal acanthosis and mild papillomatosis were reported on microscopic examination. Multiple prominent sebaceous glands without associated hair follicles, which emptied directly onto the epidermal surface, were noted in the dermis (Figure 2). Several apocrine glands were observed (Figure 3). Epidermal and dermal melanocytic nests were highlighted with SOX-10 and Melan-A immunohistochemical stains, confirming the presence of a benign compound nevus. The punch biopsy analysis confirmed the diagnosis of a nevus sebaceus (NS) of Jadassohn (organoid nevus) with incidental compound nevus. Additional 4-mm punch biopsies were obtained for genetic testing, performed by the Genomics and Pathology Services at Washington University (St. Louis, Missouri). A missense HRAS p.G12V variant was observed in the tissue. A negative blood test result ruled out a germline mutation. The patient was managed with active observation of the lesion to evaluate for potential formation of neoplasms, as well as continuity of care with the dermatology clinic, considering the extent of the lesions, to monitor the development of any new medical conditions that would be concerning for syndromes associated with NS.
Nevus sebaceus is a benign skin hamartoma caused by a congenital defect in the pilosebaceous follicular unit and consists of epidermal, sebaceous, and apocrine elements.1,2 In dermatology patients, the prevalence of NS ranges from 0.05% to 1%.1 In 90% of cases, NS presents at birth as a 1- to 10-cm, round or linear, yellowish-orange, hairless plaque located on the scalp. It also may appear on the face, neck, trunk, oral mucosa, or labia minora.1,3 Although NS is a benign condition, secondary tumors may form within the lesion.3
The physical and histologic characteristics of NS evolve as the patient ages. In childhood, NS typically appears as a yellow-pink macule or patch with mild to moderate epidermal hyperplasia. Patients exhibit underdeveloped sebaceous glands, immature hair follicles, hyperkeratosis, and acanthosis.1,3,4 The development of early lesions can be quite subtle and can lead to diagnostic uncertainty, as described in our patient. During puberty, lesions thicken due to papillomatous hyperplasia in the epidermis, and the number and size of sebaceous and apocrine glands increase.4 In adults, the risk for secondary tumor formation increases. These physical and histologic transformations, including secondary tumor formation, are thought to be stimulated by the action of postpubertal androgens.1
Nevus sebaceus is associated with both benign and malignant secondary tumor formation; however, fewer than 1% of tumors are malignant.1 In a retrospective analysis, Idriss and Elston5 (N=707) reported that 21.4% of patients with NS had secondary neoplasms; 18.9% of the secondary neoplasms were benign, and 2.5% were malignant. Additionally, this study showed that secondary tumor formation can occur in children, though it typically occurs in adults. Benign neoplasms were reported in 5 children in the subset aged 0 to 10 years and 10 children in the subset aged 11 to 17 years; 1 child developed a malignant neoplasm in the latter subset.5 The most common NS-associated benign neoplasms include trichoblastoma and syringocystadenoma papilliferum. Others include trichilemmoma, apocrine/eccrine adenoma, and sebaceoma.1 Nevus sebaceus–associated malignant neoplasms include basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, carcinosarcoma, and sebaceous carcinoma.3
Our patient was incorrectly diagnosed and treated for alopecia areata before an eventual diagnosis of NS was confirmed by biopsy. Additional genetic studies revealed a novel mutation in the HRAS gene, the most commonly affected gene in NS. The most common mutation location seen in more than 90% of NS lesions is HRAS c.37G>C (p.G13R), while KRAS mutations account for almost all the remaining cases.3 In our patient, a pathogenic missense HRAS p.G12V variant of somatic origin was detected with DNA extraction and sequencing from a fresh tissue sample acquired from two 4-mm punch biopsies performed on the lesion. The following genes were sequenced and found to be uninvolved: BRAF, FGFR1, FGFR2, FGFR3, GNA11, GNAQ, KRAS, MAP3K3, NRAS, PIK3CA, and TEK. The Sanger sequencing method for comparative analysis performed on peripheral blood was negative.
Nevus sebaceus typically is caused by a sporadic mutation, though familial cases have been reported.1 Additionally, germline HRAS mutations can lead to Costello syndrome, an autosomal-dominant disorder characterized by short stature; intellectual disabilities; coarse facial features; facial and perianal papillomata; cardiac defects; loose skin; joint hyperflexibility; and an increased risk for malignant tumors including rhabdomyosarcoma, neuroblastoma, and transitional cell carcinoma of the bladder.6
The diagnosis of NS often can be made clinically but can be difficult to confirm in underdeveloped lesions in young children. The differential diagnosis can include alopecia areata, aplasia cutis congenita, juvenile xanthogranuloma, epidermal nevus, de novo syringocystadenoma papilliferum, and solitary mastocytoma.1 Nevus sebaceus can be associated with 4 additional syndromes: Schimmelpenning syndrome; phacomatosis pigmentokeratotica; didymosis aplasticosebacea; and SCALP (sebaceus nevus, central nervous system malformations, aplasia cutis congenital, limbal dermoid, pigmented nevus) syndrome.1 Approximately 7% of NS cases may be associated with Schimmelpenning-Feuerstein-Mims (SFM) syndrome, a more severe condition that leads to systemic involvement and abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.1,3 Phacomatosis pigmentokeratotica has speckled lentiginous nevi, as well as abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.1 Didymosis aplasticosebacea is the concurrence of NS and aplasia cutis congenita.
The definitive treatment of NS is surgical excision. Alternative therapies include photodynamic therapy, fractional laser resurfacing, and dermabrasion; these are not definitive treatments, and patients must be monitored for the development of secondary neoplasms. Multiple variables must be considered when determining treatment, including patient age, risk potential for malignancy, and surgery-associated risks.1 In our patient, given the extent of the lesions, active observation and follow-up was agreed upon for management.
This case demonstrates the importance of considering NS as an alternative diagnosis when alopecia areata has been diagnosed in a child who is unresponsive to treatments. After the diagnosis of NS is confirmed, more serious associated syndromes should be ruled out, and treatment should be tailored to each case.
To the Editor:
A 12-year-old girl presented to the dermatology clinic for evaluation of a congenital scalp lesion. The patient was diagnosed with alopecia areata by a dermatologist at 4 years of age, and she was treated with topical corticosteroids and minoxidil, which failed to resolve her condition. Physical examination revealed an 8×10-cm, well-demarcated, yellowish-pink plaque located over the vertex and right parietal scalp (Figure 1A), extending down to the right preauricular cheek (Figure 1B) in a linear configuration with blaschkoid features. The scalp plaque appeared bald and completely lacking in terminal hairs but contained numerous fine vellus hairs (Figure 1A). A 6-mm, oval-appearing, pigmented papule was present in the plaque, and a few smaller, scattered, pigmented papules were noted in the vertex region (Figure 1A).
The cutaneous examination was otherwise unremarkable. A review of systems was negative, except for a history of attention-deficit/hyperactivity disorder. There was no history of seizures or other neurocognitive developmental abnormalities.
A 4-mm punch biopsy of the vertex scalp included the pigmented lesion but excluded an adnexal neoplasm. Epidermal acanthosis and mild papillomatosis were reported on microscopic examination. Multiple prominent sebaceous glands without associated hair follicles, which emptied directly onto the epidermal surface, were noted in the dermis (Figure 2). Several apocrine glands were observed (Figure 3). Epidermal and dermal melanocytic nests were highlighted with SOX-10 and Melan-A immunohistochemical stains, confirming the presence of a benign compound nevus. The punch biopsy analysis confirmed the diagnosis of a nevus sebaceus (NS) of Jadassohn (organoid nevus) with incidental compound nevus. Additional 4-mm punch biopsies were obtained for genetic testing, performed by the Genomics and Pathology Services at Washington University (St. Louis, Missouri). A missense HRAS p.G12V variant was observed in the tissue. A negative blood test result ruled out a germline mutation. The patient was managed with active observation of the lesion to evaluate for potential formation of neoplasms, as well as continuity of care with the dermatology clinic, considering the extent of the lesions, to monitor the development of any new medical conditions that would be concerning for syndromes associated with NS.
Nevus sebaceus is a benign skin hamartoma caused by a congenital defect in the pilosebaceous follicular unit and consists of epidermal, sebaceous, and apocrine elements.1,2 In dermatology patients, the prevalence of NS ranges from 0.05% to 1%.1 In 90% of cases, NS presents at birth as a 1- to 10-cm, round or linear, yellowish-orange, hairless plaque located on the scalp. It also may appear on the face, neck, trunk, oral mucosa, or labia minora.1,3 Although NS is a benign condition, secondary tumors may form within the lesion.3
The physical and histologic characteristics of NS evolve as the patient ages. In childhood, NS typically appears as a yellow-pink macule or patch with mild to moderate epidermal hyperplasia. Patients exhibit underdeveloped sebaceous glands, immature hair follicles, hyperkeratosis, and acanthosis.1,3,4 The development of early lesions can be quite subtle and can lead to diagnostic uncertainty, as described in our patient. During puberty, lesions thicken due to papillomatous hyperplasia in the epidermis, and the number and size of sebaceous and apocrine glands increase.4 In adults, the risk for secondary tumor formation increases. These physical and histologic transformations, including secondary tumor formation, are thought to be stimulated by the action of postpubertal androgens.1
Nevus sebaceus is associated with both benign and malignant secondary tumor formation; however, fewer than 1% of tumors are malignant.1 In a retrospective analysis, Idriss and Elston5 (N=707) reported that 21.4% of patients with NS had secondary neoplasms; 18.9% of the secondary neoplasms were benign, and 2.5% were malignant. Additionally, this study showed that secondary tumor formation can occur in children, though it typically occurs in adults. Benign neoplasms were reported in 5 children in the subset aged 0 to 10 years and 10 children in the subset aged 11 to 17 years; 1 child developed a malignant neoplasm in the latter subset.5 The most common NS-associated benign neoplasms include trichoblastoma and syringocystadenoma papilliferum. Others include trichilemmoma, apocrine/eccrine adenoma, and sebaceoma.1 Nevus sebaceus–associated malignant neoplasms include basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, carcinosarcoma, and sebaceous carcinoma.3
Our patient was incorrectly diagnosed and treated for alopecia areata before an eventual diagnosis of NS was confirmed by biopsy. Additional genetic studies revealed a novel mutation in the HRAS gene, the most commonly affected gene in NS. The most common mutation location seen in more than 90% of NS lesions is HRAS c.37G>C (p.G13R), while KRAS mutations account for almost all the remaining cases.3 In our patient, a pathogenic missense HRAS p.G12V variant of somatic origin was detected with DNA extraction and sequencing from a fresh tissue sample acquired from two 4-mm punch biopsies performed on the lesion. The following genes were sequenced and found to be uninvolved: BRAF, FGFR1, FGFR2, FGFR3, GNA11, GNAQ, KRAS, MAP3K3, NRAS, PIK3CA, and TEK. The Sanger sequencing method for comparative analysis performed on peripheral blood was negative.
Nevus sebaceus typically is caused by a sporadic mutation, though familial cases have been reported.1 Additionally, germline HRAS mutations can lead to Costello syndrome, an autosomal-dominant disorder characterized by short stature; intellectual disabilities; coarse facial features; facial and perianal papillomata; cardiac defects; loose skin; joint hyperflexibility; and an increased risk for malignant tumors including rhabdomyosarcoma, neuroblastoma, and transitional cell carcinoma of the bladder.6
The diagnosis of NS often can be made clinically but can be difficult to confirm in underdeveloped lesions in young children. The differential diagnosis can include alopecia areata, aplasia cutis congenita, juvenile xanthogranuloma, epidermal nevus, de novo syringocystadenoma papilliferum, and solitary mastocytoma.1 Nevus sebaceus can be associated with 4 additional syndromes: Schimmelpenning syndrome; phacomatosis pigmentokeratotica; didymosis aplasticosebacea; and SCALP (sebaceus nevus, central nervous system malformations, aplasia cutis congenital, limbal dermoid, pigmented nevus) syndrome.1 Approximately 7% of NS cases may be associated with Schimmelpenning-Feuerstein-Mims (SFM) syndrome, a more severe condition that leads to systemic involvement and abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.1,3 Phacomatosis pigmentokeratotica has speckled lentiginous nevi, as well as abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.1 Didymosis aplasticosebacea is the concurrence of NS and aplasia cutis congenita.
The definitive treatment of NS is surgical excision. Alternative therapies include photodynamic therapy, fractional laser resurfacing, and dermabrasion; these are not definitive treatments, and patients must be monitored for the development of secondary neoplasms. Multiple variables must be considered when determining treatment, including patient age, risk potential for malignancy, and surgery-associated risks.1 In our patient, given the extent of the lesions, active observation and follow-up was agreed upon for management.
This case demonstrates the importance of considering NS as an alternative diagnosis when alopecia areata has been diagnosed in a child who is unresponsive to treatments. After the diagnosis of NS is confirmed, more serious associated syndromes should be ruled out, and treatment should be tailored to each case.
- Patel P, Malik K, Khachemoune A. Sebaceus and Becker’s nevus: overview of their presentation, pathogenesis, associations, and treatment. Am J Clin Dermatol. 2015;16:197-204. doi:10.1007/s40257-015-0123-y
- Azzam MJ, Beutler BD, Calame A, et al. Osteoma cutis associated with nevus sebaceus: case report and review of cutaneous osteoma-associated skin tumors (COASTs). Cureus. 2019;11:E4959. doi:10.7759/cureus.4959
- Aslam A, Salam A, Griffiths CEM, et al. Naevus sebaceus: a mosaic RASopathy. Clin Exp Dermatol. 2014;39:1-6. doi:10.1111/ced.12209
- Basu P, Erickson CP, Calame A, et al. Nevus sebaceus with syringocystadenoma papilliferum, prurigo nodularis, apocrine cystadenoma, basaloid follicular proliferation, and sebaceoma: case report and review of nevus sebaceus-associated conditions. Dermatol Online J. 2020;26:13030/qt85k968bk.
- Idriss MH, Elston DM. Secondary neoplasms associated with nevus sebaceus of Jadassohn: a study of 707 cases. J Am Acad Dermatol. 2014;70:332-337. doi:10.1016/j.jaad.2013.10.004
- Gripp KW, Rauen KA. Costello syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 1993-2020. August 29, 2006. Updated August 29, 2019. https://pubmed.ncbi.nlm.nih.gov/20301680
- Patel P, Malik K, Khachemoune A. Sebaceus and Becker’s nevus: overview of their presentation, pathogenesis, associations, and treatment. Am J Clin Dermatol. 2015;16:197-204. doi:10.1007/s40257-015-0123-y
- Azzam MJ, Beutler BD, Calame A, et al. Osteoma cutis associated with nevus sebaceus: case report and review of cutaneous osteoma-associated skin tumors (COASTs). Cureus. 2019;11:E4959. doi:10.7759/cureus.4959
- Aslam A, Salam A, Griffiths CEM, et al. Naevus sebaceus: a mosaic RASopathy. Clin Exp Dermatol. 2014;39:1-6. doi:10.1111/ced.12209
- Basu P, Erickson CP, Calame A, et al. Nevus sebaceus with syringocystadenoma papilliferum, prurigo nodularis, apocrine cystadenoma, basaloid follicular proliferation, and sebaceoma: case report and review of nevus sebaceus-associated conditions. Dermatol Online J. 2020;26:13030/qt85k968bk.
