Nonmelanoma Skin Cancer

PORTLAND, ORE. – About 10 years ago when Arash Mostaghimi, MD, MPA, MPH, became an attending physician at Brigham and Women’s Hospital, Boston, he noticed that some of his dermatology colleagues checked the potassium levels religiously in their female patients taking spironolactone, while others never did.

“It led to this question: should we check potassium in healthy young women starting spironolactone for acne?” Dr. Mostaghimi, director of the dermatology inpatient service at Brigham and Women’s, said at the annual meeting of the Pacific Dermatologic Association.

To find out, he and his colleagues reviewed 1,802 serum potassium measurements in a study of healthy young women with no known health conditions who were taking spironolactone, published in 2015. They discovered that 13 of those tests suggested mild hyperkalemia, defined as a level greater than 5.0 mEq/L. Of these, six were rechecked and were normal; no action was taken in the other seven patients.

“This led us to conclude that we spent $78,000 at our institution on testing that did not appear to yield clinically significant information for these patients, and that routine potassium monitoring is unnecessary for most women taking spironolactone for acne,” he said. Their findings have been validated “in many cohorts of data,” he added.

The study serves as an example of efforts dermatologists can take to curb unnecessary costs within the field to be “appropriate stewards of resources,” he continued. “We have to think about the ratio of benefit over cost. It’s not just about the cost, it’s about what you’re getting for the amount of money that you’re spending. The idea of this is not restricting or not giving people medications or access to things that they need. The idea is to do it in a thoughtful way that works across the population.”
 

Value thresholds

Determining the value thresholds of a particular medicine or procedure is also essential to good dermatology practice. To illustrate, Dr. Mostaghimi cited a prospective cohort study that compared treatment patterns and clinical outcomes in 1,536 consecutive patients with nonmelanoma skin cancer (NMSC) with and without limited life expectancy. More than two-thirds of the NMSCs (69%) were treated surgically. After adjusting for tumor and patient characteristics, the researchers found that 43% of patients with low life expectancy died within 5 years, but not from NMSC.

“Does that mean we shouldn’t do surgery for NMSC patients with low life expectancy?” he asked. “Should we do it less? Should we let the patients decide? It’s complicated. As a society, we have to decide what’s worth doing and what’s not worth doing,” he said. “What about old diseases with new treatments, like alopecia areata? Is alopecia areata a cosmetic condition? Dermatologists and patients wouldn’t classify it that way, but many insurers do. How do you negotiate that?”

In 2013, the American Academy of Dermatology identified 10 evidence-based recommendations that can support conversations between patients and dermatologists about treatments, tests, and procedures that may not be necessary. One of the recommendations was not to prescribe oral antifungal therapy for suspected nail fungus without confirmation of fungal infection.

“If a clinician thinks a patient has onychomycosis, he or she is usually right,” Dr. Mostaghimi said. “But what’s the added cost/benefit of performing a KOH followed by PAS testing if negative or performing a PAS test directly versus just treating the patient?”

In 2006, he and his colleagues published the results of a decision analysis to address these questions. They determined that the costs of testing to avoid one case of clinically apparent liver injury with terbinafine treatment was $18.2-$43.7 million for the KOH screening pathway and $37.6 to $90.2 million for the PAS testing pathway.

“Is that worth it?” he asked. “Would we get more value for spending the money elsewhere? In this case, the answer is most likely yes.”

Isotretinoin lab testing

Translating research into recommendations and standards of care is one way to help curb costs in dermatology. As an example, he cited lab monitoring for patients treated with isotretinoin for acne.

“There have been a number of papers over the years that have suggested that the number of labs we do is excessive, that the value that they provide is low, and that abnormal results do not impact our decision-making,” Dr. Mostaghimi said. “Do some patients on isotretinoin get mildly elevated [liver function tests] and hypertriglyceridemia? Yes, that happens. Does it matter? Nothing has demonstrated that it matters. Does it matter that an 18-year-old has high triglycerides for 6 months? Rarely, if ever.”

To promote a new approach, he and a panel of acne experts from five continents performed a Delphi consensus study. Based on their consensus, they proposed a simple approach: For “generally healthy patients without underlying abnormalities or preexisting conditions warranting further investigation,” check ALT and triglycerides prior to initiating isotretinoin. Then start isotretinoin.

“At the peak dose, recheck ALT and triglycerides – this might be at month 2,” Dr. Mostaghimi said. “Other people wait a little bit longer. No labs are required once treatment is complete. Of course, adjust this approach based on your assessment of the patient in front of you. None of these recommendations should replace your clinical judgment and intuition.”

He proposed a new paradigm where dermatologists can ask themselves three questions for every patient they see: Why is this intervention or test being done? Why is it being done in this patient? And why do it at that time? “If we think this way, we can identify some inconsistencies in our own thinking and opportunities for improvement,” he said.

Dr. Mostaghimi reported that he is a consultant to Pfizer, Concert, Lilly, and Bioniz. He is also an advisor to Him & Hers Cosmetics and Digital Diagnostics and is an associate editor for JAMA Dermatology.

PORTLAND, ORE. – About 10 years ago when Arash Mostaghimi, MD, MPA, MPH, became an attending physician at Brigham and Women’s Hospital, Boston, he noticed that some of his dermatology colleagues checked the potassium levels religiously in their female patients taking spironolactone, while others never did.

“It led to this question: should we check potassium in healthy young women starting spironolactone for acne?” Dr. Mostaghimi, director of the dermatology inpatient service at Brigham and Women’s, said at the annual meeting of the Pacific Dermatologic Association.

To find out, he and his colleagues reviewed 1,802 serum potassium measurements in a study of healthy young women with no known health conditions who were taking spironolactone, published in 2015. They discovered that 13 of those tests suggested mild hyperkalemia, defined as a level greater than 5.0 mEq/L. Of these, six were rechecked and were normal; no action was taken in the other seven patients.

“This led us to conclude that we spent $78,000 at our institution on testing that did not appear to yield clinically significant information for these patients, and that routine potassium monitoring is unnecessary for most women taking spironolactone for acne,” he said. Their findings have been validated “in many cohorts of data,” he added.

The study serves as an example of efforts dermatologists can take to curb unnecessary costs within the field to be “appropriate stewards of resources,” he continued. “We have to think about the ratio of benefit over cost. It’s not just about the cost, it’s about what you’re getting for the amount of money that you’re spending. The idea of this is not restricting or not giving people medications or access to things that they need. The idea is to do it in a thoughtful way that works across the population.”
 

Value thresholds

Determining the value thresholds of a particular medicine or procedure is also essential to good dermatology practice. To illustrate, Dr. Mostaghimi cited a prospective cohort study that compared treatment patterns and clinical outcomes in 1,536 consecutive patients with nonmelanoma skin cancer (NMSC) with and without limited life expectancy. More than two-thirds of the NMSCs (69%) were treated surgically. After adjusting for tumor and patient characteristics, the researchers found that 43% of patients with low life expectancy died within 5 years, but not from NMSC.

“Does that mean we shouldn’t do surgery for NMSC patients with low life expectancy?” he asked. “Should we do it less? Should we let the patients decide? It’s complicated. As a society, we have to decide what’s worth doing and what’s not worth doing,” he said. “What about old diseases with new treatments, like alopecia areata? Is alopecia areata a cosmetic condition? Dermatologists and patients wouldn’t classify it that way, but many insurers do. How do you negotiate that?”

In 2013, the American Academy of Dermatology identified 10 evidence-based recommendations that can support conversations between patients and dermatologists about treatments, tests, and procedures that may not be necessary. One of the recommendations was not to prescribe oral antifungal therapy for suspected nail fungus without confirmation of fungal infection.

“If a clinician thinks a patient has onychomycosis, he or she is usually right,” Dr. Mostaghimi said. “But what’s the added cost/benefit of performing a KOH followed by PAS testing if negative or performing a PAS test directly versus just treating the patient?”

In 2006, he and his colleagues published the results of a decision analysis to address these questions. They determined that the costs of testing to avoid one case of clinically apparent liver injury with terbinafine treatment was $18.2-$43.7 million for the KOH screening pathway and $37.6 to $90.2 million for the PAS testing pathway.

“Is that worth it?” he asked. “Would we get more value for spending the money elsewhere? In this case, the answer is most likely yes.”

Isotretinoin lab testing

Translating research into recommendations and standards of care is one way to help curb costs in dermatology. As an example, he cited lab monitoring for patients treated with isotretinoin for acne.

“There have been a number of papers over the years that have suggested that the number of labs we do is excessive, that the value that they provide is low, and that abnormal results do not impact our decision-making,” Dr. Mostaghimi said. “Do some patients on isotretinoin get mildly elevated [liver function tests] and hypertriglyceridemia? Yes, that happens. Does it matter? Nothing has demonstrated that it matters. Does it matter that an 18-year-old has high triglycerides for 6 months? Rarely, if ever.”

To promote a new approach, he and a panel of acne experts from five continents performed a Delphi consensus study. Based on their consensus, they proposed a simple approach: For “generally healthy patients without underlying abnormalities or preexisting conditions warranting further investigation,” check ALT and triglycerides prior to initiating isotretinoin. Then start isotretinoin.

“At the peak dose, recheck ALT and triglycerides – this might be at month 2,” Dr. Mostaghimi said. “Other people wait a little bit longer. No labs are required once treatment is complete. Of course, adjust this approach based on your assessment of the patient in front of you. None of these recommendations should replace your clinical judgment and intuition.”

He proposed a new paradigm where dermatologists can ask themselves three questions for every patient they see: Why is this intervention or test being done? Why is it being done in this patient? And why do it at that time? “If we think this way, we can identify some inconsistencies in our own thinking and opportunities for improvement,” he said.

Dr. Mostaghimi reported that he is a consultant to Pfizer, Concert, Lilly, and Bioniz. He is also an advisor to Him & Hers Cosmetics and Digital Diagnostics and is an associate editor for JAMA Dermatology.

PORTLAND, ORE. – About 10 years ago when Arash Mostaghimi, MD, MPA, MPH, became an attending physician at Brigham and Women’s Hospital, Boston, he noticed that some of his dermatology colleagues checked the potassium levels religiously in their female patients taking spironolactone, while others never did.

“It led to this question: should we check potassium in healthy young women starting spironolactone for acne?” Dr. Mostaghimi, director of the dermatology inpatient service at Brigham and Women’s, said at the annual meeting of the Pacific Dermatologic Association.

To find out, he and his colleagues reviewed 1,802 serum potassium measurements in a study of healthy young women with no known health conditions who were taking spironolactone, published in 2015. They discovered that 13 of those tests suggested mild hyperkalemia, defined as a level greater than 5.0 mEq/L. Of these, six were rechecked and were normal; no action was taken in the other seven patients.

“This led us to conclude that we spent $78,000 at our institution on testing that did not appear to yield clinically significant information for these patients, and that routine potassium monitoring is unnecessary for most women taking spironolactone for acne,” he said. Their findings have been validated “in many cohorts of data,” he added.

The study serves as an example of efforts dermatologists can take to curb unnecessary costs within the field to be “appropriate stewards of resources,” he continued. “We have to think about the ratio of benefit over cost. It’s not just about the cost, it’s about what you’re getting for the amount of money that you’re spending. The idea of this is not restricting or not giving people medications or access to things that they need. The idea is to do it in a thoughtful way that works across the population.”
 

Value thresholds

Determining the value thresholds of a particular medicine or procedure is also essential to good dermatology practice. To illustrate, Dr. Mostaghimi cited a prospective cohort study that compared treatment patterns and clinical outcomes in 1,536 consecutive patients with nonmelanoma skin cancer (NMSC) with and without limited life expectancy. More than two-thirds of the NMSCs (69%) were treated surgically. After adjusting for tumor and patient characteristics, the researchers found that 43% of patients with low life expectancy died within 5 years, but not from NMSC.

“Does that mean we shouldn’t do surgery for NMSC patients with low life expectancy?” he asked. “Should we do it less? Should we let the patients decide? It’s complicated. As a society, we have to decide what’s worth doing and what’s not worth doing,” he said. “What about old diseases with new treatments, like alopecia areata? Is alopecia areata a cosmetic condition? Dermatologists and patients wouldn’t classify it that way, but many insurers do. How do you negotiate that?”

In 2013, the American Academy of Dermatology identified 10 evidence-based recommendations that can support conversations between patients and dermatologists about treatments, tests, and procedures that may not be necessary. One of the recommendations was not to prescribe oral antifungal therapy for suspected nail fungus without confirmation of fungal infection.

“If a clinician thinks a patient has onychomycosis, he or she is usually right,” Dr. Mostaghimi said. “But what’s the added cost/benefit of performing a KOH followed by PAS testing if negative or performing a PAS test directly versus just treating the patient?”

In 2006, he and his colleagues published the results of a decision analysis to address these questions. They determined that the costs of testing to avoid one case of clinically apparent liver injury with terbinafine treatment was $18.2-$43.7 million for the KOH screening pathway and $37.6 to $90.2 million for the PAS testing pathway.

“Is that worth it?” he asked. “Would we get more value for spending the money elsewhere? In this case, the answer is most likely yes.”

Isotretinoin lab testing

Translating research into recommendations and standards of care is one way to help curb costs in dermatology. As an example, he cited lab monitoring for patients treated with isotretinoin for acne.

“There have been a number of papers over the years that have suggested that the number of labs we do is excessive, that the value that they provide is low, and that abnormal results do not impact our decision-making,” Dr. Mostaghimi said. “Do some patients on isotretinoin get mildly elevated [liver function tests] and hypertriglyceridemia? Yes, that happens. Does it matter? Nothing has demonstrated that it matters. Does it matter that an 18-year-old has high triglycerides for 6 months? Rarely, if ever.”

To promote a new approach, he and a panel of acne experts from five continents performed a Delphi consensus study. Based on their consensus, they proposed a simple approach: For “generally healthy patients without underlying abnormalities or preexisting conditions warranting further investigation,” check ALT and triglycerides prior to initiating isotretinoin. Then start isotretinoin.