- Idriss MH, Elston DM. Secondary neoplasms associated with nevus sebaceus of Jadassohn: a study of 707 cases. J Am Acad Dermatol. 2014;70:332-337. doi:10.1016/j.jaad.2013.10.004
- Gripp KW, Rauen KA. Costello syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 1993-2020. August 29, 2006. Updated August 29, 2019. https://pubmed.ncbi.nlm.nih.gov/20301680
Practice Points
- Nevus sebaceus (NS), commonly referred to as NS of Jadassohn or organoid nevus, is a benign skin hamartoma that consists of epidermal, sebaceous, and apocrine elements and is caused by a congenital defect in the pilosebaceous follicular unit.
- Early stages of NS can be mistaken for alopecia areata.
- Once the diagnosis of NS is confirmed, the presence of associated syndromes should be evaluated.
- The definitive treatment of NS is surgical excision; however, multiple variables must be considered when determining treatment, including patient age, risk for developing malignancy, and surgery-associated risks.
Picosecond laser applications continue to expand
PHOENIX – Ever since PicoSure became the first picosecond laser cleared by the Food and Drug Administration for the treatment of unwanted tattoos and pigmented lesions in 2012, new uses for this technology continue to expand.
Now, These include PicoWay, PicoSure, Enlighten, PicoPlus, PiQo4, and Quanta Pico, among others.
“PicoWay technology has integrated nicely into my practice in Houston, the most ethnically diverse city in the country, with its ability to safely treat a number of various benign, congenital, and acquired epidermal and dermal pigmented lesions with ultrashort pulse duration and low thermal impact, which greatly reduces the risk of postinflammatory hyperpigmentation even in darker skin types,” Paul M. Friedman, MD, director of the Dermatology and Laser Surgery Center, Houston, said at the annual conference of the American Society for Laser Medicine and Surgery.
He emphasized the importance of therapeutic clinical endpoints, noting that with q-switched lasers, “you’re looking for immediate whitening, whereas with picosecond lasers, your endpoint is slight whitening or slight darkening depending on wavelength, indication, and skin type. The ability to fractionate picosecond pulses has also allowed us to utilize this technology for photoaging as well as acne scarring.”
The PicoWay system includes a 730-nm picosecond titanium sapphire handpiece, which is FDA cleared for treatment of benign pigmented lesions and blue and green tattoo removal. Dr. Friedman said that he has seen good clinical results using the handpiece for café-au-lait macules, particularly in skin of color.
In an abstract presented at the ASLMS meeting, he and his colleagues presented a retrospective review of 12 patients with café-au-lait macules with Fitzpatrick skin types III-VI who were treated with the PicoWay 730 nm handpiece between April 2021 and January 2023. Patients received a mean of 3.1 treatments at intervals that ranged from 5 to 40 weeks. Clinical photographs were graded by three board-certified dermatologists using a 5-point visual analogue scale.
Overall, patients were rated to have a mean improvement of 26%-50%. Two patients achieved 100% clearance after four to five treatment sessions. “Café-au-lait macules with smooth borders responded less well to laser treatment, confirming prior studies at our center,” he said. “We often educate parents that café-au-lait macules may recur over time, especially with repeated sun exposure.”
Treating melasma
Dr. Friedman’s go-to devices for melasma include the low-density, low-energy 1,927-nm fractional diode laser; the 1,064 nm picosecond Nd:YAG, the low-fluence 1,064 nm Q-switched Nd:YAG with a nanosecond pulse duration, and the 595-nm pulsed dye laser for lesions exhibiting underlying vascularity. He said that combining therapies that target pigment and vasculature may be ideal to prevent relapses. “Melasma is a multifactorial condition so by improving patient education and expectation alongside advances in laser treatment of melasma, we have ultimately improved our ability to treat this condition,” he said.
“We’re approaching it from all angles, with ultraviolet photography and spectrocolorimetry, behavioral modifications, topical skin-lightening agents, broad spectrum sunscreens with protection against visible light, and oral tranexamic acid in advanced cases. Then, we intervene with these energy-based modalities, and the bottom line is, less energy and density is more, with lengthened treatment intervals. In 2023, we’re better than we’ve ever been in terms of our ability to safely and effectively improve melasma.”
Novel lasers
Dr. Friedman also described the UltraClear, a novel ablative fractional 2,910-nm erbium-doped glass fiber laser that delivers a customized blend of ablation and coagulation based on the patient’s condition, skin type, and tolerability for down time. He provided an overview of the versatility of what he described as highly customizable technology for conditions such as photoaging and dyschromia in patients of various skin types, making it a very versatile platform in his practice.
The AVAVA MIRIA system is a “next generation” laser “where you’re able to use a focal point. Basically, you’re treating the skin from the inside out in a 3D manner and you’re able to focus intradermally up to 1 mm with high energy 1,064 nm or 1,550 nm,” he said. “It’s a unique conical geometry that spares the epidermis, combined with sapphire tip cooling and images the skin at the same time with the potential for personalized treatments of dyschromia and photoaging in all skin types. It’s truly remarkable where the technology is heading.”
Dr. Friedman disclosed that he has received consulting fees from Allergan, Galderma, Acclaro, Merz Aesthetics, Solta Medical, and Cytrellis. He has conducted contracted research for Sofwave and is a member of the speakers bureau for Solta Medical and Candela.
PHOENIX – Ever since PicoSure became the first picosecond laser cleared by the Food and Drug Administration for the treatment of unwanted tattoos and pigmented lesions in 2012, new uses for this technology continue to expand.
Now, These include PicoWay, PicoSure, Enlighten, PicoPlus, PiQo4, and Quanta Pico, among others.
“PicoWay technology has integrated nicely into my practice in Houston, the most ethnically diverse city in the country, with its ability to safely treat a number of various benign, congenital, and acquired epidermal and dermal pigmented lesions with ultrashort pulse duration and low thermal impact, which greatly reduces the risk of postinflammatory hyperpigmentation even in darker skin types,” Paul M. Friedman, MD, director of the Dermatology and Laser Surgery Center, Houston, said at the annual conference of the American Society for Laser Medicine and Surgery.
He emphasized the importance of therapeutic clinical endpoints, noting that with q-switched lasers, “you’re looking for immediate whitening, whereas with picosecond lasers, your endpoint is slight whitening or slight darkening depending on wavelength, indication, and skin type. The ability to fractionate picosecond pulses has also allowed us to utilize this technology for photoaging as well as acne scarring.”
The PicoWay system includes a 730-nm picosecond titanium sapphire handpiece, which is FDA cleared for treatment of benign pigmented lesions and blue and green tattoo removal. Dr. Friedman said that he has seen good clinical results using the handpiece for café-au-lait macules, particularly in skin of color.
In an abstract presented at the ASLMS meeting, he and his colleagues presented a retrospective review of 12 patients with café-au-lait macules with Fitzpatrick skin types III-VI who were treated with the PicoWay 730 nm handpiece between April 2021 and January 2023. Patients received a mean of 3.1 treatments at intervals that ranged from 5 to 40 weeks. Clinical photographs were graded by three board-certified dermatologists using a 5-point visual analogue scale.
Overall, patients were rated to have a mean improvement of 26%-50%. Two patients achieved 100% clearance after four to five treatment sessions. “Café-au-lait macules with smooth borders responded less well to laser treatment, confirming prior studies at our center,” he said. “We often educate parents that café-au-lait macules may recur over time, especially with repeated sun exposure.”
Treating melasma
Dr. Friedman’s go-to devices for melasma include the low-density, low-energy 1,927-nm fractional diode laser; the 1,064 nm picosecond Nd:YAG, the low-fluence 1,064 nm Q-switched Nd:YAG with a nanosecond pulse duration, and the 595-nm pulsed dye laser for lesions exhibiting underlying vascularity. He said that combining therapies that target pigment and vasculature may be ideal to prevent relapses. “Melasma is a multifactorial condition so by improving patient education and expectation alongside advances in laser treatment of melasma, we have ultimately improved our ability to treat this condition,” he said.
“We’re approaching it from all angles, with ultraviolet photography and spectrocolorimetry, behavioral modifications, topical skin-lightening agents, broad spectrum sunscreens with protection against visible light, and oral tranexamic acid in advanced cases. Then, we intervene with these energy-based modalities, and the bottom line is, less energy and density is more, with lengthened treatment intervals. In 2023, we’re better than we’ve ever been in terms of our ability to safely and effectively improve melasma.”
Novel lasers
Dr. Friedman also described the UltraClear, a novel ablative fractional 2,910-nm erbium-doped glass fiber laser that delivers a customized blend of ablation and coagulation based on the patient’s condition, skin type, and tolerability for down time. He provided an overview of the versatility of what he described as highly customizable technology for conditions such as photoaging and dyschromia in patients of various skin types, making it a very versatile platform in his practice.
The AVAVA MIRIA system is a “next generation” laser “where you’re able to use a focal point. Basically, you’re treating the skin from the inside out in a 3D manner and you’re able to focus intradermally up to 1 mm with high energy 1,064 nm or 1,550 nm,” he said. “It’s a unique conical geometry that spares the epidermis, combined with sapphire tip cooling and images the skin at the same time with the potential for personalized treatments of dyschromia and photoaging in all skin types. It’s truly remarkable where the technology is heading.”
Dr. Friedman disclosed that he has received consulting fees from Allergan, Galderma, Acclaro, Merz Aesthetics, Solta Medical, and Cytrellis. He has conducted contracted research for Sofwave and is a member of the speakers bureau for Solta Medical and Candela.
PHOENIX – Ever since PicoSure became the first picosecond laser cleared by the Food and Drug Administration for the treatment of unwanted tattoos and pigmented lesions in 2012, new uses for this technology continue to expand.
Now, These include PicoWay, PicoSure, Enlighten, PicoPlus, PiQo4, and Quanta Pico, among others.
“PicoWay technology has integrated nicely into my practice in Houston, the most ethnically diverse city in the country, with its ability to safely treat a number of various benign, congenital, and acquired epidermal and dermal pigmented lesions with ultrashort pulse duration and low thermal impact, which greatly reduces the risk of postinflammatory hyperpigmentation even in darker skin types,” Paul M. Friedman, MD, director of the Dermatology and Laser Surgery Center, Houston, said at the annual conference of the American Society for Laser Medicine and Surgery.
He emphasized the importance of therapeutic clinical endpoints, noting that with q-switched lasers, “you’re looking for immediate whitening, whereas with picosecond lasers, your endpoint is slight whitening or slight darkening depending on wavelength, indication, and skin type. The ability to fractionate picosecond pulses has also allowed us to utilize this technology for photoaging as well as acne scarring.”
The PicoWay system includes a 730-nm picosecond titanium sapphire handpiece, which is FDA cleared for treatment of benign pigmented lesions and blue and green tattoo removal. Dr. Friedman said that he has seen good clinical results using the handpiece for café-au-lait macules, particularly in skin of color.
In an abstract presented at the ASLMS meeting, he and his colleagues presented a retrospective review of 12 patients with café-au-lait macules with Fitzpatrick skin types III-VI who were treated with the PicoWay 730 nm handpiece between April 2021 and January 2023. Patients received a mean of 3.1 treatments at intervals that ranged from 5 to 40 weeks. Clinical photographs were graded by three board-certified dermatologists using a 5-point visual analogue scale.
Overall, patients were rated to have a mean improvement of 26%-50%. Two patients achieved 100% clearance after four to five treatment sessions. “Café-au-lait macules with smooth borders responded less well to laser treatment, confirming prior studies at our center,” he said. “We often educate parents that café-au-lait macules may recur over time, especially with repeated sun exposure.”
Treating melasma
Dr. Friedman’s go-to devices for melasma include the low-density, low-energy 1,927-nm fractional diode laser; the 1,064 nm picosecond Nd:YAG, the low-fluence 1,064 nm Q-switched Nd:YAG with a nanosecond pulse duration, and the 595-nm pulsed dye laser for lesions exhibiting underlying vascularity. He said that combining therapies that target pigment and vasculature may be ideal to prevent relapses. “Melasma is a multifactorial condition so by improving patient education and expectation alongside advances in laser treatment of melasma, we have ultimately improved our ability to treat this condition,” he said.
“We’re approaching it from all angles, with ultraviolet photography and spectrocolorimetry, behavioral modifications, topical skin-lightening agents, broad spectrum sunscreens with protection against visible light, and oral tranexamic acid in advanced cases. Then, we intervene with these energy-based modalities, and the bottom line is, less energy and density is more, with lengthened treatment intervals. In 2023, we’re better than we’ve ever been in terms of our ability to safely and effectively improve melasma.”
Novel lasers
Dr. Friedman also described the UltraClear, a novel ablative fractional 2,910-nm erbium-doped glass fiber laser that delivers a customized blend of ablation and coagulation based on the patient’s condition, skin type, and tolerability for down time. He provided an overview of the versatility of what he described as highly customizable technology for conditions such as photoaging and dyschromia in patients of various skin types, making it a very versatile platform in his practice.
The AVAVA MIRIA system is a “next generation” laser “where you’re able to use a focal point. Basically, you’re treating the skin from the inside out in a 3D manner and you’re able to focus intradermally up to 1 mm with high energy 1,064 nm or 1,550 nm,” he said. “It’s a unique conical geometry that spares the epidermis, combined with sapphire tip cooling and images the skin at the same time with the potential for personalized treatments of dyschromia and photoaging in all skin types. It’s truly remarkable where the technology is heading.”
Dr. Friedman disclosed that he has received consulting fees from Allergan, Galderma, Acclaro, Merz Aesthetics, Solta Medical, and Cytrellis. He has conducted contracted research for Sofwave and is a member of the speakers bureau for Solta Medical and Candela.
FROM ASLMS 2023
Acute Onset of Vitiligolike Depigmentation After Nivolumab Therapy for Systemic Melanoma
To the Editor:
Vitiligolike depigmentation has been known to develop around the sites of origin of melanoma or more rarely in patients treated with antimelanoma therapy.1 Vitiligo is characterized by white patchy depigmentation of the skin caused by the loss of functional melanocytes from the epidermis. The exact mechanisms of disease are unknown and multifactorial; however, autoimmunity plays a central role. Interferon gamma (IFN-γ), C-X-C chemokine ligand 10, and IL-22 have been identified as key mediators in an inflammatory cascade leading to the stimulation of the innate immune response against melanocyte antigens.2,3 Research suggests melanoma-associated vitiligolike leukoderma also results from an immune reaction directed against antigenic determinants shared by both normal and malignant melanocytes.3 Vitiligolike lesions have been associated with the use of immunomodulatory agents such as nivolumab, a fully humanized monoclonal IgG4 antibody, which blocks the programmed cell death protein 1 (PD-1) receptor that normally is expressed on T cells during the effector phase of T-cell activation.4,5 In the tumor microenvironment, the PD-1 receptor is stimulated, leading to downregulation of the T-cell effector function and destruction of T cells.5 Due to T-cell apoptosis and consequent suppression of the immune response, tumorigenesis continues. By inhibiting the PD-1 receptor, nivolumab increases the number of active T cells and antitumor response. However, the distressing side effect of vitiligolike depigmentation has been reported in 15% to 25% of treated patients.6
In a meta-analysis by Teulings et al,7 patients with new-onset vitiligo and malignant melanoma demonstrated a 2-fold decrease in cancer progression and a 4-fold decreased risk for death vs patients without vitiligo development. Thus, in patients with melanoma, vitiligolike depigmentation should be considered a good prognostic indicator as well as a visible sign of spontaneous or therapy-induced antihumoral immune response against melanocyte differentiation antigens, as it is associated with a notable survival benefit in patients receiving immunotherapy for metastatic melanoma.3 We describe a case of diffuse vitiligolike depigmentation that developed suddenly during nivolumab treatment, causing much distress to the patient.