“At the peak dose, recheck ALT and triglycerides – this might be at month 2,” Dr. Mostaghimi said. “Other people wait a little bit longer. No labs are required once treatment is complete. Of course, adjust this approach based on your assessment of the patient in front of you. None of these recommendations should replace your clinical judgment and intuition.”

He proposed a new paradigm where dermatologists can ask themselves three questions for every patient they see: Why is this intervention or test being done? Why is it being done in this patient? And why do it at that time? “If we think this way, we can identify some inconsistencies in our own thinking and opportunities for improvement,” he said.

Dr. Mostaghimi reported that he is a consultant to Pfizer, Concert, Lilly, and Bioniz. He is also an advisor to Him & Hers Cosmetics and Digital Diagnostics and is an associate editor for JAMA Dermatology.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

The Food and Drug Administration has issued a safety alert, warning of a rare but concerning potential risk of squamous cell carcinoma (SCC) and various lymphomas in the scar tissue around breast implants.

The FDA safety communication is based on several dozen reports of these cancers occurring in the capsule or scar tissue around breast implants. This issue differs from breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) – a known risk among implant recipients.

“After preliminary review of published literature as part of our ongoing monitoring of the safety of breast implants, the FDA is aware of less than 20 cases of SCC and less than 30 cases of various lymphomas in the capsule around the breast implant,” the agency’s alert explains.

One avenue through which the FDA has identified cases is via medical device reports. As of Sept. 1, the FDA has received 10 medical device reports about SCC related to breast implants and 12 about various lymphomas.

The incidence rate and risk factors for these events are currently unknown, but reports of SCC and various lymphomas in the capsule around the breast implants have been reported for both textured and smooth breast implants, as well as for both saline and silicone breast implants. In some cases, the cancers were diagnosed years after breast implant surgery.

Reported signs and symptoms included swelling, pain, lumps, or skin changes. 

Although the risks of SCC and lymphomas in the tissue around breast implants appears rare, “when safety risks with medical devices are identified, we wanted to provide clear and understandable information to the public as quickly as possible,” Binita Ashar, MD, director of the Office of Surgical and Infection Control Devices, FDA Center for Devices and Radiological Health, explained in a press release.

Patients and providers are strongly encouraged to report breast implant–related problems and cases of SCC or lymphoma of the breast implant capsule to MedWatch, the FDA’s adverse event reporting program.

The FDA plans to complete “a thorough literature review” as well as “identify ways to collect more detailed information regarding patient cases.”

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has issued a safety alert, warning of a rare but concerning potential risk of squamous cell carcinoma (SCC) and various lymphomas in the scar tissue around breast implants.

The FDA safety communication is based on several dozen reports of these cancers occurring in the capsule or scar tissue around breast implants. This issue differs from breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) – a known risk among implant recipients.

“After preliminary review of published literature as part of our ongoing monitoring of the safety of breast implants, the FDA is aware of less than 20 cases of SCC and less than 30 cases of various lymphomas in the capsule around the breast implant,” the agency’s alert explains.

One avenue through which the FDA has identified cases is via medical device reports. As of Sept. 1, the FDA has received 10 medical device reports about SCC related to breast implants and 12 about various lymphomas.

The incidence rate and risk factors for these events are currently unknown, but reports of SCC and various lymphomas in the capsule around the breast implants have been reported for both textured and smooth breast implants, as well as for both saline and silicone breast implants. In some cases, the cancers were diagnosed years after breast implant surgery.

Reported signs and symptoms included swelling, pain, lumps, or skin changes. 

Although the risks of SCC and lymphomas in the tissue around breast implants appears rare, “when safety risks with medical devices are identified, we wanted to provide clear and understandable information to the public as quickly as possible,” Binita Ashar, MD, director of the Office of Surgical and Infection Control Devices, FDA Center for Devices and Radiological Health, explained in a press release.

Patients and providers are strongly encouraged to report breast implant–related problems and cases of SCC or lymphoma of the breast implant capsule to MedWatch, the FDA’s adverse event reporting program.

The FDA plans to complete “a thorough literature review” as well as “identify ways to collect more detailed information regarding patient cases.”

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has issued a safety alert, warning of a rare but concerning potential risk of squamous cell carcinoma (SCC) and various lymphomas in the scar tissue around breast implants.

The FDA safety communication is based on several dozen reports of these cancers occurring in the capsule or scar tissue around breast implants. This issue differs from breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) – a known risk among implant recipients.

“After preliminary review of published literature as part of our ongoing monitoring of the safety of breast implants, the FDA is aware of less than 20 cases of SCC and less than 30 cases of various lymphomas in the capsule around the breast implant,” the agency’s alert explains.

One avenue through which the FDA has identified cases is via medical device reports. As of Sept. 1, the FDA has received 10 medical device reports about SCC related to breast implants and 12 about various lymphomas.

The incidence rate and risk factors for these events are currently unknown, but reports of SCC and various lymphomas in the capsule around the breast implants have been reported for both textured and smooth breast implants, as well as for both saline and silicone breast implants. In some cases, the cancers were diagnosed years after breast implant surgery.

Reported signs and symptoms included swelling, pain, lumps, or skin changes. 

Although the risks of SCC and lymphomas in the tissue around breast implants appears rare, “when safety risks with medical devices are identified, we wanted to provide clear and understandable information to the public as quickly as possible,” Binita Ashar, MD, director of the Office of Surgical and Infection Control Devices, FDA Center for Devices and Radiological Health, explained in a press release.

Patients and providers are strongly encouraged to report breast implant–related problems and cases of SCC or lymphoma of the breast implant capsule to MedWatch, the FDA’s adverse event reporting program.

The FDA plans to complete “a thorough literature review” as well as “identify ways to collect more detailed information regarding patient cases.”

A version of this article first appeared on Medscape.com.

Basal cell carcinomas (BCCs) are considered the most common cutaneous cancers. Approximately 80% of nonmelanoma skin cancers are BCCs.^1,2 Surgical management is the gold standard for early-stage and localized BCCs; it may include simple excision vs Mohs micrographic surgery.^3,4 However, if left untreated, these lesions can progress to an advanced stage (locally advanced BCC) or infrequently may spread to distant sites (metastatic BCC). In the advanced stage, the lesions are no longer manageable by surgery or radiation therapy.^5,6 Recently, inhibitors targeting the hedgehog (Hh) pathway have shown great promise for these patients. The first drug approved by the US Food and Drug Administration (FDA) for locally advanced and metastatic BCC is vismodegib.⁷ In this article, we provide a clinical review of vismodegib for the management of BCC, including a discussion of the Hh pathway in BCC, adverse effects of vismodegib, use of vismodegib in adnexal skin tumors, recommended doses for vismodegib therapy in BCC, and management of the side effects of treatment.

Hh Pathway in BCC

In embryonic development, the Hh signaling pathway is crucial across a broad spectrum of species, including humans. Various members of the Hh family have been recognized, all working as secreted regulatory proteins.⁸ The name of the Hh signaling pathway is derived from a polypeptide ligand called hedgehog found in some fruit flies. Mutations in the gene led to fruit fly larvae that had a spiky hairy pattern of denticles similar to hedgehogs, leading to the name of this molecule.⁹ The transmembrane protein smoothened (SMO) is the main component of the Hh signaling pathway and initiates a signaling cascade that in turn leads to an increased expression of target genes, such as GLI1. Patched (PTCH), also a transmembrane protein and a cell-surface receptor for the secreted Hh ligand, suppresses the signaling capacity of SMO. Upon binding of the Hh ligand to the PTCH receptor, the suppression of SMO is relieved and a signal is propagated, evoking a cellular response.¹⁰ Molecular and genetic studies have reported that genetic alterations in the Hh signaling pathway are almost universally present in all BCCs, leading to an aberrant activation of the pathway and an uncontrolled proliferation of the basal cells. Frequently, these alterations have been shown to cause loss of function of PTCH homologue 1, which usually acts to inhibit the SMO homologue signaling activity.^11,12

Because of the potential importance of Hh signaling in other solid malignancies and the failure of topical inhibition of SMO,¹³ subsequent studies on the development of Hh pathway inhibitors have mostly focused on the systemic approach. A multitude of Hh pathway inhibitors have been developed thus far, such as SANT1-SANT4, GDC-0449, IPI-926, BMS-833923 (XL139), HhAntag-691, and MK-4101.¹⁴ Many of these inhibitors have been clinically investigated.^13,15,16

Systemic SMO Inhibitor: Vismodegib

Vismodegib was the earliest systemic SMO inhibitor to fulfill early clinical evaluation^15,16 and the first drug to receive FDA approval for the management of advanced or metastatic BCC. Vismodegib is a small-molecule SMO inhibitor used for the management of selected locally advanced BCC and metastatic BCC in adults.^3,17 Although there is a possibility of recurrence following drug withdrawal, vismodegib constitutes a new therapeutic strategy presenting positive benefits to patients. It may provide superior improvement over sunitinib, which has shown efficacy in a few patients; however, the efficacy and tolerance of sunitinib have been shown to be limited.^18,19

Adverse Effects of Vismodegib Therapy

Adverse events with vismodegib use have been reported in 98% of patients (N=491); most of these were mild to moderate.²⁰ However, the frequency of adverse events could prove to be a therapeutic challenge for patients requiring extended treatment. The most frequently reported reversible side effects were muscle spasms (64%), alopecia (62%), weight loss (33%), fatigue (28%), decreased appetite (25%), diarrhea (17%), nausea (16%), dysgeusia (54%), and ageusia (22%).²⁰ In clinical trials, amenorrhea was noticed in 30% (3/10) of females with reproductive potential.² Apart from alopecia and possibly amenorrhea, these side effects are reversible.¹⁷ Alkeraye et al¹⁷ reported 3 clinical cases of persistent alopecia following the use of vismodegib. Amenorrhea is a possible side effect of unknown reversibility.⁷

Vismodegib is a pregnancy category D medication.⁴ Severe birth defects, including craniofacial abnormalities, retardations in normal growth, open perineum, and absence of digital fusion at a corresponding 20% of the recommended daily dose, were found in rat studies. Embryo-fetal death was noted when rats were exposedto concentrations comparable to the recommended human dose.⁴

Hepatic events with the use of vismodegib have been reported. The use of vismodegib in randomized controlled trials resulted in elevation of both alanine aminotransferase and aspartate aminotransferase levels compared with placebo.²¹ Moreover, severe hepatotoxicity with vismodegib has been reported.^22-24 A study conducted by Edwards et al²⁵ concluded that the use of vismodegib in patients with severe liver disease must include thorough risk-benefit assessment, with caution in using other concomitant hepatotoxic medications.

Rare adverse events also have been reported in the literature, including vismodegib-induced pancreatitis in a 79-year-old patient treated for locally advanced, recurrent BCC that was cleared following cessation of therapy.²⁶ Additionally, atypical fibroxanthoma was observed in an 83-year-old patient after 30 days of treatment with vismodegib for multiple BCCs.²⁷ The development of other secondary malignancies, such as squamous cell carcinoma, melanoma, keratoacanthomas, and pilomatricomas, during or after the long-term use of vismodegib also have been described.^28-35

Use of Vismodegib for Adnexal Skin Tumors

The role of the sonic Hh–PTCH pathway in the pathogenesis of adnexal tumors varies in the literature. Some studies propose the involvement of this pathway in the formation of adnexal tumors such as trichoblastoma, trichoepithelioma, and cylindroma, as in BCC. Various lines of evidence support this involvement. Firstly, in mice, the spontaneous generation of numerous BCCs, trichoblastomas, trichoepitheliomas, and cylindromas has been observed following constitutive activation of the sonic Hh–PTCH pathway.³⁶ Secondly, in trichoepitheliomas, there have been positive results in molecular research into the tumor suppressor gene PTCH homologue 1, PTCH1, whose mutations cause constitutive activation of the sonic Hh–PTCH pathway.³⁷ Thirdly, GLI1³⁸ and SOX9³⁹ transcription factors associated with the signaling pathway of sonic Hh–PTCH appear to have increased levels in adnexal carcinomas.¹⁹ Lepesant et al¹⁹ reported a notable clinical response to vismodegib in trichoblastic carcinoma. Baur et al⁴⁰ reported successful treatment of multiple familial trichoepitheliomas with vismodegib. Nonetheless, more studies are required to assess the efficacy and reliability of vismodegib in the management of adnexal tumors.

Recommended Dose of Vismodegib Therapy

The vismodegib dosage that is approved by the FDA is 150 mg/d until disease progression or the development of intolerable side effects.⁴ Higher dosing regimens were evaluated with 270 mg/d and 540 mg/d. No added therapeutic benefit was noted with the increase in the dose, and no dose-limiting toxic effects were observed.⁴¹

Management of Vismodegib Side Effects

Managing patient expectations is a crucial step in improving dysgeusia. The experience of dysgeusia varies among patients; thus, patients should be instructed to adjust their diets according to their level of dysgeusia, which can be achieved by changing ingredients or dressings used with their diet. This step has been proven to be effective in overcoming vismodegib-related dysgeusia. Also, fluid taste distortion may lead to dehydration and an increase in creatine level. Thus, patients should be encouraged to monitor fluid intake. Moreover, a treatment hiatus of 2 to 8 months results in near-complete improvement of taste distortion.

For muscle spasms, quinine, treatment break for 1 month, gentle exercise of affected areas, or muscle relaxants such as baclofen and temazepam all are effective methods. For vismodegib-related alopecia, managing patient expectations is key; patients should be aware that hair may take 6 to 12 months or even longer to regrow. In addition, shaving less frequently helps improve alopecia.

For gastrointestinal disorders, loperamide with or without codeine phosphate is effective in resolving diarrhea, and metoclopramide is mostly adequate in treating nausea. Another adverse event is weight loss; weight loss of 5% or more of total body weight prompts dietetic referral. If weight loss persists, a treatment break might be needed to regain weight.