A 75-year-old woman presented to the clinic with a chief concern of sudden diffuse skin discoloration primarily affecting the face, hands, and extremities of 3 weeks’ duration. She had a medical history of metastatic melanoma—the site of the primary melanoma was never identified—and she was undergoing immune-modulating therapy with nivolumab. She was on her fifth month of treatment and was experiencing a robust therapeutic response with a reported 100% clearance of the metastatic melanoma as observed on a positron emission tomography scan. The patchy depigmentation of skin was causing her much distress. Physical examination revealed diffuse patches of hypopigmentation on the trunk, face, and extremities (Figure). Shave biopsies of the right lateral arm demonstrated changes consistent with vitiligo, with an adjacent biopsy illustrating normal skin characteristics. Triamcinolone ointment 0.1% was initiated, with instruction to apply it to affected areas twice daily for 2 weeks. However, there was no improvement, and she discontinued use.
At 3-month follow-up, the depigmentation persisted, prompting a trial of hydroquinone cream 4% to be used sparingly in cosmetically sensitive areas such as the face and dorsal aspects of the hands. Additionally, diligent photoprotection was advised. Upon re-evaluation 9 months later, the patient remained in cancer remission, continued nivolumab therapy, and reported improvement in the hypopigmentation with a more even skin color with topical hydroquinone use. She no longer noticed starkly contrasting hypopigmented patches.
Vitiligo is a benign skin condition characterized by white depigmented macules and patches. The key feature of the disorder is loss of functional melanocytes from the cutaneous epidermis and sometimes from the hair follicles, with various theories on the cause. It has been suggested that the disease is multifactorial, involving both genetics and environmental factors.2 Regardless of the exact mechanism, the result is always the same: loss of melanin pigment in cells due to loss of melanocytes.
Autoimmunity plays a central role in the causation of vitiligo and was first suspected as a possible cause due to the association of vitiligo with several other autoimmune disorders, such as thyroiditis.8 An epidemiological survey from the United Kingdom and North America (N=2624) found that 19.4% of vitiligo patients aged 20 years or older also reported a clinical history of autoimmune thyroid disease compared with 2.4% of the overall White population of the same age.9 Interferon gamma, C-X-C chemokine ligand 10, and IL-22 receptors stimulate the innate immune response, resulting in an overactive danger signaling cascade, which leads to proinflammatory signals against melanocyte antigens.2,3 The adaptive immune system also participates in the progression of vitiligo by activating dermal dendritic cells to attack melanocytes along with melanocyte-specific cytotoxic T cells.
Immunomodulatory agents utilized in the treatment of metastatic melanoma have been linked to vitiligolike depigmentation. In those receiving PD-1 immunotherapy for metastatic melanoma, vitiligolike lesions have been reported in 15% to 25% of patients.6 Typically, the PD-1 molecule has a regulatory function on effector T cells. Interaction of the PD-1 receptor with its ligands occurs primarily in peripheral tissue causing apoptosis and downregulation of effector T cells with the goal of decreasing collateral damage to surrounding tissues by active T cells.5 In the tumor microenvironment, however, suppression of the host’s immune response is enhanced by aberrant stimulation of the PD-1 receptor, causing downregulation of the T-cell effector function, T-cell destruction, and apoptosis, which results in continued tumor growth. Nivolumab, a fully humanized monoclonal IgG4 antibody, selectively inhibits the PD-1 receptor, disrupting the regulator pathway that would typically end in T-cell destruction.5 Accordingly, the population of active T cells is increased along with the antitumor response.4,10 Nivolumab exhibits success as an immunotherapeutic agent, with an overall survival rate in patients with metastatic melanoma undergoing nivolumab therapy of 41% to 42% at 3 years and 35% at 5 years.11 However, therapeutic manipulation of the host’s immune response does not come without a cost. Vitiligolike lesions have been reported in up to a quarter of patients receiving PD-1 immunotherapy for metastatic melanoma.6
The relationship between vitiligolike depigmentation and melanoma can be explained by the immune activation against antigens associated with melanoma that also are expressed by normal melanocytes. In clinical observations of patients with melanoma and patients with vitiligo, antibodies to human melanocyte antigens were present in 80% (24/30) of patients vs 7% (2/28) in the control group.12 The autoimmune response results from a cross-reaction of melanoma cells that share the same antigens as normal melanocytes, such as melanoma antigen recognized by T cells 1 (MART-1), gp100, and tyrosinase.13,14
Development of vitiligolike depigmentation in patients with metastatic melanoma treated with nivolumab has been reported to occur between 2 and 15 months after the start of PD-1 therapy. This side effect of treatment correlates with favorable clinical outcomes.15,16 Enhancing immune recognition of melanocytes in patients with melanoma confers a survival advantage, as studies by Koh et al17 and Norlund et al18 involving patients who developed vitiligolike hypopigmentation associated with malignant melanoma indicated a better prognosis than for those without hypopigmentation. The 5-year survival rate of patients with both malignant melanoma and vitiligo was reported as 60% to 67% when it was estimated that only 30% to 50% of patients should have survived that duration of time.17,18 Similarly, a systematic review of patients with melanoma stages III and IV reported that those with associated hypopigmentation had a 2- to 4-fold decreased risk of disease progression and death compared to patients without depigmentation.7
Use of traditional treatment therapies for vitiligo is based on the ability of the therapy to suppress the immune system. However, in patients with metastatic melanoma undergoing immune-modulating cancer therapies, traditional treatment options may counter the antitumor effects of the targeted immunotherapies and should be used with caution. Our patient displayed improvement in the appearance of her starkly contrasting hypopigmented patches with the use of hydroquinone cream 4%, which induced necrotic death of melanocytes by inhibiting the conversion of L-3,4-dihydroxyphenylalanine to melanin by tyrosinase.19 The effect achieved by using topical hydroquinone 4% was a lighter skin appearance in areas of application.
There is no cure for vitiligo, and although it is a benign condition, it can negatively impact a patient's quality of life. In some countries, vitiligo is confused with leprosy, resulting in a social stigma attached to the diagnosis. Many patients are frightened or embarrassed by the diagnosis of vitiligo and its effects, and they often experience discrimination.2 Patients with vitiligo also experience more psychological difficulties such as depression.20 The unpredictability of vitiligo is associated with negative emotions including fear of spreading the lesions, shame, insecurity, and sadness.21 Supportive care measures, including psychological support and counseling, are recommended. Additionally, upon initiation of anti–PD-1 therapies, expectations should be discussed with patients concerning the possibilities of depigmentation and associated treatment results. Although the occurrence of vitiligo may cause the patient concern, it should be communicated that its presence is a positive indicator of a vigorous antimelanoma immunity and an increased survival rate.7
Vitiligolike depigmentation is a known rare adverse effect of nivolumab treatment. Although aesthetically unfavorable for the patient, the development of vitiligolike lesions while undergoing immunotherapy for melanoma may be a sign of a promising clinical outcome due to an effective immune response to melanoma antigens. Our patient remains in remission without any evidence of melanoma after 9 months of therapy, which offers support for a promising outcome for melanoma patients who experience vitiligolike depigmentation.
- de Golian E, Kwong BY, Swetter SM, et al. Cutaneous complications of targeted melanoma therapy. Curr Treat Options Oncol. 2016;17:57.
- Ezzedine K, Eleftheriadou V, Whitton M, et al. Vitiligo. Lancet. 2015;386:74-84.
- Ortonne, JP, Passeron, T. Vitiligo and other disorders of hypopigmentation. In: Bolognia J, Schaffer JV, Cerroni L, eds. Dermatology. 4th ed. Elsevier; 2018:1087-1114.
- Opdivo. Package insert. Bristol-Myers Squibb Company; 2023.
- Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19:5300-5309.
- Hwang SJE, Carlos G, Wakade D, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort. J Am Acad Dermatol. 2016;74:455-461.e1.
- Teulings HE, Limpens J, Jansen SN, et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol. 2015;33:773-781.
- Gey A, Diallo A, Seneschal J, et al. Autoimmune thyroid disease in vitiligo: multivariate analysis indicates intricate pathomechanisms. Br J Dermatol. 2013;168:756-761.
- Alkhateeb A, Fain PR, Thody A, et al. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 2003;16:208-214.
- Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330.
- Hodi FS, Kluger H, Sznol M, et al. Durable, long-term survival in previously treated patients with advanced melanoma who received nivolumab monotherapy in a phase I trial. Cancer Res. 2016;76(14 suppl):CT001.
- Cui J, Bystryn JC. Melanoma and vitiligo are associated with antibody responses to similar antigens on pigment cells. Arch Dermatol. 1995;131:314-318.
- Lynch SA, Bouchard BN, Vijayasaradhi S, et al. Antigens of melanocytes and melanoma. Cancer Metastasis Rev. 1991;10:141-150.
- Sanlorenzo M, Vujic I, Daud A, et al. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol. 2015;15:1206-1212.
- Hua C, Boussemart L, Mateus C, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152:45-51.
- Nakamura Y, Tanaka R, Asami Y, et al. Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study. J Dermatol. 2017;44:117-122.
- Koh HK, Sober AJ, Nakagawa H, et al. Malignant melanoma and vitiligo-like leukoderma: an electron microscope study. J Am Acad Dermatol. 1983;9:696-708.
- Nordlund JJ, Kirkwood JM, Forget BM, et al. Vitiligo in patients with metastatic melanoma: a good prognostic sign. J Am Acad Dermatol. 1983;9:689-696.
- Palumbo A, d’Ischia M, Misuraca G, et al. Mechanism of inhibition of melanogenesis by hydroquinone. Biochim Biophys Acta. 1991;1073:85-90.
- Lai YC, Yew YW, Kennedy C, et al. Vitiligo and depression: a systematic review and meta-analysis of observational studies. Br J Dermatol. 2017;177:708-718.
- Nogueira LSC, Zancanaro PCQ, Azambuja RD. Vitiligo and emotions. An Bras Dermatol. 2009;84:41-45.
To the Editor:
Vitiligolike depigmentation has been known to develop around the sites of origin of melanoma or more rarely in patients treated with antimelanoma therapy.1 Vitiligo is characterized by white patchy depigmentation of the skin caused by the loss of functional melanocytes from the epidermis. The exact mechanisms of disease are unknown and multifactorial; however, autoimmunity plays a central role. Interferon gamma (IFN-γ), C-X-C chemokine ligand 10, and IL-22 have been identified as key mediators in an inflammatory cascade leading to the stimulation of the innate immune response against melanocyte antigens.2,3 Research suggests melanoma-associated vitiligolike leukoderma also results from an immune reaction directed against antigenic determinants shared by both normal and malignant melanocytes.3 Vitiligolike lesions have been associated with the use of immunomodulatory agents such as nivolumab, a fully humanized monoclonal IgG4 antibody, which blocks the programmed cell death protein 1 (PD-1) receptor that normally is expressed on T cells during the effector phase of T-cell activation.4,5 In the tumor microenvironment, the PD-1 receptor is stimulated, leading to downregulation of the T-cell effector function and destruction of T cells.5 Due to T-cell apoptosis and consequent suppression of the immune response, tumorigenesis continues. By inhibiting the PD-1 receptor, nivolumab increases the number of active T cells and antitumor response. However, the distressing side effect of vitiligolike depigmentation has been reported in 15% to 25% of treated patients.6
In a meta-analysis by Teulings et al,7 patients with new-onset vitiligo and malignant melanoma demonstrated a 2-fold decrease in cancer progression and a 4-fold decreased risk for death vs patients without vitiligo development. Thus, in patients with melanoma, vitiligolike depigmentation should be considered a good prognostic indicator as well as a visible sign of spontaneous or therapy-induced antihumoral immune response against melanocyte differentiation antigens, as it is associated with a notable survival benefit in patients receiving immunotherapy for metastatic melanoma.3 We describe a case of diffuse vitiligolike depigmentation that developed suddenly during nivolumab treatment, causing much distress to the patient.
A 75-year-old woman presented to the clinic with a chief concern of sudden diffuse skin discoloration primarily affecting the face, hands, and extremities of 3 weeks’ duration. She had a medical history of metastatic melanoma—the site of the primary melanoma was never identified—and she was undergoing immune-modulating therapy with nivolumab. She was on her fifth month of treatment and was experiencing a robust therapeutic response with a reported 100% clearance of the metastatic melanoma as observed on a positron emission tomography scan. The patchy depigmentation of skin was causing her much distress. Physical examination revealed diffuse patches of hypopigmentation on the trunk, face, and extremities (Figure). Shave biopsies of the right lateral arm demonstrated changes consistent with vitiligo, with an adjacent biopsy illustrating normal skin characteristics. Triamcinolone ointment 0.1% was initiated, with instruction to apply it to affected areas twice daily for 2 weeks. However, there was no improvement, and she discontinued use.
At 3-month follow-up, the depigmentation persisted, prompting a trial of hydroquinone cream 4% to be used sparingly in cosmetically sensitive areas such as the face and dorsal aspects of the hands. Additionally, diligent photoprotection was advised. Upon re-evaluation 9 months later, the patient remained in cancer remission, continued nivolumab therapy, and reported improvement in the hypopigmentation with a more even skin color with topical hydroquinone use. She no longer noticed starkly contrasting hypopigmented patches.
Vitiligo is a benign skin condition characterized by white depigmented macules and patches. The key feature of the disorder is loss of functional melanocytes from the cutaneous epidermis and sometimes from the hair follicles, with various theories on the cause. It has been suggested that the disease is multifactorial, involving both genetics and environmental factors.2 Regardless of the exact mechanism, the result is always the same: loss of melanin pigment in cells due to loss of melanocytes.
Autoimmunity plays a central role in the causation of vitiligo and was first suspected as a possible cause due to the association of vitiligo with several other autoimmune disorders, such as thyroiditis.8 An epidemiological survey from the United Kingdom and North America (N=2624) found that 19.4% of vitiligo patients aged 20 years or older also reported a clinical history of autoimmune thyroid disease compared with 2.4% of the overall White population of the same age.9 Interferon gamma, C-X-C chemokine ligand 10, and IL-22 receptors stimulate the innate immune response, resulting in an overactive danger signaling cascade, which leads to proinflammatory signals against melanocyte antigens.2,3 The adaptive immune system also participates in the progression of vitiligo by activating dermal dendritic cells to attack melanocytes along with melanocyte-specific cytotoxic T cells.