Overall, treatment breaks are sufficient to resolve adverse events caused by vismodegib and do not compromise efficacy of treatment. The duration of a treatment break should be considered before initiation. In one clinical trial, a longer treatment break was associated with fewer adverse effects without affecting the efficacy of treatment.⁴²

Conclusion

Vismodegib provides an effective alternative to surgical intervention in the management of BCC. However, patients must be monitored vigilantly, as adverse events are common (>90%).

Basal cell carcinomas (BCCs) are considered the most common cutaneous cancers. Approximately 80% of nonmelanoma skin cancers are BCCs.^1,2 Surgical management is the gold standard for early-stage and localized BCCs; it may include simple excision vs Mohs micrographic surgery.^3,4 However, if left untreated, these lesions can progress to an advanced stage (locally advanced BCC) or infrequently may spread to distant sites (metastatic BCC). In the advanced stage, the lesions are no longer manageable by surgery or radiation therapy.^5,6 Recently, inhibitors targeting the hedgehog (Hh) pathway have shown great promise for these patients. The first drug approved by the US Food and Drug Administration (FDA) for locally advanced and metastatic BCC is vismodegib.⁷ In this article, we provide a clinical review of vismodegib for the management of BCC, including a discussion of the Hh pathway in BCC, adverse effects of vismodegib, use of vismodegib in adnexal skin tumors, recommended doses for vismodegib therapy in BCC, and management of the side effects of treatment.

Hh Pathway in BCC

In embryonic development, the Hh signaling pathway is crucial across a broad spectrum of species, including humans. Various members of the Hh family have been recognized, all working as secreted regulatory proteins.⁸ The name of the Hh signaling pathway is derived from a polypeptide ligand called hedgehog found in some fruit flies. Mutations in the gene led to fruit fly larvae that had a spiky hairy pattern of denticles similar to hedgehogs, leading to the name of this molecule.⁹ The transmembrane protein smoothened (SMO) is the main component of the Hh signaling pathway and initiates a signaling cascade that in turn leads to an increased expression of target genes, such as GLI1. Patched (PTCH), also a transmembrane protein and a cell-surface receptor for the secreted Hh ligand, suppresses the signaling capacity of SMO. Upon binding of the Hh ligand to the PTCH receptor, the suppression of SMO is relieved and a signal is propagated, evoking a cellular response.¹⁰ Molecular and genetic studies have reported that genetic alterations in the Hh signaling pathway are almost universally present in all BCCs, leading to an aberrant activation of the pathway and an uncontrolled proliferation of the basal cells. Frequently, these alterations have been shown to cause loss of function of PTCH homologue 1, which usually acts to inhibit the SMO homologue signaling activity.^11,12

Because of the potential importance of Hh signaling in other solid malignancies and the failure of topical inhibition of SMO,¹³ subsequent studies on the development of Hh pathway inhibitors have mostly focused on the systemic approach. A multitude of Hh pathway inhibitors have been developed thus far, such as SANT1-SANT4, GDC-0449, IPI-926, BMS-833923 (XL139), HhAntag-691, and MK-4101.¹⁴ Many of these inhibitors have been clinically investigated.^13,15,16

Systemic SMO Inhibitor: Vismodegib

Vismodegib was the earliest systemic SMO inhibitor to fulfill early clinical evaluation^15,16 and the first drug to receive FDA approval for the management of advanced or metastatic BCC. Vismodegib is a small-molecule SMO inhibitor used for the management of selected locally advanced BCC and metastatic BCC in adults.^3,17 Although there is a possibility of recurrence following drug withdrawal, vismodegib constitutes a new therapeutic strategy presenting positive benefits to patients. It may provide superior improvement over sunitinib, which has shown efficacy in a few patients; however, the efficacy and tolerance of sunitinib have been shown to be limited.^18,19

Adverse Effects of Vismodegib Therapy

Adverse events with vismodegib use have been reported in 98% of patients (N=491); most of these were mild to moderate.²⁰ However, the frequency of adverse events could prove to be a therapeutic challenge for patients requiring extended treatment. The most frequently reported reversible side effects were muscle spasms (64%), alopecia (62%), weight loss (33%), fatigue (28%), decreased appetite (25%), diarrhea (17%), nausea (16%), dysgeusia (54%), and ageusia (22%).²⁰ In clinical trials, amenorrhea was noticed in 30% (3/10) of females with reproductive potential.² Apart from alopecia and possibly amenorrhea, these side effects are reversible.¹⁷ Alkeraye et al¹⁷ reported 3 clinical cases of persistent alopecia following the use of vismodegib. Amenorrhea is a possible side effect of unknown reversibility.⁷

Vismodegib is a pregnancy category D medication.⁴ Severe birth defects, including craniofacial abnormalities, retardations in normal growth, open perineum, and absence of digital fusion at a corresponding 20% of the recommended daily dose, were found in rat studies. Embryo-fetal death was noted when rats were exposedto concentrations comparable to the recommended human dose.⁴

Hepatic events with the use of vismodegib have been reported. The use of vismodegib in randomized controlled trials resulted in elevation of both alanine aminotransferase and aspartate aminotransferase levels compared with placebo.²¹ Moreover, severe hepatotoxicity with vismodegib has been reported.^22-24 A study conducted by Edwards et al²⁵ concluded that the use of vismodegib in patients with severe liver disease must include thorough risk-benefit assessment, with caution in using other concomitant hepatotoxic medications.

Rare adverse events also have been reported in the literature, including vismodegib-induced pancreatitis in a 79-year-old patient treated for locally advanced, recurrent BCC that was cleared following cessation of therapy.²⁶ Additionally, atypical fibroxanthoma was observed in an 83-year-old patient after 30 days of treatment with vismodegib for multiple BCCs.²⁷ The development of other secondary malignancies, such as squamous cell carcinoma, melanoma, keratoacanthomas, and pilomatricomas, during or after the long-term use of vismodegib also have been described.^28-35

Use of Vismodegib for Adnexal Skin Tumors

The role of the sonic Hh–PTCH pathway in the pathogenesis of adnexal tumors varies in the literature. Some studies propose the involvement of this pathway in the formation of adnexal tumors such as trichoblastoma, trichoepithelioma, and cylindroma, as in BCC. Various lines of evidence support this involvement. Firstly, in mice, the spontaneous generation of numerous BCCs, trichoblastomas, trichoepitheliomas, and cylindromas has been observed following constitutive activation of the sonic Hh–PTCH pathway.³⁶ Secondly, in trichoepitheliomas, there have been positive results in molecular research into the tumor suppressor gene PTCH homologue 1, PTCH1, whose mutations cause constitutive activation of the sonic Hh–PTCH pathway.³⁷ Thirdly, GLI1³⁸ and SOX9³⁹ transcription factors associated with the signaling pathway of sonic Hh–PTCH appear to have increased levels in adnexal carcinomas.¹⁹ Lepesant et al¹⁹ reported a notable clinical response to vismodegib in trichoblastic carcinoma. Baur et al⁴⁰ reported successful treatment of multiple familial trichoepitheliomas with vismodegib. Nonetheless, more studies are required to assess the efficacy and reliability of vismodegib in the management of adnexal tumors.

Recommended Dose of Vismodegib Therapy

The vismodegib dosage that is approved by the FDA is 150 mg/d until disease progression or the development of intolerable side effects.⁴ Higher dosing regimens were evaluated with 270 mg/d and 540 mg/d. No added therapeutic benefit was noted with the increase in the dose, and no dose-limiting toxic effects were observed.⁴¹

Management of Vismodegib Side Effects

Managing patient expectations is a crucial step in improving dysgeusia. The experience of dysgeusia varies among patients; thus, patients should be instructed to adjust their diets according to their level of dysgeusia, which can be achieved by changing ingredients or dressings used with their diet. This step has been proven to be effective in overcoming vismodegib-related dysgeusia. Also, fluid taste distortion may lead to dehydration and an increase in creatine level. Thus, patients should be encouraged to monitor fluid intake. Moreover, a treatment hiatus of 2 to 8 months results in near-complete improvement of taste distortion.

For muscle spasms, quinine, treatment break for 1 month, gentle exercise of affected areas, or muscle relaxants such as baclofen and temazepam all are effective methods. For vismodegib-related alopecia, managing patient expectations is key; patients should be aware that hair may take 6 to 12 months or even longer to regrow. In addition, shaving less frequently helps improve alopecia.

For gastrointestinal disorders, loperamide with or without codeine phosphate is effective in resolving diarrhea, and metoclopramide is mostly adequate in treating nausea. Another adverse event is weight loss; weight loss of 5% or more of total body weight prompts dietetic referral. If weight loss persists, a treatment break might be needed to regain weight.

Overall, treatment breaks are sufficient to resolve adverse events caused by vismodegib and do not compromise efficacy of treatment. The duration of a treatment break should be considered before initiation. In one clinical trial, a longer treatment break was associated with fewer adverse effects without affecting the efficacy of treatment.⁴²

Conclusion

Vismodegib provides an effective alternative to surgical intervention in the management of BCC. However, patients must be monitored vigilantly, as adverse events are common (>90%).

Basal cell carcinomas (BCCs) are considered the most common cutaneous cancers. Approximately 80% of nonmelanoma skin cancers are BCCs.^1,2 Surgical management is the gold standard for early-stage and localized BCCs; it may include simple excision vs Mohs micrographic surgery.^3,4 However, if left untreated, these lesions can progress to an advanced stage (locally advanced BCC) or infrequently may spread to distant sites (metastatic BCC). In the advanced stage, the lesions are no longer manageable by surgery or radiation therapy.^5,6 Recently, inhibitors targeting the hedgehog (Hh) pathway have shown great promise for these patients. The first drug approved by the US Food and Drug Administration (FDA) for locally advanced and metastatic BCC is vismodegib.⁷ In this article, we provide a clinical review of vismodegib for the management of BCC, including a discussion of the Hh pathway in BCC, adverse effects of vismodegib, use of vismodegib in adnexal skin tumors, recommended doses for vismodegib therapy in BCC, and management of the side effects of treatment.

Hh Pathway in BCC

In embryonic development, the Hh signaling pathway is crucial across a broad spectrum of species, including humans. Various members of the Hh family have been recognized, all working as secreted regulatory proteins.⁸ The name of the Hh signaling pathway is derived from a polypeptide ligand called hedgehog found in some fruit flies. Mutations in the gene led to fruit fly larvae that had a spiky hairy pattern of denticles similar to hedgehogs, leading to the name of this molecule.⁹ The transmembrane protein smoothened (SMO) is the main component of the Hh signaling pathway and initiates a signaling cascade that in turn leads to an increased expression of target genes, such as GLI1. Patched (PTCH), also a transmembrane protein and a cell-surface receptor for the secreted Hh ligand, suppresses the signaling capacity of SMO. Upon binding of the Hh ligand to the PTCH receptor, the suppression of SMO is relieved and a signal is propagated, evoking a cellular response.¹⁰ Molecular and genetic studies have reported that genetic alterations in the Hh signaling pathway are almost universally present in all BCCs, leading to an aberrant activation of the pathway and an uncontrolled proliferation of the basal cells. Frequently, these alterations have been shown to cause loss of function of PTCH homologue 1, which usually acts to inhibit the SMO homologue signaling activity.^11,12

Because of the potential importance of Hh signaling in other solid malignancies and the failure of topical inhibition of SMO,¹³ subsequent studies on the development of Hh pathway inhibitors have mostly focused on the systemic approach. A multitude of Hh pathway inhibitors have been developed thus far, such as SANT1-SANT4, GDC-0449, IPI-926, BMS-833923 (XL139), HhAntag-691, and MK-4101.¹⁴ Many of these inhibitors have been clinically investigated.^13,15,16

Systemic SMO Inhibitor: Vismodegib

Vismodegib was the earliest systemic SMO inhibitor to fulfill early clinical evaluation^15,16 and the first drug to receive FDA approval for the management of advanced or metastatic BCC. Vismodegib is a small-molecule SMO inhibitor used for the management of selected locally advanced BCC and metastatic BCC in adults.^3,17 Although there is a possibility of recurrence following drug withdrawal, vismodegib constitutes a new therapeutic strategy presenting positive benefits to patients. It may provide superior improvement over sunitinib, which has shown efficacy in a few patients; however, the efficacy and tolerance of sunitinib have been shown to be limited.^18,19

Adverse Effects of Vismodegib Therapy

Adverse events with vismodegib use have been reported in 98% of patients (N=491); most of these were mild to moderate.²⁰ However, the frequency of adverse events could prove to be a therapeutic challenge for patients requiring extended treatment. The most frequently reported reversible side effects were muscle spasms (64%), alopecia (62%), weight loss (33%), fatigue (28%), decreased appetite (25%), diarrhea (17%), nausea (16%), dysgeusia (54%), and ageusia (22%).²⁰ In clinical trials, amenorrhea was noticed in 30% (3/10) of females with reproductive potential.² Apart from alopecia and possibly amenorrhea, these side effects are reversible.¹⁷ Alkeraye et al¹⁷ reported 3 clinical cases of persistent alopecia following the use of vismodegib. Amenorrhea is a possible side effect of unknown reversibility.⁷

Vismodegib is a pregnancy category D medication.⁴ Severe birth defects, including craniofacial abnormalities, retardations in normal growth, open perineum, and absence of digital fusion at a corresponding 20% of the recommended daily dose, were found in rat studies. Embryo-fetal death was noted when rats were exposedto concentrations comparable to the recommended human dose.⁴

Hepatic events with the use of vismodegib have been reported. The use of vismodegib in randomized controlled trials resulted in elevation of both alanine aminotransferase and aspartate aminotransferase levels compared with placebo.²¹ Moreover, severe hepatotoxicity with vismodegib has been reported.^22-24 A study conducted by Edwards et al²⁵ concluded that the use of vismodegib in patients with severe liver disease must include thorough risk-benefit assessment, with caution in using other concomitant hepatotoxic medications.

Rare adverse events also have been reported in the literature, including vismodegib-induced pancreatitis in a 79-year-old patient treated for locally advanced, recurrent BCC that was cleared following cessation of therapy.²⁶ Additionally, atypical fibroxanthoma was observed in an 83-year-old patient after 30 days of treatment with vismodegib for multiple BCCs.²⁷ The development of other secondary malignancies, such as squamous cell carcinoma, melanoma, keratoacanthomas, and pilomatricomas, during or after the long-term use of vismodegib also have been described.^28-35

Use of Vismodegib for Adnexal Skin Tumors

The role of the sonic Hh–PTCH pathway in the pathogenesis of adnexal tumors varies in the literature. Some studies propose the involvement of this pathway in the formation of adnexal tumors such as trichoblastoma, trichoepithelioma, and cylindroma, as in BCC. Various lines of evidence support this involvement. Firstly, in mice, the spontaneous generation of numerous BCCs, trichoblastomas, trichoepitheliomas, and cylindromas has been observed following constitutive activation of the sonic Hh–PTCH pathway.³⁶ Secondly, in trichoepitheliomas, there have been positive results in molecular research into the tumor suppressor gene PTCH homologue 1, PTCH1, whose mutations cause constitutive activation of the sonic Hh–PTCH pathway.³⁷ Thirdly, GLI1³⁸ and SOX9³⁹ transcription factors associated with the signaling pathway of sonic Hh–PTCH appear to have increased levels in adnexal carcinomas.¹⁹ Lepesant et al¹⁹ reported a notable clinical response to vismodegib in trichoblastic carcinoma. Baur et al⁴⁰ reported successful treatment of multiple familial trichoepitheliomas with vismodegib. Nonetheless, more studies are required to assess the efficacy and reliability of vismodegib in the management of adnexal tumors.

Recommended Dose of Vismodegib Therapy

The vismodegib dosage that is approved by the FDA is 150 mg/d until disease progression or the development of intolerable side effects.⁴ Higher dosing regimens were evaluated with 270 mg/d and 540 mg/d. No added therapeutic benefit was noted with the increase in the dose, and no dose-limiting toxic effects were observed.⁴¹

Management of Vismodegib Side Effects

Managing patient expectations is a crucial step in improving dysgeusia. The experience of dysgeusia varies among patients; thus, patients should be instructed to adjust their diets according to their level of dysgeusia, which can be achieved by changing ingredients or dressings used with their diet. This step has been proven to be effective in overcoming vismodegib-related dysgeusia. Also, fluid taste distortion may lead to dehydration and an increase in creatine level. Thus, patients should be encouraged to monitor fluid intake. Moreover, a treatment hiatus of 2 to 8 months results in near-complete improvement of taste distortion.

For muscle spasms, quinine, treatment break for 1 month, gentle exercise of affected areas, or muscle relaxants such as baclofen and temazepam all are effective methods. For vismodegib-related alopecia, managing patient expectations is key; patients should be aware that hair may take 6 to 12 months or even longer to regrow. In addition, shaving less frequently helps improve alopecia.

For gastrointestinal disorders, loperamide with or without codeine phosphate is effective in resolving diarrhea, and metoclopramide is mostly adequate in treating nausea. Another adverse event is weight loss; weight loss of 5% or more of total body weight prompts dietetic referral. If weight loss persists, a treatment break might be needed to regain weight.

Overall, treatment breaks are sufficient to resolve adverse events caused by vismodegib and do not compromise efficacy of treatment. The duration of a treatment break should be considered before initiation. In one clinical trial, a longer treatment break was associated with fewer adverse effects without affecting the efficacy of treatment.⁴²

Conclusion

Vismodegib provides an effective alternative to surgical intervention in the management of BCC. However, patients must be monitored vigilantly, as adverse events are common (>90%).

MILAN – Application of topical or both topical and oral polypodium leucotomos extract (PLE) was associated with significant reversal of adverse skin changes in patients with severe actinic keratoses (AKs) treated over 12 months, in a randomized, blinded study presented at the annual congress of the European Academy of Dermatology and Venereology.

At 12 months, the percentage of patients with a normal or almost normal honeycomb pattern when evaluated blindly with reflectance confocal microscopy (RCM) was about twice as great in either of the two groups that received PLE relative to those treated with topical photoprotection alone, according to Giovanni Pellacani, MD, PhD, chair of dermatology, University of Sapienza, Rome.

“In patients with severe actinic keratosis, the 12-month use of a PLE-based topical or oral photoprotection is associated with positive clinical and anatomical outcomes,” Dr. Pellacani said.

PLE, which is already commonly used in sun protection products, is derived from a South American species of fern and has been proposed for a broad array of dermatologic diseases. According to Dr. Pellacani, in vivo studies associating PLE with immune photoprotection make this agent particularly promising for severe AKs.

In this study involving two clinical research centers in Italy, 131 patients with photoaging and at least three AKs were randomized to one of three treatment arms. The control arm received topical photoprotection with an SPF of 100 or higher applied twice daily to all sun-exposed areas. The two treatment arms received the same topical photoprotection plus either a PLE-containing topical cream alone or a PLE-containing topical cream plus PLE in an oral form (240 mg) once daily

Patients were evaluated at 3 months, 6 months, and 1 year with several measures, including the Actinic Keratosis Area Score Index (AKASI) and the AK Field Assessment Scale Area (AK-FAS). They were also assessed with RCM. All clinical assessments and RCM evaluations, which assessed seven different parameters, such as honeycomb pattern, mottled pigmentation, and reticulated collagen, were performed by dermatologists blinded to the treatment assignment.

Complete data were available for 116 patients who completed all three evaluations over the 12 months of follow-up. On RCM, 50% of those receiving the oral and topical forms of PLE and 45% of those receiving topical PLE had normalization of the honeycomb pattern. These responses were significantly greater (P = .04 for both) than the 26% with normalization in the control group.

Although there were no significant differences in any of the other parameters evaluated by RCM, the improvement in the honeycomb pattern was accompanied by a 7% improvement in the AKASI score in patients taking PLE, either topically or orally and topically, while there was a 6% worsening (P < .001) among controls.

The AK-FAS score improved at 12 months by 26% in the group on oral/topical PLE and by 4% in the group on topical PLE. The score worsened by 13% among controls.

Over the course of the study, patients were permitted to take an appropriate therapy, such as imiquimod, cryotherapy, or 5-flourouracil if there was worsening of the AK-FAS score or if new lesions appeared.

On this measure, 38% of controls and 11% of those randomized to topical PLE had progressive disease versus only 2% of those randomized to take both topical and oral PLE, Dr. Pellacani reported.

The lower rate of new lesions or a start of a new drug over the course of the study in the group receiving both the topical and the oral formulations of PLE relative to those receiving topical PLE alone did not reach statistical significance, but Dr. Pellacani concluded that the addition of PLE to topical photoprotection without PLE seemed to provide a potentially clinically meaningful advantage.

Larger studies and longer term studies are needed, according to Dr. Pellacani, who noted that the substantial body of clinical studies associating PLE with benefit in a variety of dermatologic disorders has been weakened by the absence of well-designed studies that are adequately powered to guide clinical use.

Salvador González, MD, PhD, a dermatology specialist at Alcalá University, Madrid, also believes that PLE deserves further evaluation not just for photoprotection but for reinvigorating damaged skin due to its antioxidant and anti-inflammatory properties. He was the senior author of a 2020 paper in Photochemical and Photobiological Sciences that summarized the potential benefits of PLE in preventing damage related to sun exposure.

Among its mechanism, PLE generates reactive oxygen species (ROS) and prevents depletion of Langerhans cells induced by ultraviolet (UV) light, Dr. González explained in an interview. “At the cellular level, PLE activates tumor suppression p53, inhibits UV-induced COX-2 expression, reduces inflammation, and preventions immunosuppression,” he continued. In addition, he said PLE also prevents UV-A-induced common deletions related to mitochondrial damage and MMP1 expression induced by various UV wavelengths. 
“These molecular and cellular effects may translate into long-term inhibition of carcinogenesis including actinic keratosis,” he said, noting that all of these findings “justify the work by Pellacani and collaborators.”

Dr. Pellacani reports no potential conflicts of interest. Dr. González has a financial relationship with Cantabria Laboratories.

MILAN – Application of topical or both topical and oral polypodium leucotomos extract (PLE) was associated with significant reversal of adverse skin changes in patients with severe actinic keratoses (AKs) treated over 12 months, in a randomized, blinded study presented at the annual congress of the European Academy of Dermatology and Venereology.

At 12 months, the percentage of patients with a normal or almost normal honeycomb pattern when evaluated blindly with reflectance confocal microscopy (RCM) was about twice as great in either of the two groups that received PLE relative to those treated with topical photoprotection alone, according to Giovanni Pellacani, MD, PhD, chair of dermatology, University of Sapienza, Rome.

“In patients with severe actinic keratosis, the 12-month use of a PLE-based topical or oral photoprotection is associated with positive clinical and anatomical outcomes,” Dr. Pellacani said.

PLE, which is already commonly used in sun protection products, is derived from a South American species of fern and has been proposed for a broad array of dermatologic diseases. According to Dr. Pellacani, in vivo studies associating PLE with immune photoprotection make this agent particularly promising for severe AKs.

In this study involving two clinical research centers in Italy, 131 patients with photoaging and at least three AKs were randomized to one of three treatment arms. The control arm received topical photoprotection with an SPF of 100 or higher applied twice daily to all sun-exposed areas. The two treatment arms received the same topical photoprotection plus either a PLE-containing topical cream alone or a PLE-containing topical cream plus PLE in an oral form (240 mg) once daily

Patients were evaluated at 3 months, 6 months, and 1 year with several measures, including the Actinic Keratosis Area Score Index (AKASI) and the AK Field Assessment Scale Area (AK-FAS). They were also assessed with RCM. All clinical assessments and RCM evaluations, which assessed seven different parameters, such as honeycomb pattern, mottled pigmentation, and reticulated collagen, were performed by dermatologists blinded to the treatment assignment.

Complete data were available for 116 patients who completed all three evaluations over the 12 months of follow-up. On RCM, 50% of those receiving the oral and topical forms of PLE and 45% of those receiving topical PLE had normalization of the honeycomb pattern. These responses were significantly greater (P = .04 for both) than the 26% with normalization in the control group.

Although there were no significant differences in any of the other parameters evaluated by RCM, the improvement in the honeycomb pattern was accompanied by a 7% improvement in the AKASI score in patients taking PLE, either topically or orally and topically, while there was a 6% worsening (P < .001) among controls.

The AK-FAS score improved at 12 months by 26% in the group on oral/topical PLE and by 4% in the group on topical PLE. The score worsened by 13% among controls.

Over the course of the study, patients were permitted to take an appropriate therapy, such as imiquimod, cryotherapy, or 5-flourouracil if there was worsening of the AK-FAS score or if new lesions appeared.

On this measure, 38% of controls and 11% of those randomized to topical PLE had progressive disease versus only 2% of those randomized to take both topical and oral PLE, Dr. Pellacani reported.

The lower rate of new lesions or a start of a new drug over the course of the study in the group receiving both the topical and the oral formulations of PLE relative to those receiving topical PLE alone did not reach statistical significance, but Dr. Pellacani concluded that the addition of PLE to topical photoprotection without PLE seemed to provide a potentially clinically meaningful advantage.

Larger studies and longer term studies are needed, according to Dr. Pellacani, who noted that the substantial body of clinical studies associating PLE with benefit in a variety of dermatologic disorders has been weakened by the absence of well-designed studies that are adequately powered to guide clinical use.

Salvador González, MD, PhD, a dermatology specialist at Alcalá University, Madrid, also believes that PLE deserves further evaluation not just for photoprotection but for reinvigorating damaged skin due to its antioxidant and anti-inflammatory properties. He was the senior author of a 2020 paper in Photochemical and Photobiological Sciences that summarized the potential benefits of PLE in preventing damage related to sun exposure.

Among its mechanism, PLE generates reactive oxygen species (ROS) and prevents depletion of Langerhans cells induced by ultraviolet (UV) light, Dr. González explained in an interview. “At the cellular level, PLE activates tumor suppression p53, inhibits UV-induced COX-2 expression, reduces inflammation, and preventions immunosuppression,” he continued. In addition, he said PLE also prevents UV-A-induced common deletions related to mitochondrial damage and MMP1 expression induced by various UV wavelengths. 
“These molecular and cellular effects may translate into long-term inhibition of carcinogenesis including actinic keratosis,” he said, noting that all of these findings “justify the work by Pellacani and collaborators.”

Dr. Pellacani reports no potential conflicts of interest. Dr. González has a financial relationship with Cantabria Laboratories.

MILAN – Application of topical or both topical and oral polypodium leucotomos extract (PLE) was associated with significant reversal of adverse skin changes in patients with severe actinic keratoses (AKs) treated over 12 months, in a randomized, blinded study presented at the annual congress of the European Academy of Dermatology and Venereology.

At 12 months, the percentage of patients with a normal or almost normal honeycomb pattern when evaluated blindly with reflectance confocal microscopy (RCM) was about twice as great in either of the two groups that received PLE relative to those treated with topical photoprotection alone, according to Giovanni Pellacani, MD, PhD, chair of dermatology, University of Sapienza, Rome.

“In patients with severe actinic keratosis, the 12-month use of a PLE-based topical or oral photoprotection is associated with positive clinical and anatomical outcomes,” Dr. Pellacani said.

PLE, which is already commonly used in sun protection products, is derived from a South American species of fern and has been proposed for a broad array of dermatologic diseases. According to Dr. Pellacani, in vivo studies associating PLE with immune photoprotection make this agent particularly promising for severe AKs.

In this study involving two clinical research centers in Italy, 131 patients with photoaging and at least three AKs were randomized to one of three treatment arms. The control arm received topical photoprotection with an SPF of 100 or higher applied twice daily to all sun-exposed areas. The two treatment arms received the same topical photoprotection plus either a PLE-containing topical cream alone or a PLE-containing topical cream plus PLE in an oral form (240 mg) once daily

Patients were evaluated at 3 months, 6 months, and 1 year with several measures, including the Actinic Keratosis Area Score Index (AKASI) and the AK Field Assessment Scale Area (AK-FAS). They were also assessed with RCM. All clinical assessments and RCM evaluations, which assessed seven different parameters, such as honeycomb pattern, mottled pigmentation, and reticulated collagen, were performed by dermatologists blinded to the treatment assignment.