Immunomodulatory agents utilized in the treatment of metastatic melanoma have been linked to vitiligolike depigmentation. In those receiving PD-1 immunotherapy for metastatic melanoma, vitiligolike lesions have been reported in 15% to 25% of patients.6 Typically, the PD-1 molecule has a regulatory function on effector T cells. Interaction of the PD-1 receptor with its ligands occurs primarily in peripheral tissue causing apoptosis and downregulation of effector T cells with the goal of decreasing collateral damage to surrounding tissues by active T cells.5 In the tumor microenvironment, however, suppression of the host’s immune response is enhanced by aberrant stimulation of the PD-1 receptor, causing downregulation of the T-cell effector function, T-cell destruction, and apoptosis, which results in continued tumor growth. Nivolumab, a fully humanized monoclonal IgG4 antibody, selectively inhibits the PD-1 receptor, disrupting the regulator pathway that would typically end in T-cell destruction.5 Accordingly, the population of active T cells is increased along with the antitumor response.4,10 Nivolumab exhibits success as an immunotherapeutic agent, with an overall survival rate in patients with metastatic melanoma undergoing nivolumab therapy of 41% to 42% at 3 years and 35% at 5 years.11 However, therapeutic manipulation of the host’s immune response does not come without a cost. Vitiligolike lesions have been reported in up to a quarter of patients receiving PD-1 immunotherapy for metastatic melanoma.6
The relationship between vitiligolike depigmentation and melanoma can be explained by the immune activation against antigens associated with melanoma that also are expressed by normal melanocytes. In clinical observations of patients with melanoma and patients with vitiligo, antibodies to human melanocyte antigens were present in 80% (24/30) of patients vs 7% (2/28) in the control group.12 The autoimmune response results from a cross-reaction of melanoma cells that share the same antigens as normal melanocytes, such as melanoma antigen recognized by T cells 1 (MART-1), gp100, and tyrosinase.13,14
Development of vitiligolike depigmentation in patients with metastatic melanoma treated with nivolumab has been reported to occur between 2 and 15 months after the start of PD-1 therapy. This side effect of treatment correlates with favorable clinical outcomes.15,16 Enhancing immune recognition of melanocytes in patients with melanoma confers a survival advantage, as studies by Koh et al17 and Norlund et al18 involving patients who developed vitiligolike hypopigmentation associated with malignant melanoma indicated a better prognosis than for those without hypopigmentation. The 5-year survival rate of patients with both malignant melanoma and vitiligo was reported as 60% to 67% when it was estimated that only 30% to 50% of patients should have survived that duration of time.17,18 Similarly, a systematic review of patients with melanoma stages III and IV reported that those with associated hypopigmentation had a 2- to 4-fold decreased risk of disease progression and death compared to patients without depigmentation.7
Use of traditional treatment therapies for vitiligo is based on the ability of the therapy to suppress the immune system. However, in patients with metastatic melanoma undergoing immune-modulating cancer therapies, traditional treatment options may counter the antitumor effects of the targeted immunotherapies and should be used with caution. Our patient displayed improvement in the appearance of her starkly contrasting hypopigmented patches with the use of hydroquinone cream 4%, which induced necrotic death of melanocytes by inhibiting the conversion of L-3,4-dihydroxyphenylalanine to melanin by tyrosinase.19 The effect achieved by using topical hydroquinone 4% was a lighter skin appearance in areas of application.
There is no cure for vitiligo, and although it is a benign condition, it can negatively impact a patient's quality of life. In some countries, vitiligo is confused with leprosy, resulting in a social stigma attached to the diagnosis. Many patients are frightened or embarrassed by the diagnosis of vitiligo and its effects, and they often experience discrimination.2 Patients with vitiligo also experience more psychological difficulties such as depression.20 The unpredictability of vitiligo is associated with negative emotions including fear of spreading the lesions, shame, insecurity, and sadness.21 Supportive care measures, including psychological support and counseling, are recommended. Additionally, upon initiation of anti–PD-1 therapies, expectations should be discussed with patients concerning the possibilities of depigmentation and associated treatment results. Although the occurrence of vitiligo may cause the patient concern, it should be communicated that its presence is a positive indicator of a vigorous antimelanoma immunity and an increased survival rate.7
Vitiligolike depigmentation is a known rare adverse effect of nivolumab treatment. Although aesthetically unfavorable for the patient, the development of vitiligolike lesions while undergoing immunotherapy for melanoma may be a sign of a promising clinical outcome due to an effective immune response to melanoma antigens. Our patient remains in remission without any evidence of melanoma after 9 months of therapy, which offers support for a promising outcome for melanoma patients who experience vitiligolike depigmentation.
To the Editor:
Vitiligolike depigmentation has been known to develop around the sites of origin of melanoma or more rarely in patients treated with antimelanoma therapy.1 Vitiligo is characterized by white patchy depigmentation of the skin caused by the loss of functional melanocytes from the epidermis. The exact mechanisms of disease are unknown and multifactorial; however, autoimmunity plays a central role. Interferon gamma (IFN-γ), C-X-C chemokine ligand 10, and IL-22 have been identified as key mediators in an inflammatory cascade leading to the stimulation of the innate immune response against melanocyte antigens.2,3 Research suggests melanoma-associated vitiligolike leukoderma also results from an immune reaction directed against antigenic determinants shared by both normal and malignant melanocytes.3 Vitiligolike lesions have been associated with the use of immunomodulatory agents such as nivolumab, a fully humanized monoclonal IgG4 antibody, which blocks the programmed cell death protein 1 (PD-1) receptor that normally is expressed on T cells during the effector phase of T-cell activation.4,5 In the tumor microenvironment, the PD-1 receptor is stimulated, leading to downregulation of the T-cell effector function and destruction of T cells.5 Due to T-cell apoptosis and consequent suppression of the immune response, tumorigenesis continues. By inhibiting the PD-1 receptor, nivolumab increases the number of active T cells and antitumor response. However, the distressing side effect of vitiligolike depigmentation has been reported in 15% to 25% of treated patients.6
In a meta-analysis by Teulings et al,7 patients with new-onset vitiligo and malignant melanoma demonstrated a 2-fold decrease in cancer progression and a 4-fold decreased risk for death vs patients without vitiligo development. Thus, in patients with melanoma, vitiligolike depigmentation should be considered a good prognostic indicator as well as a visible sign of spontaneous or therapy-induced antihumoral immune response against melanocyte differentiation antigens, as it is associated with a notable survival benefit in patients receiving immunotherapy for metastatic melanoma.3 We describe a case of diffuse vitiligolike depigmentation that developed suddenly during nivolumab treatment, causing much distress to the patient.
A 75-year-old woman presented to the clinic with a chief concern of sudden diffuse skin discoloration primarily affecting the face, hands, and extremities of 3 weeks’ duration. She had a medical history of metastatic melanoma—the site of the primary melanoma was never identified—and she was undergoing immune-modulating therapy with nivolumab. She was on her fifth month of treatment and was experiencing a robust therapeutic response with a reported 100% clearance of the metastatic melanoma as observed on a positron emission tomography scan. The patchy depigmentation of skin was causing her much distress. Physical examination revealed diffuse patches of hypopigmentation on the trunk, face, and extremities (Figure). Shave biopsies of the right lateral arm demonstrated changes consistent with vitiligo, with an adjacent biopsy illustrating normal skin characteristics. Triamcinolone ointment 0.1% was initiated, with instruction to apply it to affected areas twice daily for 2 weeks. However, there was no improvement, and she discontinued use.
At 3-month follow-up, the depigmentation persisted, prompting a trial of hydroquinone cream 4% to be used sparingly in cosmetically sensitive areas such as the face and dorsal aspects of the hands. Additionally, diligent photoprotection was advised. Upon re-evaluation 9 months later, the patient remained in cancer remission, continued nivolumab therapy, and reported improvement in the hypopigmentation with a more even skin color with topical hydroquinone use. She no longer noticed starkly contrasting hypopigmented patches.
Vitiligo is a benign skin condition characterized by white depigmented macules and patches. The key feature of the disorder is loss of functional melanocytes from the cutaneous epidermis and sometimes from the hair follicles, with various theories on the cause. It has been suggested that the disease is multifactorial, involving both genetics and environmental factors.2 Regardless of the exact mechanism, the result is always the same: loss of melanin pigment in cells due to loss of melanocytes.
Autoimmunity plays a central role in the causation of vitiligo and was first suspected as a possible cause due to the association of vitiligo with several other autoimmune disorders, such as thyroiditis.8 An epidemiological survey from the United Kingdom and North America (N=2624) found that 19.4% of vitiligo patients aged 20 years or older also reported a clinical history of autoimmune thyroid disease compared with 2.4% of the overall White population of the same age.9 Interferon gamma, C-X-C chemokine ligand 10, and IL-22 receptors stimulate the innate immune response, resulting in an overactive danger signaling cascade, which leads to proinflammatory signals against melanocyte antigens.2,3 The adaptive immune system also participates in the progression of vitiligo by activating dermal dendritic cells to attack melanocytes along with melanocyte-specific cytotoxic T cells.
Immunomodulatory agents utilized in the treatment of metastatic melanoma have been linked to vitiligolike depigmentation. In those receiving PD-1 immunotherapy for metastatic melanoma, vitiligolike lesions have been reported in 15% to 25% of patients.6 Typically, the PD-1 molecule has a regulatory function on effector T cells. Interaction of the PD-1 receptor with its ligands occurs primarily in peripheral tissue causing apoptosis and downregulation of effector T cells with the goal of decreasing collateral damage to surrounding tissues by active T cells.5 In the tumor microenvironment, however, suppression of the host’s immune response is enhanced by aberrant stimulation of the PD-1 receptor, causing downregulation of the T-cell effector function, T-cell destruction, and apoptosis, which results in continued tumor growth. Nivolumab, a fully humanized monoclonal IgG4 antibody, selectively inhibits the PD-1 receptor, disrupting the regulator pathway that would typically end in T-cell destruction.5 Accordingly, the population of active T cells is increased along with the antitumor response.4,10 Nivolumab exhibits success as an immunotherapeutic agent, with an overall survival rate in patients with metastatic melanoma undergoing nivolumab therapy of 41% to 42% at 3 years and 35% at 5 years.11 However, therapeutic manipulation of the host’s immune response does not come without a cost. Vitiligolike lesions have been reported in up to a quarter of patients receiving PD-1 immunotherapy for metastatic melanoma.6
The relationship between vitiligolike depigmentation and melanoma can be explained by the immune activation against antigens associated with melanoma that also are expressed by normal melanocytes. In clinical observations of patients with melanoma and patients with vitiligo, antibodies to human melanocyte antigens were present in 80% (24/30) of patients vs 7% (2/28) in the control group.12 The autoimmune response results from a cross-reaction of melanoma cells that share the same antigens as normal melanocytes, such as melanoma antigen recognized by T cells 1 (MART-1), gp100, and tyrosinase.13,14
Development of vitiligolike depigmentation in patients with metastatic melanoma treated with nivolumab has been reported to occur between 2 and 15 months after the start of PD-1 therapy. This side effect of treatment correlates with favorable clinical outcomes.15,16 Enhancing immune recognition of melanocytes in patients with melanoma confers a survival advantage, as studies by Koh et al17 and Norlund et al18 involving patients who developed vitiligolike hypopigmentation associated with malignant melanoma indicated a better prognosis than for those without hypopigmentation. The 5-year survival rate of patients with both malignant melanoma and vitiligo was reported as 60% to 67% when it was estimated that only 30% to 50% of patients should have survived that duration of time.17,18 Similarly, a systematic review of patients with melanoma stages III and IV reported that those with associated hypopigmentation had a 2- to 4-fold decreased risk of disease progression and death compared to patients without depigmentation.7
Use of traditional treatment therapies for vitiligo is based on the ability of the therapy to suppress the immune system. However, in patients with metastatic melanoma undergoing immune-modulating cancer therapies, traditional treatment options may counter the antitumor effects of the targeted immunotherapies and should be used with caution. Our patient displayed improvement in the appearance of her starkly contrasting hypopigmented patches with the use of hydroquinone cream 4%, which induced necrotic death of melanocytes by inhibiting the conversion of L-3,4-dihydroxyphenylalanine to melanin by tyrosinase.19 The effect achieved by using topical hydroquinone 4% was a lighter skin appearance in areas of application.
There is no cure for vitiligo, and although it is a benign condition, it can negatively impact a patient's quality of life. In some countries, vitiligo is confused with leprosy, resulting in a social stigma attached to the diagnosis. Many patients are frightened or embarrassed by the diagnosis of vitiligo and its effects, and they often experience discrimination.2 Patients with vitiligo also experience more psychological difficulties such as depression.20 The unpredictability of vitiligo is associated with negative emotions including fear of spreading the lesions, shame, insecurity, and sadness.21 Supportive care measures, including psychological support and counseling, are recommended. Additionally, upon initiation of anti–PD-1 therapies, expectations should be discussed with patients concerning the possibilities of depigmentation and associated treatment results. Although the occurrence of vitiligo may cause the patient concern, it should be communicated that its presence is a positive indicator of a vigorous antimelanoma immunity and an increased survival rate.7
Vitiligolike depigmentation is a known rare adverse effect of nivolumab treatment. Although aesthetically unfavorable for the patient, the development of vitiligolike lesions while undergoing immunotherapy for melanoma may be a sign of a promising clinical outcome due to an effective immune response to melanoma antigens. Our patient remains in remission without any evidence of melanoma after 9 months of therapy, which offers support for a promising outcome for melanoma patients who experience vitiligolike depigmentation.
- de Golian E, Kwong BY, Swetter SM, et al. Cutaneous complications of targeted melanoma therapy. Curr Treat Options Oncol. 2016;17:57.
- Ezzedine K, Eleftheriadou V, Whitton M, et al. Vitiligo. Lancet. 2015;386:74-84.
- Ortonne, JP, Passeron, T. Vitiligo and other disorders of hypopigmentation. In: Bolognia J, Schaffer JV, Cerroni L, eds. Dermatology. 4th ed. Elsevier; 2018:1087-1114.
- Opdivo. Package insert. Bristol-Myers Squibb Company; 2023.
- Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19:5300-5309.
- Hwang SJE, Carlos G, Wakade D, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort. J Am Acad Dermatol. 2016;74:455-461.e1.
- Teulings HE, Limpens J, Jansen SN, et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol. 2015;33:773-781.
- Gey A, Diallo A, Seneschal J, et al. Autoimmune thyroid disease in vitiligo: multivariate analysis indicates intricate pathomechanisms. Br J Dermatol. 2013;168:756-761.
- Alkhateeb A, Fain PR, Thody A, et al. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 2003;16:208-214.
- Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330.
- Hodi FS, Kluger H, Sznol M, et al. Durable, long-term survival in previously treated patients with advanced melanoma who received nivolumab monotherapy in a phase I trial. Cancer Res. 2016;76(14 suppl):CT001.
- Cui J, Bystryn JC. Melanoma and vitiligo are associated with antibody responses to similar antigens on pigment cells. Arch Dermatol. 1995;131:314-318.
- Lynch SA, Bouchard BN, Vijayasaradhi S, et al. Antigens of melanocytes and melanoma. Cancer Metastasis Rev. 1991;10:141-150.
- Sanlorenzo M, Vujic I, Daud A, et al. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol. 2015;15:1206-1212.
- Hua C, Boussemart L, Mateus C, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152:45-51.
- Nakamura Y, Tanaka R, Asami Y, et al. Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study. J Dermatol. 2017;44:117-122.
- Koh HK, Sober AJ, Nakagawa H, et al. Malignant melanoma and vitiligo-like leukoderma: an electron microscope study. J Am Acad Dermatol. 1983;9:696-708.
- Nordlund JJ, Kirkwood JM, Forget BM, et al. Vitiligo in patients with metastatic melanoma: a good prognostic sign. J Am Acad Dermatol. 1983;9:689-696.