Complete data were available for 116 patients who completed all three evaluations over the 12 months of follow-up. On RCM, 50% of those receiving the oral and topical forms of PLE and 45% of those receiving topical PLE had normalization of the honeycomb pattern. These responses were significantly greater (P = .04 for both) than the 26% with normalization in the control group.

Although there were no significant differences in any of the other parameters evaluated by RCM, the improvement in the honeycomb pattern was accompanied by a 7% improvement in the AKASI score in patients taking PLE, either topically or orally and topically, while there was a 6% worsening (P < .001) among controls.

The AK-FAS score improved at 12 months by 26% in the group on oral/topical PLE and by 4% in the group on topical PLE. The score worsened by 13% among controls.

Over the course of the study, patients were permitted to take an appropriate therapy, such as imiquimod, cryotherapy, or 5-flourouracil if there was worsening of the AK-FAS score or if new lesions appeared.

On this measure, 38% of controls and 11% of those randomized to topical PLE had progressive disease versus only 2% of those randomized to take both topical and oral PLE, Dr. Pellacani reported.

The lower rate of new lesions or a start of a new drug over the course of the study in the group receiving both the topical and the oral formulations of PLE relative to those receiving topical PLE alone did not reach statistical significance, but Dr. Pellacani concluded that the addition of PLE to topical photoprotection without PLE seemed to provide a potentially clinically meaningful advantage.

Larger studies and longer term studies are needed, according to Dr. Pellacani, who noted that the substantial body of clinical studies associating PLE with benefit in a variety of dermatologic disorders has been weakened by the absence of well-designed studies that are adequately powered to guide clinical use.

Salvador González, MD, PhD, a dermatology specialist at Alcalá University, Madrid, also believes that PLE deserves further evaluation not just for photoprotection but for reinvigorating damaged skin due to its antioxidant and anti-inflammatory properties. He was the senior author of a 2020 paper in Photochemical and Photobiological Sciences that summarized the potential benefits of PLE in preventing damage related to sun exposure.

Among its mechanism, PLE generates reactive oxygen species (ROS) and prevents depletion of Langerhans cells induced by ultraviolet (UV) light, Dr. González explained in an interview. “At the cellular level, PLE activates tumor suppression p53, inhibits UV-induced COX-2 expression, reduces inflammation, and preventions immunosuppression,” he continued. In addition, he said PLE also prevents UV-A-induced common deletions related to mitochondrial damage and MMP1 expression induced by various UV wavelengths. 
“These molecular and cellular effects may translate into long-term inhibition of carcinogenesis including actinic keratosis,” he said, noting that all of these findings “justify the work by Pellacani and collaborators.”

Dr. Pellacani reports no potential conflicts of interest. Dr. González has a financial relationship with Cantabria Laboratories.

Occupational sun exposure is a well-known risk factor for the development of melanoma and nonmelanoma skin cancer (NMSC). In addition to sun exposure, US military personnel may face other risk factors such as lack of access to adequate sun protection, work in equatorial latitudes, and increased exposure to carcinogens. In one study, fewer than 30% of surveyed soldiers reported regular sunscreen use during deployment and reported the face, neck, and upper extremities were unprotected at least 70% of the time.¹ Skin cancer risk factors that are more common in military service members include inadequate sunscreen access, insufficient sun protection, harsh weather conditions, more immediate safety concerns than sun protection, and male gender. A higher incidence of melanoma and NMSC has been correlated with the more common demographics of US veterans such as male sex, older age, and White race.²

Although not uncommon in both civilian and military populations, we present the case of a military service member who developed skin cancer at an early age potentially due to occupational sun exposure. We also provide a review of the literature to examine the risk factors and incidence of melanoma and NMSC in US military personnel and veterans and provide recommendations for skin cancer prevention, screening, and intervention in the military population.

Case Report

A 37-year-old White active-duty male service member in the US Navy (USN) presented with a nonhealing lesion on the nose of 2 years’ duration that had been gradually growing and bleeding for several weeks. He participated in several sea deployments while onboard a naval destroyer over his 10-year military career. He did not routinely use sunscreen during his deployments. His personal and family medical history lacked risk factors for skin cancer other than his skin tone and frequent sun exposure.

Physical examination revealed a 1-cm ulcerated plaque with rolled borders and prominent telangiectases on the mid nasal dorsum. A shave biopsy was performed to confirm the diagnosis of nodular basal cell carcinoma (BCC). The patient underwent Mohs micrographic surgery, which required repair with an advancement flap. He currently continues his active-duty service and is preparing for his next overseas deployment.

Literature Review

We conducted a review of PubMed articles indexed for MEDLINE using the search terms skin cancer, melanoma, nonmelanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, Merkel cell carcinoma, dermatofibrosarcoma protuberans, or sebaceous carcinoma along with military, Army, Navy, Air Force, or veterans. Studies from January 1984 to April 2020 were included in our qualitative review. All articles were reviewed, and those that did not examine skin cancer and the military population in the United States were excluded. Relevant data, such as results of skin cancer incidence or risk factors or insights about developing skin cancer in this affected population, were extracted from the selected publications.

Several studies showed overall increased age-adjusted incidence rates of melanoma and NMSC among military service personnel compared to age-matched controls in the general population.² A survey of draft-age men during World War II found a slightly higher percentage of respondents with history of melanoma compared to the control group (83% [74/89] vs 76% [49/65]). Of those who had a history of melanoma, 34% (30/89) served in the tropics compared to 6% (4/65) in the control group.³ A tumor registry review found the age-adjusted melanoma incidence rates per 100,000 person-years for White individuals in the military vs the general population was 33.6 vs 27.5 among those aged 45 to 49 years, 49.8 vs 32.2 among those aged 50 to 54 years, and 178.5 vs 39.2 among those aged 55 to 59 years.⁴ Among published literature reviews, members of the US Air Force (USAF) had the highest rates of melanoma compared to other military branches, with an incidence rate of 7.6 vs 6.3 among USAF males vs Army males and 9.0 vs 5.5 among USAF females vs Army females.⁴ These findings were further supported by another study showing a higher incidence rate of melanoma in USAF members compared to Army personnel (17.8 vs 9.5) and a 62% greater melanoma incidence in active-duty military personnel compared to the general population when adjusted for age, race, sex, and year of diagnosis.⁵ Additionally, a meta-analysis reported a standardized incidence ratio of 1.4 (95% CI, 1.1-1.9) for malignant melanoma and 1.8 (95% CI, 1.3-2.8) for NMSC among military pilots compared to the general population.⁶ It is important to note that these data are limited to published peer-reviewed studies within PubMed and may not reflect the true skin cancer incidence.

More comprehensive studies are needed to compare NMSC incidence rates in nonpilot military populations compared to the general population. From 2005 to 2014, the average annual NMSC incidence rate in the USAF was 64.4 per 100,000 person-years, with the highest rate at 97.4 per 100,000 person-years in 2007.⁷ However, this study did not directly compare military service members to the general population. Service in tropical environments among World War II veterans was associated with an increased risk for NMSC. Sixty-six percent of patients with BCC (n=197) and 68% with squamous cell carcinoma (SCC)(n=41) were stationed in the Pacific, despite the number and demographics of soldiers deployed to the Pacific and Europe being approximately equal.⁸ During a 6-month period in 2008, a Combat Dermatology Clinic in Iraq showed 5% (n=129) of visits were for treatment of actinic keratoses (AKs), while 8% of visits (n=205) were related to skin cancer, including BCC, SCC, mycosis fungoides, and melanoma.⁹ Overall, these studies confirm a higher rate of melanoma in military service members vs the general population and indicate USAF members may be at the greatest risk for developing melanoma and NMSC among the service branches. Further studies are needed to elucidate why this might be the case and should concentrate on demographics, service locations, uniform wear and personal protective equipment standards, and use of sun-protective measures across each service branch.

Our search yielded no aggregate studies to determine if there is an increased rate of other types of skin cancer in military service members such as Merkel cell carcinoma, dermatofibrosarcoma protuberans, and microcystic adnexal carcinoma (MAC). Gerall et al¹⁰ described a case of MAC in a 43-year-old USAF U-2 pilot with a 15-year history of a slow-growing soft-tissue nodule on the cheek. The patient’s young age differed from the typical age of MAC occurrence (ie, 60–70 years), which led to the possibility that his profession contributed to the development of MAC and the relatively young age of onset.¹⁰

Etiology of Disease

The results of our literature review indicated that skin cancers are more prevalent among active-duty military personnel and veterans than in the general population; they also suggest that frequent sun exposure and lack of sun protection may be key etiologic factors. In 2015, only 23% of veterans (n=49) reported receiving skin cancer awareness education from the US Military.¹ Among soldiers returning from Iraq and Afghanistan (n=212), only 13% reported routine sunscreen use, and less than 30% reported having routine access to sunscreen while working more than 4 hours per day in direct sunlight or 75% of the day working in direct sunlight. Of these, the majority reported sustaining at least 1 sunburn, while 43% had at least 2 sunburns and 20% reported a history of a blistering sunburn during deployment.¹ The intermittent exposure hypothesis—defined as the theory that intense periods of exposure to UV radiation increase the risk for melanoma more than chronic cumulative UV radiation exposure—may explain how occupational exposure in the military may lead to increased skin cancer incidence. Individuals exposed to brief periods of intense, inconsistent, or unpredictable UV radiation may lack protective adaptive mechanisms compared to those who are chronically exposed.²

Exposure to UV radiation at higher altitudes (with corresponding higher UV energy) and altered sleep-wake cycles (with resulting altered immune defenses) may contribute to higher rates of melanoma and NMSC among USAF pilots.¹¹ During a 57-minute flight at 30,000-ft altitude, a pilot is exposed to a UVA dose equivalent to 20 minutes inside a tanning booth.¹² Although UVB transmission through plastic and glass windshields was reported to be less than 1%, UVA transmission ranged from 0.4% to 53.5%. The UVA dose for a pilot flying a light aircraft in Las Vegas, Nevada, was reported to be 127 μW/cm² at ground level vs 242 μW/cm² at a 30,000-ft altitude.¹² Therefore, cosmic radiation exposure for military pilots is higher than for commercial pilots, as they fly at higher altitudes. U-2 pilots are exposed to 20 times the cosmic radiation dose at sea level and 10 times the exposure of commercial pilots.¹⁰

It currently is unknown why service in the USAF would increase skin cancer risk compared to service in other branches; however, there are some differences between military branches that require further research, including ethnic demographics, uniform wear and personal protective equipment standards, duty assignment locations, and the hours the military members are asked to work outside with direct sunlight exposure for each branch of service. Environmental exposures may differ based on the military branch gear requirements; for example, when on the flight line or flight deck, USN aircrews are required to wear cranials (helmets), eyewear (visor or goggles), and long-sleeved shirts. When at sea, USN flight crews wear gloves, headgear, goggles, pants, and long-sleeved shirts to identify their duty onboard. All of these measures offer good sun protection and are carried over to the land-based flight lines in the USN and Marine Corps. Neither the Army nor the USAF commonly utilize these practices. Conversely, the USAF does not allow flight line workers including fuelers, maintainers, and aircrew to wear coveralls due to the risk of being blown off, becoming foreign object debris, and being sucked into jet engines. However, in-flight protective gear such as goggles, gloves, and coveralls are worn.¹² Perhaps the USAF may attract, recruit, or commission people with inherently more risk for skin cancer (eg, White individuals). How racial and ethnic factors may affect skin cancer incidence in military branches is an area for future research efforts.

Recommendations

Given the considerable increase in risk factors, efforts are needed to reduce the disparity in skin cancer rates between US military personnel and their civilian counterparts through appropriate prevention, screening, and intervention programs.

Prevention—In wartime settings as well as in training and other peacetime activities, active-duty military members cannot avoid harmful midday sun exposure. Additionally, application and reapplication of sunscreen can be challenging. Sunscreen, broad-spectrum lip balm, and wide-brimmed “boonie” hats can be ordered by supply personnel.¹³ We recommend that a standard sunscreen supply be available to all active-duty military service members. The long-sleeved, tightly woven fabric of military uniforms also can provide protection from the sun but can be difficult to tolerate for extended periods of time in warm climates. Breathable, lightweight, sun-protective clothing is commercially available and could be incorporated into military uniforms.

All service members should be educated about skin cancer risks while addressing common myths and inaccuracies. Fifty percent (n=50) of surveyed veterans thought discussions of skin cancer prevention and safety during basic training could help prevent skin cancer in service members.¹⁴ Suggestions from respondents included education about sun exposure consequences, use of graphic images of skin cancer in teaching, providing protective clothing and sunscreen to active-duty military service members, and discussion about sun protection with physicians during annual physicals. When veterans with a history of skin cancer were surveyed about their personal risk for skin cancer, most believed they were at little risk (average perceived risk response score, 2.2 out of 5 [1=no risk; 5=high risk]).¹⁴ The majority explained that they did not seek sun protection after warnings of skin cancer risk because they did not think skin cancer would happen to them,¹⁴ though the incidence of NMSC in the United States at the time of these surveys was estimated to be 3.5 million per year.^14,15 Another study found that only 13% of veterans knew the back is the most common site of melanoma in men.¹ The Army Public Health Center has informational fact sheets available online or in dermatologists’ offices that detail correct sunscreen application techniques and how to reduce sun exposure.^16,17 However, military service members reported that they prefer physicians to communicate with them directly about skin cancer risks vs reading brochures in physician offices or gaining information from television, radio, military training, or the Internet (4.4 out 5 rating for communication methods of risks associated with skin cancer [1=ineffective; 5=very effective]).¹⁴ However, only 27% of nondermatologist physicians counseled or screened their patients on skin cancer or sunscreen yearly, 49% even less frequently, with 24% never counseling or screening at all. Because not all service members may be able to regularly see a dermatologist, efforts should be focused on increasing primary care physician awareness on counseling and screening.¹⁸

Early Detection—Military service members should be educated on how to perform skin self-examinations to alert their providers earlier to concerning lesions. The American Academy of Dermatology publishes infographics regarding the ABCDEs of melanoma and how to perform skin self-examinations.^19,20 Although the US Preventive Services Task Force concluded there was insufficient evidence to recommend skin self-examination for all adults, the increased risk that military service members and veterans have requires further studies to examine the utility of self-screening in this population.²⁰ Given the evidence of a higher incidence of melanoma in military service members vs the general population after 45 years of age,⁴ we recommend starting yearly in-person screenings performed by primary care physicians or dermatologists at this age. Ensuring every service member has routine in-office skin examinations can be difficult given the limited number of active-duty military dermatologists. Civilian dermatologists also could be helpful in this respect.