- Palumbo A, d’Ischia M, Misuraca G, et al. Mechanism of inhibition of melanogenesis by hydroquinone. Biochim Biophys Acta. 1991;1073:85-90.
- Lai YC, Yew YW, Kennedy C, et al. Vitiligo and depression: a systematic review and meta-analysis of observational studies. Br J Dermatol. 2017;177:708-718.
- Nogueira LSC, Zancanaro PCQ, Azambuja RD. Vitiligo and emotions. An Bras Dermatol. 2009;84:41-45.
- de Golian E, Kwong BY, Swetter SM, et al. Cutaneous complications of targeted melanoma therapy. Curr Treat Options Oncol. 2016;17:57.
- Ezzedine K, Eleftheriadou V, Whitton M, et al. Vitiligo. Lancet. 2015;386:74-84.
- Ortonne, JP, Passeron, T. Vitiligo and other disorders of hypopigmentation. In: Bolognia J, Schaffer JV, Cerroni L, eds. Dermatology. 4th ed. Elsevier; 2018:1087-1114.
- Opdivo. Package insert. Bristol-Myers Squibb Company; 2023.
- Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19:5300-5309.
- Hwang SJE, Carlos G, Wakade D, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort. J Am Acad Dermatol. 2016;74:455-461.e1.
- Teulings HE, Limpens J, Jansen SN, et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol. 2015;33:773-781.
- Gey A, Diallo A, Seneschal J, et al. Autoimmune thyroid disease in vitiligo: multivariate analysis indicates intricate pathomechanisms. Br J Dermatol. 2013;168:756-761.
- Alkhateeb A, Fain PR, Thody A, et al. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 2003;16:208-214.
- Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330.
- Hodi FS, Kluger H, Sznol M, et al. Durable, long-term survival in previously treated patients with advanced melanoma who received nivolumab monotherapy in a phase I trial. Cancer Res. 2016;76(14 suppl):CT001.
- Cui J, Bystryn JC. Melanoma and vitiligo are associated with antibody responses to similar antigens on pigment cells. Arch Dermatol. 1995;131:314-318.
- Lynch SA, Bouchard BN, Vijayasaradhi S, et al. Antigens of melanocytes and melanoma. Cancer Metastasis Rev. 1991;10:141-150.
- Sanlorenzo M, Vujic I, Daud A, et al. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol. 2015;15:1206-1212.
- Hua C, Boussemart L, Mateus C, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152:45-51.
- Nakamura Y, Tanaka R, Asami Y, et al. Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study. J Dermatol. 2017;44:117-122.
- Koh HK, Sober AJ, Nakagawa H, et al. Malignant melanoma and vitiligo-like leukoderma: an electron microscope study. J Am Acad Dermatol. 1983;9:696-708.
- Nordlund JJ, Kirkwood JM, Forget BM, et al. Vitiligo in patients with metastatic melanoma: a good prognostic sign. J Am Acad Dermatol. 1983;9:689-696.
- Palumbo A, d’Ischia M, Misuraca G, et al. Mechanism of inhibition of melanogenesis by hydroquinone. Biochim Biophys Acta. 1991;1073:85-90.
- Lai YC, Yew YW, Kennedy C, et al. Vitiligo and depression: a systematic review and meta-analysis of observational studies. Br J Dermatol. 2017;177:708-718.
- Nogueira LSC, Zancanaro PCQ, Azambuja RD. Vitiligo and emotions. An Bras Dermatol. 2009;84:41-45.
Practice Points
- New-onset vitiligo coinciding with malignant melanoma should be considered a good prognostic indicator.
- Daily use of hydroquinone cream 4% in conjunction with diligent photoprotection was shown to even overall skin tone in a patient experiencing leukoderma from nivolumab therapy.
Bergamot
Citrus bergamia (bergamot) is a fruit tree thought to originate in the Mediterranean area; its fruit has been a part of the diet in that region since the early 18th century.1 Bergamot is known to confer antioxidant as well as anti-inflammatory activity, and yields proapoptotic effects in the sebaceous gland.2,3 The plant contains the natural furocoumarin bergapten, which is also known as 5-methoxypsoralen.4
5 In this capacity, bergamot oil has been used for photodynamic therapy of cutaneous conditions such as vitiligo.6 In fact, for several years 5-methoxypsoralen and 8-methoxypsoralen have been used to achieve acceptable clearance rates of psoriasis and vitiligo.7 This column focuses on bergapten, as well as the cutaneous conditions for which bergamot has been shown to have some benefits warranting application or further investigation.
Bergapten
In a 2021 literature review, Liang et al. cited the anti-inflammatory, antimicrobial, anticancer, and other salutary effects associated with bergapten. Based on numerous citations, they also cautioned about the phototoxicity of the compound combined with ultraviolet (UV) light while noting the photoactivation of bergapten for anticancer uses.4
The following year, Quetglas-Llabrés et al. acknowledged, in another literature review, the numerous preclinical and in vitro studies demonstrating the therapeutic activity of bergapten and highlighted clinical trials revealing notable lesion clearance rates of psoriasis or vitiligo imparted by oral or topical bergapten along with UV irradiation. Bergapten was also found to be effective as hypolipemic therapy.5
Anti-inflammatory topical uses
In a 2017 study by Han et al. of 10 essential oils, bergamot was among the investigated oils, all of which exhibited significant anti-proliferative activity in a preinflamed human dermal fibroblast system simulating chronic inflammation. Bergamot was among three essential oils that also suppressed protein molecules involved with inflammation, immune responses, and tissue remodeling, indicating anti-inflammatory and wound healing characteristics.8
More recently, Cristiano et al. reported that ultradeformable nanocarriers containing bergamot essential oil and ammonium glycyrrhizinate were demonstrated in healthy human volunteers to be characterized by the appropriate mean size, size distribution, surface charge, and long-term stability for topical administration. Topical administration on human volunteers also revealed greater activity of the combined agents as compared with a nanosystem loaded only with ammonium glycyrrhizinate. The researchers concluded that this combination of ingredients in ultradeformable vesicles shows potential as topical anti-inflammatory treatment.3
Acne
In a 2020 study using golden hamsters, Sun et al. assessed the effects of the juice and essential oils of bergamot and sweet orange on acne vulgaris engendered by excessive androgen secretion. Among 80 male hamsters randomly divided into 10 groups ranging from low to high doses, all results demonstrated improvement with treatment as seen by decreased growth rates of sebaceous glands, suppressed triglyceride accumulation, lowered inflammatory cytokine release, and apoptosis promotion in sebaceous glands. The authors noted that the essential oils yielded better dose-dependent effects than the juices.2
Psoriasis
In 2019, Perna et al. conducted a literature review on the effects of bergamot essential oil, extract, juice, and polyphenolic fraction on various health metrics. Thirty-one studies (20 involving humans with 1,709 subjects and 11 in rats and mice) were identified. Animal models indicated that bergamot essential oil (10 mg/kg or 20 mg/kg daily for 20 weeks) reduced psoriatic plaques, increased skin collagen content, and fostered hair growth and that bergamot juice (20 mg/kg) diminished proinflammatory cytokines. Human studies showed that bergamot extract and essential oil may reduce blood pressure and improve mental conditions.9
Vitiligo
In 2019, Shaaban et al. prepared elastic nanocarriers (spanlastics) to deliver psoralen-containing bergamot oil along with PUVB with the intention of harnessing melanogenic activity to treat vitiligo. Histopathologic assessment on rat skin was conducted before clinical treatment in patients with vitiligo. The spanlastics were deemed to be of suitable nanosize and deformable, yielding consistent bergamot oil release. The bergamot oil included in the nanocarrier was found to enhance photostability and photodynamic activity, with the researchers concluding that bergamot oil nanospanlastics with psoralen-UVB therapy shows potential as a vitiligo therapy.10
Two years later, Shaaban evaluated bergamot oil formulated in nanostructured lipid carriers as a photosensitizer for photodynamic treatment of vitiligo. The botanical oil was effectively used in the nanostructured lipid carriers with a gel consistency that delivered sustained release of the oil for 24 hours. Preclinical and clinical results in patients were encouraging for the topical photodynamic treatment of vitiligo, with the nanostructured lipid carriers improving the photostability and photodynamic activity of bergamot oil.6
Photoaging, photoprotection, and safety concerns
Three decades ago, an international cooperative study of the photophysical, photomutagenic, and photocarcinogenic characteristics of bergamot oil and the effect of UVA and UVB sunscreens found that UVB and UVA sunscreens at low concentration (0.5%-1%) in perfumes could not inhibit the phototoxicity of bergamot oil on human skin.11
In a 2015 study assessing the impact of 38% bergamot polyphenolic fraction (a highly concentrated Citrus bergamia fruit extract) on UVB-generated photoaging, Nisticò et al. found that the bergamot compound dose-dependently protected HaCaT cells against UVB-caused oxidative stress and photoaging markers. Suggesting that the high-antioxidant bergamot polyphenolic fraction has potential for use in skin care formulations, the researchers added that the extract seems to induce antiproliferative, immune-modulating, and antiaging activity.12In 2022, Alexa et al. performed in vitro tests and found that natural preparations containing bergamot, orange, and clove essential oils do not significantly alter physiological skin parameters and were deemed safe for topical use. An emulsion with bergamot essential oil was also found to reduce the viability of oral squamous cell carcinoma cells.13
Conclusion
As a photosensitizing agent, bergamot has an established role in skin care. Beyond its niche role in treatments for vitiligo and psoriasis, this botanical product appears to show potential as an anti-inflammatory agent as well as an ingredient to combat photoaging and skin cancer. Much more research is needed to elucidate the possible wider benefits of this Mediterranean staple.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at [email protected].
References
1. Juber M. Health benefits of bergamot. WebMD. November 29, 2022. Accessed March 21, 2023.
2. Sun P et al. Mediators Inflamm. 2020 Oct 6;2020:8868107.
3. Cristiano MC et al. Biomedicines. 2022 Apr 30;10(5):1039.
4. Liang Y et al. Phytother Res. 2021 Nov;35(11):6131-47.
5. Quetglas-Llabrés MM et al. Oxid Med Cell Longev. 2022 Apr 25;2022:8615242.
6. Shaaban M et al. Expert Opin Drug Deliv. 2021 Jan;18(1):139-50.
7. McNeely W, Goa KL. Drugs. 1998 Oct;56(4):667-90.
8. Han X, Beaumont C, Stevens N. Biochim Open. 2017 Apr 26;5:1-7.
9. Perna S et al. Food Sci Nutr. 2019 Jan 25;7(2):369-84.
10. Shaaban M et al. Drug Deliv Transl Res. 2019 Dec;9(6):1106-16.
11. Dubertret L et al. J Photochem Photobiol B. 1990 Nov;7(2-4):251-9.
12. Nisticò S et al. J Biol Regul Homeost Agents. 2015 Jul-Sep;29(3):723-8.
13. Alexa VT et al. Molecules. 2022 Feb 1;27(3):990.
Citrus bergamia (bergamot) is a fruit tree thought to originate in the Mediterranean area; its fruit has been a part of the diet in that region since the early 18th century.1 Bergamot is known to confer antioxidant as well as anti-inflammatory activity, and yields proapoptotic effects in the sebaceous gland.2,3 The plant contains the natural furocoumarin bergapten, which is also known as 5-methoxypsoralen.4
5 In this capacity, bergamot oil has been used for photodynamic therapy of cutaneous conditions such as vitiligo.6 In fact, for several years 5-methoxypsoralen and 8-methoxypsoralen have been used to achieve acceptable clearance rates of psoriasis and vitiligo.7 This column focuses on bergapten, as well as the cutaneous conditions for which bergamot has been shown to have some benefits warranting application or further investigation.
Bergapten
In a 2021 literature review, Liang et al. cited the anti-inflammatory, antimicrobial, anticancer, and other salutary effects associated with bergapten. Based on numerous citations, they also cautioned about the phototoxicity of the compound combined with ultraviolet (UV) light while noting the photoactivation of bergapten for anticancer uses.4
The following year, Quetglas-Llabrés et al. acknowledged, in another literature review, the numerous preclinical and in vitro studies demonstrating the therapeutic activity of bergapten and highlighted clinical trials revealing notable lesion clearance rates of psoriasis or vitiligo imparted by oral or topical bergapten along with UV irradiation. Bergapten was also found to be effective as hypolipemic therapy.5
Anti-inflammatory topical uses
In a 2017 study by Han et al. of 10 essential oils, bergamot was among the investigated oils, all of which exhibited significant anti-proliferative activity in a preinflamed human dermal fibroblast system simulating chronic inflammation. Bergamot was among three essential oils that also suppressed protein molecules involved with inflammation, immune responses, and tissue remodeling, indicating anti-inflammatory and wound healing characteristics.8
More recently, Cristiano et al. reported that ultradeformable nanocarriers containing bergamot essential oil and ammonium glycyrrhizinate were demonstrated in healthy human volunteers to be characterized by the appropriate mean size, size distribution, surface charge, and long-term stability for topical administration. Topical administration on human volunteers also revealed greater activity of the combined agents as compared with a nanosystem loaded only with ammonium glycyrrhizinate. The researchers concluded that this combination of ingredients in ultradeformable vesicles shows potential as topical anti-inflammatory treatment.3
Acne
In a 2020 study using golden hamsters, Sun et al. assessed the effects of the juice and essential oils of bergamot and sweet orange on acne vulgaris engendered by excessive androgen secretion. Among 80 male hamsters randomly divided into 10 groups ranging from low to high doses, all results demonstrated improvement with treatment as seen by decreased growth rates of sebaceous glands, suppressed triglyceride accumulation, lowered inflammatory cytokine release, and apoptosis promotion in sebaceous glands. The authors noted that the essential oils yielded better dose-dependent effects than the juices.2
Psoriasis
In 2019, Perna et al. conducted a literature review on the effects of bergamot essential oil, extract, juice, and polyphenolic fraction on various health metrics. Thirty-one studies (20 involving humans with 1,709 subjects and 11 in rats and mice) were identified. Animal models indicated that bergamot essential oil (10 mg/kg or 20 mg/kg daily for 20 weeks) reduced psoriatic plaques, increased skin collagen content, and fostered hair growth and that bergamot juice (20 mg/kg) diminished proinflammatory cytokines. Human studies showed that bergamot extract and essential oil may reduce blood pressure and improve mental conditions.9
Vitiligo
In 2019, Shaaban et al. prepared elastic nanocarriers (spanlastics) to deliver psoralen-containing bergamot oil along with PUVB with the intention of harnessing melanogenic activity to treat vitiligo. Histopathologic assessment on rat skin was conducted before clinical treatment in patients with vitiligo. The spanlastics were deemed to be of suitable nanosize and deformable, yielding consistent bergamot oil release. The bergamot oil included in the nanocarrier was found to enhance photostability and photodynamic activity, with the researchers concluding that bergamot oil nanospanlastics with psoralen-UVB therapy shows potential as a vitiligo therapy.10
Two years later, Shaaban evaluated bergamot oil formulated in nanostructured lipid carriers as a photosensitizer for photodynamic treatment of vitiligo. The botanical oil was effectively used in the nanostructured lipid carriers with a gel consistency that delivered sustained release of the oil for 24 hours. Preclinical and clinical results in patients were encouraging for the topical photodynamic treatment of vitiligo, with the nanostructured lipid carriers improving the photostability and photodynamic activity of bergamot oil.6
Photoaging, photoprotection, and safety concerns
Three decades ago, an international cooperative study of the photophysical, photomutagenic, and photocarcinogenic characteristics of bergamot oil and the effect of UVA and UVB sunscreens found that UVB and UVA sunscreens at low concentration (0.5%-1%) in perfumes could not inhibit the phototoxicity of bergamot oil on human skin.11
In a 2015 study assessing the impact of 38% bergamot polyphenolic fraction (a highly concentrated Citrus bergamia fruit extract) on UVB-generated photoaging, Nisticò et al. found that the bergamot compound dose-dependently protected HaCaT cells against UVB-caused oxidative stress and photoaging markers. Suggesting that the high-antioxidant bergamot polyphenolic fraction has potential for use in skin care formulations, the researchers added that the extract seems to induce antiproliferative, immune-modulating, and antiaging activity.12In 2022, Alexa et al. performed in vitro tests and found that natural preparations containing bergamot, orange, and clove essential oils do not significantly alter physiological skin parameters and were deemed safe for topical use. An emulsion with bergamot essential oil was also found to reduce the viability of oral squamous cell carcinoma cells.13
Conclusion
As a photosensitizing agent, bergamot has an established role in skin care. Beyond its niche role in treatments for vitiligo and psoriasis, this botanical product appears to show potential as an anti-inflammatory agent as well as an ingredient to combat photoaging and skin cancer. Much more research is needed to elucidate the possible wider benefits of this Mediterranean staple.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at [email protected].
References
1. Juber M. Health benefits of bergamot. WebMD. November 29, 2022. Accessed March 21, 2023.
2. Sun P et al. Mediators Inflamm. 2020 Oct 6;2020:8868107.
3. Cristiano MC et al. Biomedicines. 2022 Apr 30;10(5):1039.
4. Liang Y et al. Phytother Res. 2021 Nov;35(11):6131-47.
5. Quetglas-Llabrés MM et al. Oxid Med Cell Longev. 2022 Apr 25;2022:8615242.
6. Shaaban M et al. Expert Opin Drug Deliv. 2021 Jan;18(1):139-50.
7. McNeely W, Goa KL. Drugs. 1998 Oct;56(4):667-90.
8. Han X, Beaumont C, Stevens N. Biochim Open. 2017 Apr 26;5:1-7.
9. Perna S et al. Food Sci Nutr. 2019 Jan 25;7(2):369-84.
10. Shaaban M et al. Drug Deliv Transl Res. 2019 Dec;9(6):1106-16.
11. Dubertret L et al. J Photochem Photobiol B. 1990 Nov;7(2-4):251-9.
12. Nisticò S et al. J Biol Regul Homeost Agents. 2015 Jul-Sep;29(3):723-8.
13. Alexa VT et al. Molecules. 2022 Feb 1;27(3):990.
Citrus bergamia (bergamot) is a fruit tree thought to originate in the Mediterranean area; its fruit has been a part of the diet in that region since the early 18th century.1 Bergamot is known to confer antioxidant as well as anti-inflammatory activity, and yields proapoptotic effects in the sebaceous gland.2,3 The plant contains the natural furocoumarin bergapten, which is also known as 5-methoxypsoralen.4
5 In this capacity, bergamot oil has been used for photodynamic therapy of cutaneous conditions such as vitiligo.6 In fact, for several years 5-methoxypsoralen and 8-methoxypsoralen have been used to achieve acceptable clearance rates of psoriasis and vitiligo.7 This column focuses on bergapten, as well as the cutaneous conditions for which bergamot has been shown to have some benefits warranting application or further investigation.
Bergapten
In a 2021 literature review, Liang et al. cited the anti-inflammatory, antimicrobial, anticancer, and other salutary effects associated with bergapten. Based on numerous citations, they also cautioned about the phototoxicity of the compound combined with ultraviolet (UV) light while noting the photoactivation of bergapten for anticancer uses.4
The following year, Quetglas-Llabrés et al. acknowledged, in another literature review, the numerous preclinical and in vitro studies demonstrating the therapeutic activity of bergapten and highlighted clinical trials revealing notable lesion clearance rates of psoriasis or vitiligo imparted by oral or topical bergapten along with UV irradiation. Bergapten was also found to be effective as hypolipemic therapy.5
Anti-inflammatory topical uses
In a 2017 study by Han et al. of 10 essential oils, bergamot was among the investigated oils, all of which exhibited significant anti-proliferative activity in a preinflamed human dermal fibroblast system simulating chronic inflammation. Bergamot was among three essential oils that also suppressed protein molecules involved with inflammation, immune responses, and tissue remodeling, indicating anti-inflammatory and wound healing characteristics.8
More recently, Cristiano et al. reported that ultradeformable nanocarriers containing bergamot essential oil and ammonium glycyrrhizinate were demonstrated in healthy human volunteers to be characterized by the appropriate mean size, size distribution, surface charge, and long-term stability for topical administration. Topical administration on human volunteers also revealed greater activity of the combined agents as compared with a nanosystem loaded only with ammonium glycyrrhizinate. The researchers concluded that this combination of ingredients in ultradeformable vesicles shows potential as topical anti-inflammatory treatment.3
Acne
In a 2020 study using golden hamsters, Sun et al. assessed the effects of the juice and essential oils of bergamot and sweet orange on acne vulgaris engendered by excessive androgen secretion. Among 80 male hamsters randomly divided into 10 groups ranging from low to high doses, all results demonstrated improvement with treatment as seen by decreased growth rates of sebaceous glands, suppressed triglyceride accumulation, lowered inflammatory cytokine release, and apoptosis promotion in sebaceous glands. The authors noted that the essential oils yielded better dose-dependent effects than the juices.2
Psoriasis
In 2019, Perna et al. conducted a literature review on the effects of bergamot essential oil, extract, juice, and polyphenolic fraction on various health metrics. Thirty-one studies (20 involving humans with 1,709 subjects and 11 in rats and mice) were identified. Animal models indicated that bergamot essential oil (10 mg/kg or 20 mg/kg daily for 20 weeks) reduced psoriatic plaques, increased skin collagen content, and fostered hair growth and that bergamot juice (20 mg/kg) diminished proinflammatory cytokines. Human studies showed that bergamot extract and essential oil may reduce blood pressure and improve mental conditions.9
Vitiligo
In 2019, Shaaban et al. prepared elastic nanocarriers (spanlastics) to deliver psoralen-containing bergamot oil along with PUVB with the intention of harnessing melanogenic activity to treat vitiligo. Histopathologic assessment on rat skin was conducted before clinical treatment in patients with vitiligo. The spanlastics were deemed to be of suitable nanosize and deformable, yielding consistent bergamot oil release. The bergamot oil included in the nanocarrier was found to enhance photostability and photodynamic activity, with the researchers concluding that bergamot oil nanospanlastics with psoralen-UVB therapy shows potential as a vitiligo therapy.10
Two years later, Shaaban evaluated bergamot oil formulated in nanostructured lipid carriers as a photosensitizer for photodynamic treatment of vitiligo. The botanical oil was effectively used in the nanostructured lipid carriers with a gel consistency that delivered sustained release of the oil for 24 hours. Preclinical and clinical results in patients were encouraging for the topical photodynamic treatment of vitiligo, with the nanostructured lipid carriers improving the photostability and photodynamic activity of bergamot oil.6
Photoaging, photoprotection, and safety concerns
Three decades ago, an international cooperative study of the photophysical, photomutagenic, and photocarcinogenic characteristics of bergamot oil and the effect of UVA and UVB sunscreens found that UVB and UVA sunscreens at low concentration (0.5%-1%) in perfumes could not inhibit the phototoxicity of bergamot oil on human skin.11
In a 2015 study assessing the impact of 38% bergamot polyphenolic fraction (a highly concentrated Citrus bergamia fruit extract) on UVB-generated photoaging, Nisticò et al. found that the bergamot compound dose-dependently protected HaCaT cells against UVB-caused oxidative stress and photoaging markers. Suggesting that the high-antioxidant bergamot polyphenolic fraction has potential for use in skin care formulations, the researchers added that the extract seems to induce antiproliferative, immune-modulating, and antiaging activity.12In 2022, Alexa et al. performed in vitro tests and found that natural preparations containing bergamot, orange, and clove essential oils do not significantly alter physiological skin parameters and were deemed safe for topical use. An emulsion with bergamot essential oil was also found to reduce the viability of oral squamous cell carcinoma cells.13
Conclusion
As a photosensitizing agent, bergamot has an established role in skin care. Beyond its niche role in treatments for vitiligo and psoriasis, this botanical product appears to show potential as an anti-inflammatory agent as well as an ingredient to combat photoaging and skin cancer. Much more research is needed to elucidate the possible wider benefits of this Mediterranean staple.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at [email protected].
References
1. Juber M. Health benefits of bergamot. WebMD. November 29, 2022. Accessed March 21, 2023.
2. Sun P et al. Mediators Inflamm. 2020 Oct 6;2020:8868107.
3. Cristiano MC et al. Biomedicines. 2022 Apr 30;10(5):1039.
4. Liang Y et al. Phytother Res. 2021 Nov;35(11):6131-47.
5. Quetglas-Llabrés MM et al. Oxid Med Cell Longev. 2022 Apr 25;2022:8615242.
6. Shaaban M et al. Expert Opin Drug Deliv. 2021 Jan;18(1):139-50.
7. McNeely W, Goa KL. Drugs. 1998 Oct;56(4):667-90.
8. Han X, Beaumont C, Stevens N. Biochim Open. 2017 Apr 26;5:1-7.
9. Perna S et al. Food Sci Nutr. 2019 Jan 25;7(2):369-84.
10. Shaaban M et al. Drug Deliv Transl Res. 2019 Dec;9(6):1106-16.
11. Dubertret L et al. J Photochem Photobiol B. 1990 Nov;7(2-4):251-9.
12. Nisticò S et al. J Biol Regul Homeost Agents. 2015 Jul-Sep;29(3):723-8.
13. Alexa VT et al. Molecules. 2022 Feb 1;27(3):990.
Annular Erythematous Plaques With Central Hypopigmentation on Sun-Exposed Skin
A biopsy showed a markedly elastotic dermis consisting of a palisading granulomatous inflammatory infiltrate and numerous multinucleated histiocytes (Figure). These histopathologic findings along with the clinical presentation confirmed a diagnosis of annular elastolytic granuloma (AEG). Treatment consisting of 3 months of oral minocycline, 2 months of oral doxycycline, and clobetasol ointment all failed. At that point, oral hydroxychloroquine was recommended. Our patient was lost to follow-up by dermatology, then subsequently was placed on hydroxychloroquine by rheumatology to treat both the osteoarthritis and AEG. A follow-up appointment with dermatology was planned for 3 months to monitor hydroxychloroquine treatment and monitor treatment progress; however, she did not follow-up or seek further treatment.
Annular elastolytic granuloma clinically is similar to granuloma annulare (GA), with both presenting as annular plaques surrounded by an elevated border.1 Although AEG clinically is distinct with hypopigmented atrophied plaque centers,2 a biopsy is required to confirm the lack of elastic tissue in zones of atrophy and the presence of multinucleated histiocytes.1,3 Lesions most commonly are seen clinically on sun-exposed areas in middle-aged White women; however, they rarely have been seen on frequently covered skin.4 Our case illustrates the striking photodistribution of AEG, especially on the posterior neck area. The clinical diagnoses of AEG, annular elastolytic giant cell granuloma, and GA in sun-exposed areas are synonymous and can be used interchangeably.5,6
Pathologies considered in the diagnosis of AEG include but are not limited to tinea corporis, annular lichen planus, erythema annulare centrifugum, and necrobiosis lipoidica. Scaling typically is absent in AEG, while tinea corporis presents with hyphae within the stratum corneum of the plaques.7 Papules along the periphery of annular lesions are more typical of annular lichen planus than AEG, and they tend to have a more purple hue.8 Erythema annulare centrifugum has annular erythematous plaques similar to those found in AEG but differs with scaling on the inner margins of these plaques. Histopathology presenting with a lymphocytic infiltrate surrounding vasculature and no indication of elastolytic degradation would further indicate a diagnosis of erythema annulare centrifugum.9 Histopathology showing necrobiosis, lipid depositions, and vascular wall thickenings is indicative of necrobiosis lipoidica.10
Similar to GA,11 the cause of AEG is idiopathic.2 Annular elastolytic granuloma and GA differ in the fact that elastin degradation is characteristic of AEG compared to collagen degradation in GA. It is suspected that elastin degradation in AEG patients is caused by an immune response triggering phagocytosis of elastin by multinucleated histiocytes.2 Actinic damage also is considered a possible cause of elastin fiber degradation in AEG.12 Granuloma annulare can be ruled out and the diagnosis of AEG confirmed with the absence of elastin fibers and mucin on pathology.13
Although there is no established first-line treatment of AEG, successful treatment has been achieved with antimalarial drugs paired with topical steroids.14 Treatment recommendations for AEG include minocycline, chloroquine, hydroxychloroquine, tranilast, and oral retinoids, as well as oral and topical steroids. In clinical cases where AEG occurs in the setting of a chronic disease such as diabetes mellitus, vascular occlusion, arthritis, or hypertension, treatment of underlying disease has been shown to resolve AEG symptoms.14
Although light therapy is not common for AEG, UV light radiation has demonstrated success in treating AEG.15,16 One study showed complete clearance of granulomatous papules after narrowband UVB treatment.15 Another study showed that 2 patients treated with psoralen plus UVA therapy reached complete clearance of AEG lasting at least 3 months after treatment.16
1. Lai JH, Murray SJ, Walsh NM. Evolution of granuloma annulare to mid-dermal elastolysis: report of a case and review of the literature. J Cutan Pathol. 2014;41:462-468. doi:10.1111/cup.12292 2. Klemke CD, Siebold D, Dippel E, et al. Generalised annular elastolytic giant cell granuloma. Dermatology. 2003;207:420-422. doi:10.1159/000074132 3. Limas C. The spectrum of primary cutaneous elastolytic granulomas and their distinction from granuloma annulare: a clinicopathological analysis. Histopathology. 2004;44:277-282. doi:10.1111/j.0309-0167.2004.01755.x 4. Revenga F, Rovira I, Pimentel J, et al. Annular elastolytic giant cell granuloma—actinic granuloma? Clin Exp Dermatol. 1996;21:51-53. 5. Hawryluk EB, Izikson L, English JC 3rd. Non-infectious granulomatous diseases of the skin and their associated systemic diseases: an evidence-based update to important clinical questions. Am J Clin Dermatol. 2010;11:171-181. doi:10.2165/11530080-000000000-00000 6. Berliner JG, Haemel A, LeBoit PE, et al. The sarcoidal variant of annular elastolytic granuloma. J Cutan Pathol. 2013;40:918-920. doi:10.1111/cup.12237 7. Pflederer RT, Ahmed S, Tonkovic-Capin V, et al. Annular polycyclic plaques on the chest and upper back [published online April 24, 2018]. JAAD Case Rep. 2018;4:405-407. doi:10.1016/j.jdcr.2017.07.022 8. Trayes KP, Savage K, Studdiford JS. Annular lesions: diagnosis and treatment. Am Fam Physician. 2018;98:283-291. 9. Weyers W, Diaz-Cascajo C, Weyers I. Erythema annulare centrifugum: results of a clinicopathologic study of 73 patients. Am J Dermatopathol. 2003;25:451-462. doi:10.1097/00000372-200312000-00001 10. Dowling GB, Jones EW. Atypical (annular) necrobiosis lipoidica of the face and scalp. a report of the clinical and histological features of 7 cases. Dermatologica. 1967;135:11-26. doi:10.1159/000254156 11. Piette EW, Rosenbach M. Granuloma annulare: pathogenesis, disease associations and triggers, and therapeutic options. J Am Acad Dermatol. 2016;75:467-479. doi:10.1016/j.jaad.2015 .03.055 12. O’Brien JP, Regan W. Actinically degenerate elastic tissue is the likely antigenic basis of actinic granuloma of the skin and of temporal arteritis [published correction appears in J Am Acad Dermatol. 2000; 42(1 pt 1):148]. J Am Acad Dermatol. 1999;40(2 pt 1):214-222. doi:10.1016/s0190-9622(99)70191-x 13. Rencic A, Nousari CH. Other rheumatologic diseases. In: Bolognia JL, Jorizzo JL, Rapini RP, et al, eds. Dermatology. 2nd ed. Elsevier Limited; 2008:600-601. 14. Burlando M, Herzum A, Cozzani E, et al. Can methotrexate be a successful treatment for unresponsive generalized annular elastolytic giant cell granuloma? case report and review of the literature. Dermatol Ther. 2021;34:E14705. doi:10.1111/dth.14705 15. Takata T, Ikeda M, Kodama H, et al. Regression of papular elastolytic giant cell granuloma using narrow-band UVB irradiation. Dermatology. 2006;212:77-79. doi:10.1159/000089028 16. Pérez-Pérez L, García-Gavín J, Allegue F, et al. Successful treatment of generalized elastolytic giant cell granuloma with psoralenultraviolet A. Photodermatol Photoimmunol Photomed. 2012;28:264-266. doi:10.1111/j.1600-0781.2012.00680.x
A biopsy showed a markedly elastotic dermis consisting of a palisading granulomatous inflammatory infiltrate and numerous multinucleated histiocytes (Figure). These histopathologic findings along with the clinical presentation confirmed a diagnosis of annular elastolytic granuloma (AEG). Treatment consisting of 3 months of oral minocycline, 2 months of oral doxycycline, and clobetasol ointment all failed. At that point, oral hydroxychloroquine was recommended. Our patient was lost to follow-up by dermatology, then subsequently was placed on hydroxychloroquine by rheumatology to treat both the osteoarthritis and AEG. A follow-up appointment with dermatology was planned for 3 months to monitor hydroxychloroquine treatment and monitor treatment progress; however, she did not follow-up or seek further treatment.