Teleconsultation, teledermoscopy, or store-and-forward imaging services for concerning lesions could be utilized when in-person consultations with a dermatologist are not feasible or cannot be performed in a timely manner. From 2004 to 2012, 40% of 10,817 teleconsultations were dermatology consultations from deployed or remote environments.²¹ Teleconsultation can be performed via email through the global military teleconsultation portal.²² These methods can lead to earlier detection of skin cancer rather than delaying evaluation for an in-person consultation.²³

Intervention—High-risk patients who have been diagnosed with NMSC or many AKs should consider oral, procedural, or topical chemoprevention to reduce the risk for additional skin cancers as both primary and secondary prevention. In a double-blind, randomized, controlled trial of 386 individuals with a history of 2 or more NMSCs, participants were randomly assigned to receive either 500 mg of nicotinamide twice daily or placebo for 12 months. Compared to the placebo group, the nicotinamide group had a 23% lower rate of new NMSCs and an 11% lower rate of new AKs at 12 months.²⁴ The use of acitretin also has been studied in transplant recipients for the chemoprevention of NMSC. In a double-blind, randomized, controlled trial of renal transplant recipients with more than 10 AKs randomized to receive either 30 mg/d of acitretin or placebo for 6 months, 11% of the acitretin group reported a new NMSC compared to 47% in the placebo group.²⁵ An open-label study of 27 renal transplant recipients treated with methyl-esterified aminolevulinic acid–photodynamic therapy and red light demonstrated an increased mean time to occurrence of an AK, SCC, BCC, keratoacanthoma, or wart from 6.8 months in untreated areas compared to 9.6 months in treated areas.²⁵ In active-duty locations where access to red and blue light sources is unavailable, the use of daylight photodynamic therapy can be considered, as it does not require any special equipment. Topical treatments such as 5-fluorouracil and imiquimod can be used for treatment and chemoprevention of NMSC. In a follow-up study from the Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial, patients who applied 5-fluorouracil cream 5% twice daily to the face and ears for 4 weeks had a 75% risk reduction in developing SCC requiring surgery compared to the control group for the first year after treatment.^26,27

Final Thoughts

Focusing on the efforts we propose can help the US Military expand their prevention, screening, and intervention programs for skin cancer in service members. Further research can then be performed to determine which programs have the greatest impact on rates of skin cancer among military and veteran personnel. Given these higher incidences and risk of exposure for skin cancer among service members, the various services may consider mandating sunscreen use as part of the uniform to prevent skin cancer. To maximize effectiveness, these efforts to prevent the development of skin cancer among military and veteran personnel should be adopted nationally.

Occupational sun exposure is a well-known risk factor for the development of melanoma and nonmelanoma skin cancer (NMSC). In addition to sun exposure, US military personnel may face other risk factors such as lack of access to adequate sun protection, work in equatorial latitudes, and increased exposure to carcinogens. In one study, fewer than 30% of surveyed soldiers reported regular sunscreen use during deployment and reported the face, neck, and upper extremities were unprotected at least 70% of the time.¹ Skin cancer risk factors that are more common in military service members include inadequate sunscreen access, insufficient sun protection, harsh weather conditions, more immediate safety concerns than sun protection, and male gender. A higher incidence of melanoma and NMSC has been correlated with the more common demographics of US veterans such as male sex, older age, and White race.²

Although not uncommon in both civilian and military populations, we present the case of a military service member who developed skin cancer at an early age potentially due to occupational sun exposure. We also provide a review of the literature to examine the risk factors and incidence of melanoma and NMSC in US military personnel and veterans and provide recommendations for skin cancer prevention, screening, and intervention in the military population.

Case Report

A 37-year-old White active-duty male service member in the US Navy (USN) presented with a nonhealing lesion on the nose of 2 years’ duration that had been gradually growing and bleeding for several weeks. He participated in several sea deployments while onboard a naval destroyer over his 10-year military career. He did not routinely use sunscreen during his deployments. His personal and family medical history lacked risk factors for skin cancer other than his skin tone and frequent sun exposure.

Physical examination revealed a 1-cm ulcerated plaque with rolled borders and prominent telangiectases on the mid nasal dorsum. A shave biopsy was performed to confirm the diagnosis of nodular basal cell carcinoma (BCC). The patient underwent Mohs micrographic surgery, which required repair with an advancement flap. He currently continues his active-duty service and is preparing for his next overseas deployment.

Literature Review

We conducted a review of PubMed articles indexed for MEDLINE using the search terms skin cancer, melanoma, nonmelanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, Merkel cell carcinoma, dermatofibrosarcoma protuberans, or sebaceous carcinoma along with military, Army, Navy, Air Force, or veterans. Studies from January 1984 to April 2020 were included in our qualitative review. All articles were reviewed, and those that did not examine skin cancer and the military population in the United States were excluded. Relevant data, such as results of skin cancer incidence or risk factors or insights about developing skin cancer in this affected population, were extracted from the selected publications.

Several studies showed overall increased age-adjusted incidence rates of melanoma and NMSC among military service personnel compared to age-matched controls in the general population.² A survey of draft-age men during World War II found a slightly higher percentage of respondents with history of melanoma compared to the control group (83% [74/89] vs 76% [49/65]). Of those who had a history of melanoma, 34% (30/89) served in the tropics compared to 6% (4/65) in the control group.³ A tumor registry review found the age-adjusted melanoma incidence rates per 100,000 person-years for White individuals in the military vs the general population was 33.6 vs 27.5 among those aged 45 to 49 years, 49.8 vs 32.2 among those aged 50 to 54 years, and 178.5 vs 39.2 among those aged 55 to 59 years.⁴ Among published literature reviews, members of the US Air Force (USAF) had the highest rates of melanoma compared to other military branches, with an incidence rate of 7.6 vs 6.3 among USAF males vs Army males and 9.0 vs 5.5 among USAF females vs Army females.⁴ These findings were further supported by another study showing a higher incidence rate of melanoma in USAF members compared to Army personnel (17.8 vs 9.5) and a 62% greater melanoma incidence in active-duty military personnel compared to the general population when adjusted for age, race, sex, and year of diagnosis.⁵ Additionally, a meta-analysis reported a standardized incidence ratio of 1.4 (95% CI, 1.1-1.9) for malignant melanoma and 1.8 (95% CI, 1.3-2.8) for NMSC among military pilots compared to the general population.⁶ It is important to note that these data are limited to published peer-reviewed studies within PubMed and may not reflect the true skin cancer incidence.

More comprehensive studies are needed to compare NMSC incidence rates in nonpilot military populations compared to the general population. From 2005 to 2014, the average annual NMSC incidence rate in the USAF was 64.4 per 100,000 person-years, with the highest rate at 97.4 per 100,000 person-years in 2007.⁷ However, this study did not directly compare military service members to the general population. Service in tropical environments among World War II veterans was associated with an increased risk for NMSC. Sixty-six percent of patients with BCC (n=197) and 68% with squamous cell carcinoma (SCC)(n=41) were stationed in the Pacific, despite the number and demographics of soldiers deployed to the Pacific and Europe being approximately equal.⁸ During a 6-month period in 2008, a Combat Dermatology Clinic in Iraq showed 5% (n=129) of visits were for treatment of actinic keratoses (AKs), while 8% of visits (n=205) were related to skin cancer, including BCC, SCC, mycosis fungoides, and melanoma.⁹ Overall, these studies confirm a higher rate of melanoma in military service members vs the general population and indicate USAF members may be at the greatest risk for developing melanoma and NMSC among the service branches. Further studies are needed to elucidate why this might be the case and should concentrate on demographics, service locations, uniform wear and personal protective equipment standards, and use of sun-protective measures across each service branch.

Our search yielded no aggregate studies to determine if there is an increased rate of other types of skin cancer in military service members such as Merkel cell carcinoma, dermatofibrosarcoma protuberans, and microcystic adnexal carcinoma (MAC). Gerall et al¹⁰ described a case of MAC in a 43-year-old USAF U-2 pilot with a 15-year history of a slow-growing soft-tissue nodule on the cheek. The patient’s young age differed from the typical age of MAC occurrence (ie, 60–70 years), which led to the possibility that his profession contributed to the development of MAC and the relatively young age of onset.¹⁰

Etiology of Disease

The results of our literature review indicated that skin cancers are more prevalent among active-duty military personnel and veterans than in the general population; they also suggest that frequent sun exposure and lack of sun protection may be key etiologic factors. In 2015, only 23% of veterans (n=49) reported receiving skin cancer awareness education from the US Military.¹ Among soldiers returning from Iraq and Afghanistan (n=212), only 13% reported routine sunscreen use, and less than 30% reported having routine access to sunscreen while working more than 4 hours per day in direct sunlight or 75% of the day working in direct sunlight. Of these, the majority reported sustaining at least 1 sunburn, while 43% had at least 2 sunburns and 20% reported a history of a blistering sunburn during deployment.¹ The intermittent exposure hypothesis—defined as the theory that intense periods of exposure to UV radiation increase the risk for melanoma more than chronic cumulative UV radiation exposure—may explain how occupational exposure in the military may lead to increased skin cancer incidence. Individuals exposed to brief periods of intense, inconsistent, or unpredictable UV radiation may lack protective adaptive mechanisms compared to those who are chronically exposed.²

Exposure to UV radiation at higher altitudes (with corresponding higher UV energy) and altered sleep-wake cycles (with resulting altered immune defenses) may contribute to higher rates of melanoma and NMSC among USAF pilots.¹¹ During a 57-minute flight at 30,000-ft altitude, a pilot is exposed to a UVA dose equivalent to 20 minutes inside a tanning booth.¹² Although UVB transmission through plastic and glass windshields was reported to be less than 1%, UVA transmission ranged from 0.4% to 53.5%. The UVA dose for a pilot flying a light aircraft in Las Vegas, Nevada, was reported to be 127 μW/cm² at ground level vs 242 μW/cm² at a 30,000-ft altitude.¹² Therefore, cosmic radiation exposure for military pilots is higher than for commercial pilots, as they fly at higher altitudes. U-2 pilots are exposed to 20 times the cosmic radiation dose at sea level and 10 times the exposure of commercial pilots.¹⁰

It currently is unknown why service in the USAF would increase skin cancer risk compared to service in other branches; however, there are some differences between military branches that require further research, including ethnic demographics, uniform wear and personal protective equipment standards, duty assignment locations, and the hours the military members are asked to work outside with direct sunlight exposure for each branch of service. Environmental exposures may differ based on the military branch gear requirements; for example, when on the flight line or flight deck, USN aircrews are required to wear cranials (helmets), eyewear (visor or goggles), and long-sleeved shirts. When at sea, USN flight crews wear gloves, headgear, goggles, pants, and long-sleeved shirts to identify their duty onboard. All of these measures offer good sun protection and are carried over to the land-based flight lines in the USN and Marine Corps. Neither the Army nor the USAF commonly utilize these practices. Conversely, the USAF does not allow flight line workers including fuelers, maintainers, and aircrew to wear coveralls due to the risk of being blown off, becoming foreign object debris, and being sucked into jet engines. However, in-flight protective gear such as goggles, gloves, and coveralls are worn.¹² Perhaps the USAF may attract, recruit, or commission people with inherently more risk for skin cancer (eg, White individuals). How racial and ethnic factors may affect skin cancer incidence in military branches is an area for future research efforts.

Recommendations

Given the considerable increase in risk factors, efforts are needed to reduce the disparity in skin cancer rates between US military personnel and their civilian counterparts through appropriate prevention, screening, and intervention programs.

Prevention—In wartime settings as well as in training and other peacetime activities, active-duty military members cannot avoid harmful midday sun exposure. Additionally, application and reapplication of sunscreen can be challenging. Sunscreen, broad-spectrum lip balm, and wide-brimmed “boonie” hats can be ordered by supply personnel.¹³ We recommend that a standard sunscreen supply be available to all active-duty military service members. The long-sleeved, tightly woven fabric of military uniforms also can provide protection from the sun but can be difficult to tolerate for extended periods of time in warm climates. Breathable, lightweight, sun-protective clothing is commercially available and could be incorporated into military uniforms.