Annular elastolytic granuloma clinically is similar to granuloma annulare (GA), with both presenting as annular plaques surrounded by an elevated border.1 Although AEG clinically is distinct with hypopigmented atrophied plaque centers,2 a biopsy is required to confirm the lack of elastic tissue in zones of atrophy and the presence of multinucleated histiocytes.1,3 Lesions most commonly are seen clinically on sun-exposed areas in middle-aged White women; however, they rarely have been seen on frequently covered skin.4 Our case illustrates the striking photodistribution of AEG, especially on the posterior neck area. The clinical diagnoses of AEG, annular elastolytic giant cell granuloma, and GA in sun-exposed areas are synonymous and can be used interchangeably.5,6
Pathologies considered in the diagnosis of AEG include but are not limited to tinea corporis, annular lichen planus, erythema annulare centrifugum, and necrobiosis lipoidica. Scaling typically is absent in AEG, while tinea corporis presents with hyphae within the stratum corneum of the plaques.7 Papules along the periphery of annular lesions are more typical of annular lichen planus than AEG, and they tend to have a more purple hue.8 Erythema annulare centrifugum has annular erythematous plaques similar to those found in AEG but differs with scaling on the inner margins of these plaques. Histopathology presenting with a lymphocytic infiltrate surrounding vasculature and no indication of elastolytic degradation would further indicate a diagnosis of erythema annulare centrifugum.9 Histopathology showing necrobiosis, lipid depositions, and vascular wall thickenings is indicative of necrobiosis lipoidica.10
Similar to GA,11 the cause of AEG is idiopathic.2 Annular elastolytic granuloma and GA differ in the fact that elastin degradation is characteristic of AEG compared to collagen degradation in GA. It is suspected that elastin degradation in AEG patients is caused by an immune response triggering phagocytosis of elastin by multinucleated histiocytes.2 Actinic damage also is considered a possible cause of elastin fiber degradation in AEG.12 Granuloma annulare can be ruled out and the diagnosis of AEG confirmed with the absence of elastin fibers and mucin on pathology.13
Although there is no established first-line treatment of AEG, successful treatment has been achieved with antimalarial drugs paired with topical steroids.14 Treatment recommendations for AEG include minocycline, chloroquine, hydroxychloroquine, tranilast, and oral retinoids, as well as oral and topical steroids. In clinical cases where AEG occurs in the setting of a chronic disease such as diabetes mellitus, vascular occlusion, arthritis, or hypertension, treatment of underlying disease has been shown to resolve AEG symptoms.14
Although light therapy is not common for AEG, UV light radiation has demonstrated success in treating AEG.15,16 One study showed complete clearance of granulomatous papules after narrowband UVB treatment.15 Another study showed that 2 patients treated with psoralen plus UVA therapy reached complete clearance of AEG lasting at least 3 months after treatment.16
A biopsy showed a markedly elastotic dermis consisting of a palisading granulomatous inflammatory infiltrate and numerous multinucleated histiocytes (Figure). These histopathologic findings along with the clinical presentation confirmed a diagnosis of annular elastolytic granuloma (AEG). Treatment consisting of 3 months of oral minocycline, 2 months of oral doxycycline, and clobetasol ointment all failed. At that point, oral hydroxychloroquine was recommended. Our patient was lost to follow-up by dermatology, then subsequently was placed on hydroxychloroquine by rheumatology to treat both the osteoarthritis and AEG. A follow-up appointment with dermatology was planned for 3 months to monitor hydroxychloroquine treatment and monitor treatment progress; however, she did not follow-up or seek further treatment.
Annular elastolytic granuloma clinically is similar to granuloma annulare (GA), with both presenting as annular plaques surrounded by an elevated border.1 Although AEG clinically is distinct with hypopigmented atrophied plaque centers,2 a biopsy is required to confirm the lack of elastic tissue in zones of atrophy and the presence of multinucleated histiocytes.1,3 Lesions most commonly are seen clinically on sun-exposed areas in middle-aged White women; however, they rarely have been seen on frequently covered skin.4 Our case illustrates the striking photodistribution of AEG, especially on the posterior neck area. The clinical diagnoses of AEG, annular elastolytic giant cell granuloma, and GA in sun-exposed areas are synonymous and can be used interchangeably.5,6
Pathologies considered in the diagnosis of AEG include but are not limited to tinea corporis, annular lichen planus, erythema annulare centrifugum, and necrobiosis lipoidica. Scaling typically is absent in AEG, while tinea corporis presents with hyphae within the stratum corneum of the plaques.7 Papules along the periphery of annular lesions are more typical of annular lichen planus than AEG, and they tend to have a more purple hue.8 Erythema annulare centrifugum has annular erythematous plaques similar to those found in AEG but differs with scaling on the inner margins of these plaques. Histopathology presenting with a lymphocytic infiltrate surrounding vasculature and no indication of elastolytic degradation would further indicate a diagnosis of erythema annulare centrifugum.9 Histopathology showing necrobiosis, lipid depositions, and vascular wall thickenings is indicative of necrobiosis lipoidica.10
Similar to GA,11 the cause of AEG is idiopathic.2 Annular elastolytic granuloma and GA differ in the fact that elastin degradation is characteristic of AEG compared to collagen degradation in GA. It is suspected that elastin degradation in AEG patients is caused by an immune response triggering phagocytosis of elastin by multinucleated histiocytes.2 Actinic damage also is considered a possible cause of elastin fiber degradation in AEG.12 Granuloma annulare can be ruled out and the diagnosis of AEG confirmed with the absence of elastin fibers and mucin on pathology.13
Although there is no established first-line treatment of AEG, successful treatment has been achieved with antimalarial drugs paired with topical steroids.14 Treatment recommendations for AEG include minocycline, chloroquine, hydroxychloroquine, tranilast, and oral retinoids, as well as oral and topical steroids. In clinical cases where AEG occurs in the setting of a chronic disease such as diabetes mellitus, vascular occlusion, arthritis, or hypertension, treatment of underlying disease has been shown to resolve AEG symptoms.14
Although light therapy is not common for AEG, UV light radiation has demonstrated success in treating AEG.15,16 One study showed complete clearance of granulomatous papules after narrowband UVB treatment.15 Another study showed that 2 patients treated with psoralen plus UVA therapy reached complete clearance of AEG lasting at least 3 months after treatment.16
1. Lai JH, Murray SJ, Walsh NM. Evolution of granuloma annulare to mid-dermal elastolysis: report of a case and review of the literature. J Cutan Pathol. 2014;41:462-468. doi:10.1111/cup.12292 2. Klemke CD, Siebold D, Dippel E, et al. Generalised annular elastolytic giant cell granuloma. Dermatology. 2003;207:420-422. doi:10.1159/000074132 3. Limas C. The spectrum of primary cutaneous elastolytic granulomas and their distinction from granuloma annulare: a clinicopathological analysis. Histopathology. 2004;44:277-282. doi:10.1111/j.0309-0167.2004.01755.x 4. Revenga F, Rovira I, Pimentel J, et al. Annular elastolytic giant cell granuloma—actinic granuloma? Clin Exp Dermatol. 1996;21:51-53. 5. Hawryluk EB, Izikson L, English JC 3rd. Non-infectious granulomatous diseases of the skin and their associated systemic diseases: an evidence-based update to important clinical questions. Am J Clin Dermatol. 2010;11:171-181. doi:10.2165/11530080-000000000-00000 6. Berliner JG, Haemel A, LeBoit PE, et al. The sarcoidal variant of annular elastolytic granuloma. J Cutan Pathol. 2013;40:918-920. doi:10.1111/cup.12237 7. Pflederer RT, Ahmed S, Tonkovic-Capin V, et al. Annular polycyclic plaques on the chest and upper back [published online April 24, 2018]. JAAD Case Rep. 2018;4:405-407. doi:10.1016/j.jdcr.2017.07.022 8. Trayes KP, Savage K, Studdiford JS. Annular lesions: diagnosis and treatment. Am Fam Physician. 2018;98:283-291. 9. Weyers W, Diaz-Cascajo C, Weyers I. Erythema annulare centrifugum: results of a clinicopathologic study of 73 patients. Am J Dermatopathol. 2003;25:451-462. doi:10.1097/00000372-200312000-00001 10. Dowling GB, Jones EW. Atypical (annular) necrobiosis lipoidica of the face and scalp. a report of the clinical and histological features of 7 cases. Dermatologica. 1967;135:11-26. doi:10.1159/000254156 11. Piette EW, Rosenbach M. Granuloma annulare: pathogenesis, disease associations and triggers, and therapeutic options. J Am Acad Dermatol. 2016;75:467-479. doi:10.1016/j.jaad.2015 .03.055 12. O’Brien JP, Regan W. Actinically degenerate elastic tissue is the likely antigenic basis of actinic granuloma of the skin and of temporal arteritis [published correction appears in J Am Acad Dermatol. 2000; 42(1 pt 1):148]. J Am Acad Dermatol. 1999;40(2 pt 1):214-222. doi:10.1016/s0190-9622(99)70191-x 13. Rencic A, Nousari CH. Other rheumatologic diseases. In: Bolognia JL, Jorizzo JL, Rapini RP, et al, eds. Dermatology. 2nd ed. Elsevier Limited; 2008:600-601. 14. Burlando M, Herzum A, Cozzani E, et al. Can methotrexate be a successful treatment for unresponsive generalized annular elastolytic giant cell granuloma? case report and review of the literature. Dermatol Ther. 2021;34:E14705. doi:10.1111/dth.14705 15. Takata T, Ikeda M, Kodama H, et al. Regression of papular elastolytic giant cell granuloma using narrow-band UVB irradiation. Dermatology. 2006;212:77-79. doi:10.1159/000089028 16. Pérez-Pérez L, García-Gavín J, Allegue F, et al. Successful treatment of generalized elastolytic giant cell granuloma with psoralenultraviolet A. Photodermatol Photoimmunol Photomed. 2012;28:264-266. doi:10.1111/j.1600-0781.2012.00680.x
1. Lai JH, Murray SJ, Walsh NM. Evolution of granuloma annulare to mid-dermal elastolysis: report of a case and review of the literature. J Cutan Pathol. 2014;41:462-468. doi:10.1111/cup.12292 2. Klemke CD, Siebold D, Dippel E, et al. Generalised annular elastolytic giant cell granuloma. Dermatology. 2003;207:420-422. doi:10.1159/000074132 3. Limas C. The spectrum of primary cutaneous elastolytic granulomas and their distinction from granuloma annulare: a clinicopathological analysis. Histopathology. 2004;44:277-282. doi:10.1111/j.0309-0167.2004.01755.x 4. Revenga F, Rovira I, Pimentel J, et al. Annular elastolytic giant cell granuloma—actinic granuloma? Clin Exp Dermatol. 1996;21:51-53. 5. Hawryluk EB, Izikson L, English JC 3rd. Non-infectious granulomatous diseases of the skin and their associated systemic diseases: an evidence-based update to important clinical questions. Am J Clin Dermatol. 2010;11:171-181. doi:10.2165/11530080-000000000-00000 6. Berliner JG, Haemel A, LeBoit PE, et al. The sarcoidal variant of annular elastolytic granuloma. J Cutan Pathol. 2013;40:918-920. doi:10.1111/cup.12237 7. Pflederer RT, Ahmed S, Tonkovic-Capin V, et al. Annular polycyclic plaques on the chest and upper back [published online April 24, 2018]. JAAD Case Rep. 2018;4:405-407. doi:10.1016/j.jdcr.2017.07.022 8. Trayes KP, Savage K, Studdiford JS. Annular lesions: diagnosis and treatment. Am Fam Physician. 2018;98:283-291. 9. Weyers W, Diaz-Cascajo C, Weyers I. Erythema annulare centrifugum: results of a clinicopathologic study of 73 patients. Am J Dermatopathol. 2003;25:451-462. doi:10.1097/00000372-200312000-00001 10. Dowling GB, Jones EW. Atypical (annular) necrobiosis lipoidica of the face and scalp. a report of the clinical and histological features of 7 cases. Dermatologica. 1967;135:11-26. doi:10.1159/000254156 11. Piette EW, Rosenbach M. Granuloma annulare: pathogenesis, disease associations and triggers, and therapeutic options. J Am Acad Dermatol. 2016;75:467-479. doi:10.1016/j.jaad.2015 .03.055 12. O’Brien JP, Regan W. Actinically degenerate elastic tissue is the likely antigenic basis of actinic granuloma of the skin and of temporal arteritis [published correction appears in J Am Acad Dermatol. 2000; 42(1 pt 1):148]. J Am Acad Dermatol. 1999;40(2 pt 1):214-222. doi:10.1016/s0190-9622(99)70191-x 13. Rencic A, Nousari CH. Other rheumatologic diseases. In: Bolognia JL, Jorizzo JL, Rapini RP, et al, eds. Dermatology. 2nd ed. Elsevier Limited; 2008:600-601. 14. Burlando M, Herzum A, Cozzani E, et al. Can methotrexate be a successful treatment for unresponsive generalized annular elastolytic giant cell granuloma? case report and review of the literature. Dermatol Ther. 2021;34:E14705. doi:10.1111/dth.14705 15. Takata T, Ikeda M, Kodama H, et al. Regression of papular elastolytic giant cell granuloma using narrow-band UVB irradiation. Dermatology. 2006;212:77-79. doi:10.1159/000089028 16. Pérez-Pérez L, García-Gavín J, Allegue F, et al. Successful treatment of generalized elastolytic giant cell granuloma with psoralenultraviolet A. Photodermatol Photoimmunol Photomed. 2012;28:264-266. doi:10.1111/j.1600-0781.2012.00680.x
A 67-year-old White woman presented to our dermatology clinic with pruritic annular erythematous plaques with central hypopigmentation on the forearms, dorsal aspect of the hands, neck, and fingers of 3 to 4 months’ duration. The patient rated the severity of pruritus an 8 on a 10-point scale. A review of symptoms was positive for fatigue, joint pain, and headache. The patient had a history of type 2 diabetes mellitus, osteoarthritis, thyroid disease, and stage 3 renal failure. A punch biopsy from the left forearm was performed.