All service members should be educated about skin cancer risks while addressing common myths and inaccuracies. Fifty percent (n=50) of surveyed veterans thought discussions of skin cancer prevention and safety during basic training could help prevent skin cancer in service members.¹⁴ Suggestions from respondents included education about sun exposure consequences, use of graphic images of skin cancer in teaching, providing protective clothing and sunscreen to active-duty military service members, and discussion about sun protection with physicians during annual physicals. When veterans with a history of skin cancer were surveyed about their personal risk for skin cancer, most believed they were at little risk (average perceived risk response score, 2.2 out of 5 [1=no risk; 5=high risk]).¹⁴ The majority explained that they did not seek sun protection after warnings of skin cancer risk because they did not think skin cancer would happen to them,¹⁴ though the incidence of NMSC in the United States at the time of these surveys was estimated to be 3.5 million per year.^14,15 Another study found that only 13% of veterans knew the back is the most common site of melanoma in men.¹ The Army Public Health Center has informational fact sheets available online or in dermatologists’ offices that detail correct sunscreen application techniques and how to reduce sun exposure.^16,17 However, military service members reported that they prefer physicians to communicate with them directly about skin cancer risks vs reading brochures in physician offices or gaining information from television, radio, military training, or the Internet (4.4 out 5 rating for communication methods of risks associated with skin cancer [1=ineffective; 5=very effective]).¹⁴ However, only 27% of nondermatologist physicians counseled or screened their patients on skin cancer or sunscreen yearly, 49% even less frequently, with 24% never counseling or screening at all. Because not all service members may be able to regularly see a dermatologist, efforts should be focused on increasing primary care physician awareness on counseling and screening.¹⁸

Early Detection—Military service members should be educated on how to perform skin self-examinations to alert their providers earlier to concerning lesions. The American Academy of Dermatology publishes infographics regarding the ABCDEs of melanoma and how to perform skin self-examinations.^19,20 Although the US Preventive Services Task Force concluded there was insufficient evidence to recommend skin self-examination for all adults, the increased risk that military service members and veterans have requires further studies to examine the utility of self-screening in this population.²⁰ Given the evidence of a higher incidence of melanoma in military service members vs the general population after 45 years of age,⁴ we recommend starting yearly in-person screenings performed by primary care physicians or dermatologists at this age. Ensuring every service member has routine in-office skin examinations can be difficult given the limited number of active-duty military dermatologists. Civilian dermatologists also could be helpful in this respect.

Teleconsultation, teledermoscopy, or store-and-forward imaging services for concerning lesions could be utilized when in-person consultations with a dermatologist are not feasible or cannot be performed in a timely manner. From 2004 to 2012, 40% of 10,817 teleconsultations were dermatology consultations from deployed or remote environments.²¹ Teleconsultation can be performed via email through the global military teleconsultation portal.²² These methods can lead to earlier detection of skin cancer rather than delaying evaluation for an in-person consultation.²³

Intervention—High-risk patients who have been diagnosed with NMSC or many AKs should consider oral, procedural, or topical chemoprevention to reduce the risk for additional skin cancers as both primary and secondary prevention. In a double-blind, randomized, controlled trial of 386 individuals with a history of 2 or more NMSCs, participants were randomly assigned to receive either 500 mg of nicotinamide twice daily or placebo for 12 months. Compared to the placebo group, the nicotinamide group had a 23% lower rate of new NMSCs and an 11% lower rate of new AKs at 12 months.²⁴ The use of acitretin also has been studied in transplant recipients for the chemoprevention of NMSC. In a double-blind, randomized, controlled trial of renal transplant recipients with more than 10 AKs randomized to receive either 30 mg/d of acitretin or placebo for 6 months, 11% of the acitretin group reported a new NMSC compared to 47% in the placebo group.²⁵ An open-label study of 27 renal transplant recipients treated with methyl-esterified aminolevulinic acid–photodynamic therapy and red light demonstrated an increased mean time to occurrence of an AK, SCC, BCC, keratoacanthoma, or wart from 6.8 months in untreated areas compared to 9.6 months in treated areas.²⁵ In active-duty locations where access to red and blue light sources is unavailable, the use of daylight photodynamic therapy can be considered, as it does not require any special equipment. Topical treatments such as 5-fluorouracil and imiquimod can be used for treatment and chemoprevention of NMSC. In a follow-up study from the Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial, patients who applied 5-fluorouracil cream 5% twice daily to the face and ears for 4 weeks had a 75% risk reduction in developing SCC requiring surgery compared to the control group for the first year after treatment.^26,27

Final Thoughts

Focusing on the efforts we propose can help the US Military expand their prevention, screening, and intervention programs for skin cancer in service members. Further research can then be performed to determine which programs have the greatest impact on rates of skin cancer among military and veteran personnel. Given these higher incidences and risk of exposure for skin cancer among service members, the various services may consider mandating sunscreen use as part of the uniform to prevent skin cancer. To maximize effectiveness, these efforts to prevent the development of skin cancer among military and veteran personnel should be adopted nationally.

Occupational sun exposure is a well-known risk factor for the development of melanoma and nonmelanoma skin cancer (NMSC). In addition to sun exposure, US military personnel may face other risk factors such as lack of access to adequate sun protection, work in equatorial latitudes, and increased exposure to carcinogens. In one study, fewer than 30% of surveyed soldiers reported regular sunscreen use during deployment and reported the face, neck, and upper extremities were unprotected at least 70% of the time.¹ Skin cancer risk factors that are more common in military service members include inadequate sunscreen access, insufficient sun protection, harsh weather conditions, more immediate safety concerns than sun protection, and male gender. A higher incidence of melanoma and NMSC has been correlated with the more common demographics of US veterans such as male sex, older age, and White race.²

Although not uncommon in both civilian and military populations, we present the case of a military service member who developed skin cancer at an early age potentially due to occupational sun exposure. We also provide a review of the literature to examine the risk factors and incidence of melanoma and NMSC in US military personnel and veterans and provide recommendations for skin cancer prevention, screening, and intervention in the military population.

Case Report

A 37-year-old White active-duty male service member in the US Navy (USN) presented with a nonhealing lesion on the nose of 2 years’ duration that had been gradually growing and bleeding for several weeks. He participated in several sea deployments while onboard a naval destroyer over his 10-year military career. He did not routinely use sunscreen during his deployments. His personal and family medical history lacked risk factors for skin cancer other than his skin tone and frequent sun exposure.

Physical examination revealed a 1-cm ulcerated plaque with rolled borders and prominent telangiectases on the mid nasal dorsum. A shave biopsy was performed to confirm the diagnosis of nodular basal cell carcinoma (BCC). The patient underwent Mohs micrographic surgery, which required repair with an advancement flap. He currently continues his active-duty service and is preparing for his next overseas deployment.

Literature Review

We conducted a review of PubMed articles indexed for MEDLINE using the search terms skin cancer, melanoma, nonmelanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, Merkel cell carcinoma, dermatofibrosarcoma protuberans, or sebaceous carcinoma along with military, Army, Navy, Air Force, or veterans. Studies from January 1984 to April 2020 were included in our qualitative review. All articles were reviewed, and those that did not examine skin cancer and the military population in the United States were excluded. Relevant data, such as results of skin cancer incidence or risk factors or insights about developing skin cancer in this affected population, were extracted from the selected publications.

Several studies showed overall increased age-adjusted incidence rates of melanoma and NMSC among military service personnel compared to age-matched controls in the general population.² A survey of draft-age men during World War II found a slightly higher percentage of respondents with history of melanoma compared to the control group (83% [74/89] vs 76% [49/65]). Of those who had a history of melanoma, 34% (30/89) served in the tropics compared to 6% (4/65) in the control group.³ A tumor registry review found the age-adjusted melanoma incidence rates per 100,000 person-years for White individuals in the military vs the general population was 33.6 vs 27.5 among those aged 45 to 49 years, 49.8 vs 32.2 among those aged 50 to 54 years, and 178.5 vs 39.2 among those aged 55 to 59 years.⁴ Among published literature reviews, members of the US Air Force (USAF) had the highest rates of melanoma compared to other military branches, with an incidence rate of 7.6 vs 6.3 among USAF males vs Army males and 9.0 vs 5.5 among USAF females vs Army females.⁴ These findings were further supported by another study showing a higher incidence rate of melanoma in USAF members compared to Army personnel (17.8 vs 9.5) and a 62% greater melanoma incidence in active-duty military personnel compared to the general population when adjusted for age, race, sex, and year of diagnosis.⁵ Additionally, a meta-analysis reported a standardized incidence ratio of 1.4 (95% CI, 1.1-1.9) for malignant melanoma and 1.8 (95% CI, 1.3-2.8) for NMSC among military pilots compared to the general population.⁶ It is important to note that these data are limited to published peer-reviewed studies within PubMed and may not reflect the true skin cancer incidence.

More comprehensive studies are needed to compare NMSC incidence rates in nonpilot military populations compared to the general population. From 2005 to 2014, the average annual NMSC incidence rate in the USAF was 64.4 per 100,000 person-years, with the highest rate at 97.4 per 100,000 person-years in 2007.⁷ However, this study did not directly compare military service members to the general population. Service in tropical environments among World War II veterans was associated with an increased risk for NMSC. Sixty-six percent of patients with BCC (n=197) and 68% with squamous cell carcinoma (SCC)(n=41) were stationed in the Pacific, despite the number and demographics of soldiers deployed to the Pacific and Europe being approximately equal.⁸ During a 6-month period in 2008, a Combat Dermatology Clinic in Iraq showed 5% (n=129) of visits were for treatment of actinic keratoses (AKs), while 8% of visits (n=205) were related to skin cancer, including BCC, SCC, mycosis fungoides, and melanoma.⁹ Overall, these studies confirm a higher rate of melanoma in military service members vs the general population and indicate USAF members may be at the greatest risk for developing melanoma and NMSC among the service branches. Further studies are needed to elucidate why this might be the case and should concentrate on demographics, service locations, uniform wear and personal protective equipment standards, and use of sun-protective measures across each service branch.

Our search yielded no aggregate studies to determine if there is an increased rate of other types of skin cancer in military service members such as Merkel cell carcinoma, dermatofibrosarcoma protuberans, and microcystic adnexal carcinoma (MAC). Gerall et al¹⁰ described a case of MAC in a 43-year-old USAF U-2 pilot with a 15-year history of a slow-growing soft-tissue nodule on the cheek. The patient’s young age differed from the typical age of MAC occurrence (ie, 60–70 years), which led to the possibility that his profession contributed to the development of MAC and the relatively young age of onset.¹⁰

Etiology of Disease

The results of our literature review indicated that skin cancers are more prevalent among active-duty military personnel and veterans than in the general population; they also suggest that frequent sun exposure and lack of sun protection may be key etiologic factors. In 2015, only 23% of veterans (n=49) reported receiving skin cancer awareness education from the US Military.¹ Among soldiers returning from Iraq and Afghanistan (n=212), only 13% reported routine sunscreen use, and less than 30% reported having routine access to sunscreen while working more than 4 hours per day in direct sunlight or 75% of the day working in direct sunlight. Of these, the majority reported sustaining at least 1 sunburn, while 43% had at least 2 sunburns and 20% reported a history of a blistering sunburn during deployment.¹ The intermittent exposure hypothesis—defined as the theory that intense periods of exposure to UV radiation increase the risk for melanoma more than chronic cumulative UV radiation exposure—may explain how occupational exposure in the military may lead to increased skin cancer incidence. Individuals exposed to brief periods of intense, inconsistent, or unpredictable UV radiation may lack protective adaptive mechanisms compared to those who are chronically exposed.²

Exposure to UV radiation at higher altitudes (with corresponding higher UV energy) and altered sleep-wake cycles (with resulting altered immune defenses) may contribute to higher rates of melanoma and NMSC among USAF pilots.¹¹ During a 57-minute flight at 30,000-ft altitude, a pilot is exposed to a UVA dose equivalent to 20 minutes inside a tanning booth.¹² Although UVB transmission through plastic and glass windshields was reported to be less than 1%, UVA transmission ranged from 0.4% to 53.5%. The UVA dose for a pilot flying a light aircraft in Las Vegas, Nevada, was reported to be 127 μW/cm² at ground level vs 242 μW/cm² at a 30,000-ft altitude.¹² Therefore, cosmic radiation exposure for military pilots is higher than for commercial pilots, as they fly at higher altitudes. U-2 pilots are exposed to 20 times the cosmic radiation dose at sea level and 10 times the exposure of commercial pilots.¹⁰

It currently is unknown why service in the USAF would increase skin cancer risk compared to service in other branches; however, there are some differences between military branches that require further research, including ethnic demographics, uniform wear and personal protective equipment standards, duty assignment locations, and the hours the military members are asked to work outside with direct sunlight exposure for each branch of service. Environmental exposures may differ based on the military branch gear requirements; for example, when on the flight line or flight deck, USN aircrews are required to wear cranials (helmets), eyewear (visor or goggles), and long-sleeved shirts. When at sea, USN flight crews wear gloves, headgear, goggles, pants, and long-sleeved shirts to identify their duty onboard. All of these measures offer good sun protection and are carried over to the land-based flight lines in the USN and Marine Corps. Neither the Army nor the USAF commonly utilize these practices. Conversely, the USAF does not allow flight line workers including fuelers, maintainers, and aircrew to wear coveralls due to the risk of being blown off, becoming foreign object debris, and being sucked into jet engines. However, in-flight protective gear such as goggles, gloves, and coveralls are worn.¹² Perhaps the USAF may attract, recruit, or commission people with inherently more risk for skin cancer (eg, White individuals). How racial and ethnic factors may affect skin cancer incidence in military branches is an area for future research efforts.

Recommendations

Given the considerable increase in risk factors, efforts are needed to reduce the disparity in skin cancer rates between US military personnel and their civilian counterparts through appropriate prevention, screening, and intervention programs.

Prevention—In wartime settings as well as in training and other peacetime activities, active-duty military members cannot avoid harmful midday sun exposure. Additionally, application and reapplication of sunscreen can be challenging. Sunscreen, broad-spectrum lip balm, and wide-brimmed “boonie” hats can be ordered by supply personnel.¹³ We recommend that a standard sunscreen supply be available to all active-duty military service members. The long-sleeved, tightly woven fabric of military uniforms also can provide protection from the sun but can be difficult to tolerate for extended periods of time in warm climates. Breathable, lightweight, sun-protective clothing is commercially available and could be incorporated into military uniforms.