Periorbital Orange Spots
The Diagnosis: Orange Palpebral Spots
The clinical presentation of our patient was consistent with a diagnosis of orange palpebral spots (OPSs), an uncommon discoloration that most often appears in White patients in the fifth or sixth decades of life. Orange palpebral spots were first described in 2008 by Assouly et al1 in 27 patients (23 females and 4 males). In 2015, Belliveau et al2 expanded the designation to yellow-orange palpebral spots because they felt the term more fully expressed the color variations depicted in their patients; however, this term more frequently is used in ophthalmology.
Orange palpebral spots commonly appear as asymptomatic, yellow-orange, symmetric lesions with a predilection for the recessed areas of the superior eyelids but also can present on the canthi and inferior eyelids. The discolorations are more easily visible on fair skin and have been reported to measure from 10 to 15 mm in the long axis.3 Assouly et al1 described the orange spots as having indistinct margins, with borders similar to “sand on a sea shore.” Orange palpebral spots can be a persistent discoloration, and there are no reports of spontaneous regression. No known association with malignancy or systemic illness has been reported.
Case reports of OPSs describe histologic similarities between specimens, including increased adipose tissue and pigment-laden macrophages in the superficial dermis.2 The pigmented deposits sometimes may be found in the basal keratinocytes of the epidermis and turn black with Fontana-Masson stain.1 No inflammatory infiltrates, necrosis, or xanthomization are characteristically found. Stains for iron, mucin, and amyloid also have been negative.2
The cause of pigmentation in OPSs is unknown; however, lipofuscin deposits and high-situated adipocytes in the reticular dermis colored by carotenoids have been proposed as possible mechanisms.1 No unifying cause for pigmentation in the serum (eg, cholesterol, triglycerides, thyroid-stimulating hormone, free retinol, vitamin E, carotenoids) was found in 11 of 27 patients with OPSs assessed by Assouly et al.1 In one case, lipofuscin, a degradation product of lysosomes, was detected by microscopic autofluorescence in the superficial dermis. However, lipofuscin typically is a breakdown product associated with aging, and OPSs have been present in patients as young as 28 years.1 Local trauma related to eye rubbing is another theory that has been proposed due to the finding of melanin in the superficial dermis. However, the absence of hemosiderin deposits as well as the extensive duration of the discolorations makes local trauma a less likely explanation for the etiology of OPSs.2
The clinical differential diagnosis for OPSs includes xanthelasma, jaundice, and carotenoderma. Xanthelasma presents as elevated yellow plaques usually found over the medial aspect of the eyes. In contrast, OPSs are nonelevated with both orange and yellow hues typically present. Histologic samples of xanthelasma are characterized by lipid-laden macrophages (foam cells) in the dermis in contrast to the adipose tissue seen in OPSs that has not been phagocytized.1,2 The lack of scleral icterus made jaundice an unlikely diagnosis in our patient. Bilirubin elevations substantial enough to cause skin discoloration also would be expected to discolor the conjunctiva. In carotenoderma, carotenoids are deposited in the sweat and sebum of the stratum corneum with the orange pigmentation most prominent in regions of increased sweating such as the palms, soles, and nasolabial folds.4 Our patient’s lack of discoloration in places other than the periorbital region made carotenoderma less likely.
In the study by Assouly et al,1 10 of 11 patients who underwent laboratory analysis self-reported eating a diet rich in fruit and vegetables, though no standardized questionnaire was given. One patient was found to have an elevated vitamin E level, and in 5 cases there was an elevated level of β-cryptoxanthin. The significance of these elevations in such a small minority is unknown, and increased β-cryptoxanthin has been attributed to increased consumption of citrus fruits during the winter season. Our patient reported ingesting a daily oral supplement rich in carotenoids that constituted 60% of the daily value of vitamin E including mixed tocopherols as well as 90% of the daily value of vitamin A with many sources of carotenoids including beta-carotenes, lutein/zeaxanthin, lycopene, and astaxanthin. An invasive biopsy was not taken in this case, as OPSs largely are diagnosed clinically. Greater awareness and recognition of OPSs may help to identify common underlying causes for this unique diagnosis.
- Assouly P, Cavelier-Balloy B, Dupré T. Orange palpebral spots. Dermatology. 2008;216:166-170.
- Belliveau MJ, Odashiro AN, Harvey JT. Yellow-orange palpebral spots. Ophthalmology. 2015;122:2139-2140.
- Kluger N, Guillot B. Bilateral orange discoloration of the upper eyelids: a quiz. Acta Derm Venereol. 2011;91:211-212.
- Maharshak N, Shapiro J, Trau H. Carotenoderma—a review of the current literature. Int J Dermatol. 2003;42:178-181.
The Diagnosis: Orange Palpebral Spots
The clinical presentation of our patient was consistent with a diagnosis of orange palpebral spots (OPSs), an uncommon discoloration that most often appears in White patients in the fifth or sixth decades of life. Orange palpebral spots were first described in 2008 by Assouly et al1 in 27 patients (23 females and 4 males). In 2015, Belliveau et al2 expanded the designation to yellow-orange palpebral spots because they felt the term more fully expressed the color variations depicted in their patients; however, this term more frequently is used in ophthalmology.
Orange palpebral spots commonly appear as asymptomatic, yellow-orange, symmetric lesions with a predilection for the recessed areas of the superior eyelids but also can present on the canthi and inferior eyelids. The discolorations are more easily visible on fair skin and have been reported to measure from 10 to 15 mm in the long axis.3 Assouly et al1 described the orange spots as having indistinct margins, with borders similar to “sand on a sea shore.” Orange palpebral spots can be a persistent discoloration, and there are no reports of spontaneous regression. No known association with malignancy or systemic illness has been reported.
Case reports of OPSs describe histologic similarities between specimens, including increased adipose tissue and pigment-laden macrophages in the superficial dermis.2 The pigmented deposits sometimes may be found in the basal keratinocytes of the epidermis and turn black with Fontana-Masson stain.1 No inflammatory infiltrates, necrosis, or xanthomization are characteristically found. Stains for iron, mucin, and amyloid also have been negative.2
The cause of pigmentation in OPSs is unknown; however, lipofuscin deposits and high-situated adipocytes in the reticular dermis colored by carotenoids have been proposed as possible mechanisms.1 No unifying cause for pigmentation in the serum (eg, cholesterol, triglycerides, thyroid-stimulating hormone, free retinol, vitamin E, carotenoids) was found in 11 of 27 patients with OPSs assessed by Assouly et al.1 In one case, lipofuscin, a degradation product of lysosomes, was detected by microscopic autofluorescence in the superficial dermis. However, lipofuscin typically is a breakdown product associated with aging, and OPSs have been present in patients as young as 28 years.1 Local trauma related to eye rubbing is another theory that has been proposed due to the finding of melanin in the superficial dermis. However, the absence of hemosiderin deposits as well as the extensive duration of the discolorations makes local trauma a less likely explanation for the etiology of OPSs.2
The clinical differential diagnosis for OPSs includes xanthelasma, jaundice, and carotenoderma. Xanthelasma presents as elevated yellow plaques usually found over the medial aspect of the eyes. In contrast, OPSs are nonelevated with both orange and yellow hues typically present. Histologic samples of xanthelasma are characterized by lipid-laden macrophages (foam cells) in the dermis in contrast to the adipose tissue seen in OPSs that has not been phagocytized.1,2 The lack of scleral icterus made jaundice an unlikely diagnosis in our patient. Bilirubin elevations substantial enough to cause skin discoloration also would be expected to discolor the conjunctiva. In carotenoderma, carotenoids are deposited in the sweat and sebum of the stratum corneum with the orange pigmentation most prominent in regions of increased sweating such as the palms, soles, and nasolabial folds.4 Our patient’s lack of discoloration in places other than the periorbital region made carotenoderma less likely.
In the study by Assouly et al,1 10 of 11 patients who underwent laboratory analysis self-reported eating a diet rich in fruit and vegetables, though no standardized questionnaire was given. One patient was found to have an elevated vitamin E level, and in 5 cases there was an elevated level of β-cryptoxanthin. The significance of these elevations in such a small minority is unknown, and increased β-cryptoxanthin has been attributed to increased consumption of citrus fruits during the winter season. Our patient reported ingesting a daily oral supplement rich in carotenoids that constituted 60% of the daily value of vitamin E including mixed tocopherols as well as 90% of the daily value of vitamin A with many sources of carotenoids including beta-carotenes, lutein/zeaxanthin, lycopene, and astaxanthin. An invasive biopsy was not taken in this case, as OPSs largely are diagnosed clinically. Greater awareness and recognition of OPSs may help to identify common underlying causes for this unique diagnosis.
The Diagnosis: Orange Palpebral Spots
The clinical presentation of our patient was consistent with a diagnosis of orange palpebral spots (OPSs), an uncommon discoloration that most often appears in White patients in the fifth or sixth decades of life. Orange palpebral spots were first described in 2008 by Assouly et al1 in 27 patients (23 females and 4 males). In 2015, Belliveau et al2 expanded the designation to yellow-orange palpebral spots because they felt the term more fully expressed the color variations depicted in their patients; however, this term more frequently is used in ophthalmology.
Orange palpebral spots commonly appear as asymptomatic, yellow-orange, symmetric lesions with a predilection for the recessed areas of the superior eyelids but also can present on the canthi and inferior eyelids. The discolorations are more easily visible on fair skin and have been reported to measure from 10 to 15 mm in the long axis.3 Assouly et al1 described the orange spots as having indistinct margins, with borders similar to “sand on a sea shore.” Orange palpebral spots can be a persistent discoloration, and there are no reports of spontaneous regression. No known association with malignancy or systemic illness has been reported.
Case reports of OPSs describe histologic similarities between specimens, including increased adipose tissue and pigment-laden macrophages in the superficial dermis.2 The pigmented deposits sometimes may be found in the basal keratinocytes of the epidermis and turn black with Fontana-Masson stain.1 No inflammatory infiltrates, necrosis, or xanthomization are characteristically found. Stains for iron, mucin, and amyloid also have been negative.2
The cause of pigmentation in OPSs is unknown; however, lipofuscin deposits and high-situated adipocytes in the reticular dermis colored by carotenoids have been proposed as possible mechanisms.1 No unifying cause for pigmentation in the serum (eg, cholesterol, triglycerides, thyroid-stimulating hormone, free retinol, vitamin E, carotenoids) was found in 11 of 27 patients with OPSs assessed by Assouly et al.1 In one case, lipofuscin, a degradation product of lysosomes, was detected by microscopic autofluorescence in the superficial dermis. However, lipofuscin typically is a breakdown product associated with aging, and OPSs have been present in patients as young as 28 years.1 Local trauma related to eye rubbing is another theory that has been proposed due to the finding of melanin in the superficial dermis. However, the absence of hemosiderin deposits as well as the extensive duration of the discolorations makes local trauma a less likely explanation for the etiology of OPSs.2
The clinical differential diagnosis for OPSs includes xanthelasma, jaundice, and carotenoderma. Xanthelasma presents as elevated yellow plaques usually found over the medial aspect of the eyes. In contrast, OPSs are nonelevated with both orange and yellow hues typically present. Histologic samples of xanthelasma are characterized by lipid-laden macrophages (foam cells) in the dermis in contrast to the adipose tissue seen in OPSs that has not been phagocytized.1,2 The lack of scleral icterus made jaundice an unlikely diagnosis in our patient. Bilirubin elevations substantial enough to cause skin discoloration also would be expected to discolor the conjunctiva. In carotenoderma, carotenoids are deposited in the sweat and sebum of the stratum corneum with the orange pigmentation most prominent in regions of increased sweating such as the palms, soles, and nasolabial folds.4 Our patient’s lack of discoloration in places other than the periorbital region made carotenoderma less likely.
In the study by Assouly et al,1 10 of 11 patients who underwent laboratory analysis self-reported eating a diet rich in fruit and vegetables, though no standardized questionnaire was given. One patient was found to have an elevated vitamin E level, and in 5 cases there was an elevated level of β-cryptoxanthin. The significance of these elevations in such a small minority is unknown, and increased β-cryptoxanthin has been attributed to increased consumption of citrus fruits during the winter season. Our patient reported ingesting a daily oral supplement rich in carotenoids that constituted 60% of the daily value of vitamin E including mixed tocopherols as well as 90% of the daily value of vitamin A with many sources of carotenoids including beta-carotenes, lutein/zeaxanthin, lycopene, and astaxanthin. An invasive biopsy was not taken in this case, as OPSs largely are diagnosed clinically. Greater awareness and recognition of OPSs may help to identify common underlying causes for this unique diagnosis.
- Assouly P, Cavelier-Balloy B, Dupré T. Orange palpebral spots. Dermatology. 2008;216:166-170.
- Belliveau MJ, Odashiro AN, Harvey JT. Yellow-orange palpebral spots. Ophthalmology. 2015;122:2139-2140.
- Kluger N, Guillot B. Bilateral orange discoloration of the upper eyelids: a quiz. Acta Derm Venereol. 2011;91:211-212.
- Maharshak N, Shapiro J, Trau H. Carotenoderma—a review of the current literature. Int J Dermatol. 2003;42:178-181.
- Assouly P, Cavelier-Balloy B, Dupré T. Orange palpebral spots. Dermatology. 2008;216:166-170.
- Belliveau MJ, Odashiro AN, Harvey JT. Yellow-orange palpebral spots. Ophthalmology. 2015;122:2139-2140.
- Kluger N, Guillot B. Bilateral orange discoloration of the upper eyelids: a quiz. Acta Derm Venereol. 2011;91:211-212.
- Maharshak N, Shapiro J, Trau H. Carotenoderma—a review of the current literature. Int J Dermatol. 2003;42:178-181.
A 63-year-old White man with a history of melanoma presented to our dermatology clinic for evaluation of gradually worsening yellow discoloration around the eyes of 2 years’ duration. Physical examination revealed periorbital yellow-orange patches (top). The discolorations were nonelevated and nonpalpable. Dermoscopy revealed yellow blotches with sparing of the hair follicles (bottom). The remainder of the skin examination was unremarkable.