All service members should be educated about skin cancer risks while addressing common myths and inaccuracies. Fifty percent (n=50) of surveyed veterans thought discussions of skin cancer prevention and safety during basic training could help prevent skin cancer in service members.¹⁴ Suggestions from respondents included education about sun exposure consequences, use of graphic images of skin cancer in teaching, providing protective clothing and sunscreen to active-duty military service members, and discussion about sun protection with physicians during annual physicals. When veterans with a history of skin cancer were surveyed about their personal risk for skin cancer, most believed they were at little risk (average perceived risk response score, 2.2 out of 5 [1=no risk; 5=high risk]).¹⁴ The majority explained that they did not seek sun protection after warnings of skin cancer risk because they did not think skin cancer would happen to them,¹⁴ though the incidence of NMSC in the United States at the time of these surveys was estimated to be 3.5 million per year.^14,15 Another study found that only 13% of veterans knew the back is the most common site of melanoma in men.¹ The Army Public Health Center has informational fact sheets available online or in dermatologists’ offices that detail correct sunscreen application techniques and how to reduce sun exposure.^16,17 However, military service members reported that they prefer physicians to communicate with them directly about skin cancer risks vs reading brochures in physician offices or gaining information from television, radio, military training, or the Internet (4.4 out 5 rating for communication methods of risks associated with skin cancer [1=ineffective; 5=very effective]).¹⁴ However, only 27% of nondermatologist physicians counseled or screened their patients on skin cancer or sunscreen yearly, 49% even less frequently, with 24% never counseling or screening at all. Because not all service members may be able to regularly see a dermatologist, efforts should be focused on increasing primary care physician awareness on counseling and screening.¹⁸

Early Detection—Military service members should be educated on how to perform skin self-examinations to alert their providers earlier to concerning lesions. The American Academy of Dermatology publishes infographics regarding the ABCDEs of melanoma and how to perform skin self-examinations.^19,20 Although the US Preventive Services Task Force concluded there was insufficient evidence to recommend skin self-examination for all adults, the increased risk that military service members and veterans have requires further studies to examine the utility of self-screening in this population.²⁰ Given the evidence of a higher incidence of melanoma in military service members vs the general population after 45 years of age,⁴ we recommend starting yearly in-person screenings performed by primary care physicians or dermatologists at this age. Ensuring every service member has routine in-office skin examinations can be difficult given the limited number of active-duty military dermatologists. Civilian dermatologists also could be helpful in this respect.

Teleconsultation, teledermoscopy, or store-and-forward imaging services for concerning lesions could be utilized when in-person consultations with a dermatologist are not feasible or cannot be performed in a timely manner. From 2004 to 2012, 40% of 10,817 teleconsultations were dermatology consultations from deployed or remote environments.²¹ Teleconsultation can be performed via email through the global military teleconsultation portal.²² These methods can lead to earlier detection of skin cancer rather than delaying evaluation for an in-person consultation.²³

Intervention—High-risk patients who have been diagnosed with NMSC or many AKs should consider oral, procedural, or topical chemoprevention to reduce the risk for additional skin cancers as both primary and secondary prevention. In a double-blind, randomized, controlled trial of 386 individuals with a history of 2 or more NMSCs, participants were randomly assigned to receive either 500 mg of nicotinamide twice daily or placebo for 12 months. Compared to the placebo group, the nicotinamide group had a 23% lower rate of new NMSCs and an 11% lower rate of new AKs at 12 months.²⁴ The use of acitretin also has been studied in transplant recipients for the chemoprevention of NMSC. In a double-blind, randomized, controlled trial of renal transplant recipients with more than 10 AKs randomized to receive either 30 mg/d of acitretin or placebo for 6 months, 11% of the acitretin group reported a new NMSC compared to 47% in the placebo group.²⁵ An open-label study of 27 renal transplant recipients treated with methyl-esterified aminolevulinic acid–photodynamic therapy and red light demonstrated an increased mean time to occurrence of an AK, SCC, BCC, keratoacanthoma, or wart from 6.8 months in untreated areas compared to 9.6 months in treated areas.²⁵ In active-duty locations where access to red and blue light sources is unavailable, the use of daylight photodynamic therapy can be considered, as it does not require any special equipment. Topical treatments such as 5-fluorouracil and imiquimod can be used for treatment and chemoprevention of NMSC. In a follow-up study from the Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial, patients who applied 5-fluorouracil cream 5% twice daily to the face and ears for 4 weeks had a 75% risk reduction in developing SCC requiring surgery compared to the control group for the first year after treatment.^26,27

Final Thoughts

Focusing on the efforts we propose can help the US Military expand their prevention, screening, and intervention programs for skin cancer in service members. Further research can then be performed to determine which programs have the greatest impact on rates of skin cancer among military and veteran personnel. Given these higher incidences and risk of exposure for skin cancer among service members, the various services may consider mandating sunscreen use as part of the uniform to prevent skin cancer. To maximize effectiveness, these efforts to prevent the development of skin cancer among military and veteran personnel should be adopted nationally.

PORTLAND, ORE. – When individuals with skin of color seek help from dermatologists to optimize the treatment and management of scalp and hair disorders, they expect them to understand their concerns, but sometimes their doctors fall short.

“Many times, you may not have race concordant visits with patients of color,” Janiene Luke, MD, said at the annual meeting of the Pacific Dermatologic Association. She referred to a survey of 200 Black women aged 21-83 years, which found that 28% had visited a physician to discuss hair or scalp issues. Of those, 68% felt like their dermatologists did not understand African American hair.

“I recommend trying the best you can to familiarize yourself with various common cultural hair styling methods and practices in patients of color. It’s important to understand what your patients are engaging in and the types of styles they’re using,” said Dr. Luke, associate professor of dermatology at Loma Linda (Calif.) University. “Approach all patients with cultural humility. We know from studies that patients value dermatologists who take time to listen to their concerns, involve them in the decision-making process, and educate them about their conditions,” she added.

National efforts to educate clinicians on treating skin of color have emerged in recent years, including textbooks, CME courses at dermatology conferences, and the American Academy of Dermatology’s Skin of Color Curriculum, which consists of 15-minute modules that can be viewed online.

At the meeting, Dr. Luke, shared her approach to assessing hair and scalp disorders in skin of color. She begins by taking a thorough history, “because not all things that are associated with hair styling will be the reason why your patient comes in,” she said. “Patients of color can have telogen effluvium and seborrheic dermatitis just like anyone else. I ask about the hair styling practices they use. I also ask how often they wash their hair, because sometimes our recommendations for treatment are not realistic based on their current routine.”

Next, she examines the scalp with her hands – which sometimes surprises patients. “I’ve had so many patients come in and say, ‘the dermatologist never touched my scalp,’ or ‘they never even looked at my hair,’ ” said Dr. Luke, who directs the university’s dermatology residency program. She asks patients to remove any hair extensions or weaves prior to the office visit and to remove wigs prior to the exam itself. The lab tests she customarily orders include CBC, TSH, iron, total iron binding capacity, ferritin, vitamin D, and zinc. If there are signs of androgen excess, she may check testosterone, sex hormone binding globulin, and dehydroepiandrosterone sulfate (DHEA-S). She routinely incorporates a dermoscopy-directed biopsy into the evaluation.

Dr. Luke examines the patient from above, the sides, and the back to assess the pattern/distribution of hair loss. A visible scalp at the vertex indicates a 50% reduction in normal hair density. “I’m looking at the hairline, their part width, and the length of their hair,” she said. “I also look at the eyebrows and eyelashes, because these can be involved in alopecia areata, frontal fibrosing alopecia, or congenital hair shaft disorders.”

On closeup examination, she looks for scarring versus non-scarring types of hair loss, and for the presence or absence of follicular ostia. “I also look at hair changes,” she said. “Is the texture of their hair different? Are there signs of breakage or fragility? It’s been noted in studies that breakage can be an early sign of central centrifugal cicatricial alopecia.” (For more tips on examining tightly coiled hair among patients with hair loss in race discordant patient-physician interactions, she recommended a 2021 article in JAMA Dermatology)..

Trichoscopy allows for magnified observation of the hair shafts, hair follicle openings, perifollicular dermis, and blood vessels. Normal trichoscopy findings in skin of color reveal a perifollicular pigment network (honeycomb pattern) and pinpoint white dots that are regularly distributed between follicular units.

Common abnormalities seen on trichoscopy include central centrifugal cicatricial alopecia (CCCA), with one or two hairs emerging together, surrounded by a gray halo; lichen planopilaris/frontal fibrosing alopecia, characterized by hair with peripilar casts and absence of vellus hairs; discoid lupus erythematosus, characterized by keratotic plugs; and traction, characterized by hair casts.

Once a diagnosis is confirmed, Dr. Luke provides other general advice for optimal skin health, including a balanced (whole food) diet to ensure adequate nutrition. “I tend to find a lot of nutrient deficiencies that contribute to and compound their condition,” she said. Other recommendations include avoiding excess tension on the hair, such as hair styles with tight ponytails, buns, braids, and weaves; avoiding or limiting chemical treatments with hair color, relaxers, and permanents; and avoiding or limiting excessive heat styling with blow dryers, flat irons, and curling irons.


 

Photoprotection misconceptions

At the meeting, Dr. Luke also discussed three misconceptions of photoprotection in skin of color, drawn from an article on the topic published in 2021.

• Myth No. 1: Endogenous melanin provides complete photoprotection for Fitzpatrick skin types IV-V. Many people with skin of color may believe sunscreen is not needed given the melanin already present in their skin, but research has shown that the epidermis of dark skin has an intrinsic sun protection factor (SPF) of 13.4, compared with an SPF of 3.3 in light skin. “That may not provide them with full protection,” Dr. Luke said. “Many dermatologists are not counseling their skin of color patients about photoprotection.”
• Myth No. 2: Individuals with skin of color have negligible risks associated with skin cancer. Skin cancer prevalence in patients with skin of color is significantly lower compared with those with light skin. However, people with skin of color tend to be diagnosed with cancers at a more advanced stage, and cancers associated with a worse prognosis and poorer survival rate. An analysis of ethnic differences among patients with cutaneous melanoma that drew from the Surveillance, Epidemiology, and End Results (SEER) program found that Hispanic individuals (odds ratio [OR], 3.6), Black individuals (OR, 4.2), and Asian individuals (OR, 2.4), were more likely than were White individuals to have stage IV melanoma at the time of presentation. “For melanoma in skin of color, UV radiation does not seem to be a major risk factor, as melanoma tends to occur on palmar/plantar and subungual skin as well as mucous membranes,” Dr. Luke said. “For squamous cell carcinoma in skin of color, lesions are more likely to be present in areas that are not sun exposed. The risk factors for this tend to be chronic wounds, nonhealing ulcers, and people with chronic inflammatory conditions.” For basal cell carcinoma, she added, UV radiation seems to play more of a role and tends to occur in sun-exposed areas in patients with lighter Fitzpatrick skin types. Patients are more likely to present with pigmented BCCs.

• Myth No. 3: Broad-spectrum sunscreens provide photoprotection against all wavelengths of light that cause skin damage. To be labeled “broad-spectrum” the Food and Drug Administration requires that sunscreens have a critical wavelength of 370 nm or below, but Dr. Luke noted that broad-spectrum sunscreens do not necessarily protect against visible light (VL) and UV-A1. Research has demonstrated that VL exposure induces both transient and long-term cutaneous pigmentation in a dose-dependent manner.

“This induces free radicals and reactive oxygen species, leading to a cascade of events including the induction of pro-inflammatory cytokines, matrix metalloproteinases, and melanogenesis,” she said. “More intense and persistent VL-induced pigmentation occurs in subjects with darker skin. However, there is increasing evidence that antioxidants may help to mitigate these negative effects, so we are starting to see the addition of antioxidants into sunscreens.”

Dr. Luke recommends a broad-spectrum sunscreen with an SPF of 30 or higher for skin of color patients. Tinted sunscreens, which contain iron oxide pigments, are recommended for the prevention and treatment of pigmentary disorders in patients with Fitzpatrick skin types IV-VI skin. “What about adding antioxidants to prevent formation of reactive oxygen species?” she asked. “It’s possible but we don’t have a lot of research yet. You also want a sunscreen that’s aesthetically elegant, meaning it doesn’t leave a white cast.”

Dr. Luke reported having no relevant disclosures.

PORTLAND, ORE. – When individuals with skin of color seek help from dermatologists to optimize the treatment and management of scalp and hair disorders, they expect them to understand their concerns, but sometimes their doctors fall short.

“Many times, you may not have race concordant visits with patients of color,” Janiene Luke, MD, said at the annual meeting of the Pacific Dermatologic Association. She referred to a survey of 200 Black women aged 21-83 years, which found that 28% had visited a physician to discuss hair or scalp issues. Of those, 68% felt like their dermatologists did not understand African American hair.

“I recommend trying the best you can to familiarize yourself with various common cultural hair styling methods and practices in patients of color. It’s important to understand what your patients are engaging in and the types of styles they’re using,” said Dr. Luke, associate professor of dermatology at Loma Linda (Calif.) University. “Approach all patients with cultural humility. We know from studies that patients value dermatologists who take time to listen to their concerns, involve them in the decision-making process, and educate them about their conditions,” she added.

National efforts to educate clinicians on treating skin of color have emerged in recent years, including textbooks, CME courses at dermatology conferences, and the American Academy of Dermatology’s Skin of Color Curriculum, which consists of 15-minute modules that can be viewed online.

At the meeting, Dr. Luke, shared her approach to assessing hair and scalp disorders in skin of color. She begins by taking a thorough history, “because not all things that are associated with hair styling will be the reason why your patient comes in,” she said. “Patients of color can have telogen effluvium and seborrheic dermatitis just like anyone else. I ask about the hair styling practices they use. I also ask how often they wash their hair, because sometimes our recommendations for treatment are not realistic based on their current routine.”

Next, she examines the scalp with her hands – which sometimes surprises patients. “I’ve had so many patients come in and say, ‘the dermatologist never touched my scalp,’ or ‘they never even looked at my hair,’ ” said Dr. Luke, who directs the university’s dermatology residency program. She asks patients to remove any hair extensions or weaves prior to the office visit and to remove wigs prior to the exam itself. The lab tests she customarily orders include CBC, TSH, iron, total iron binding capacity, ferritin, vitamin D, and zinc. If there are signs of androgen excess, she may check testosterone, sex hormone binding globulin, and dehydroepiandrosterone sulfate (DHEA-S). She routinely incorporates a dermoscopy-directed biopsy into the evaluation.

Dr. Luke examines the patient from above, the sides, and the back to assess the pattern/distribution of hair loss. A visible scalp at the vertex indicates a 50% reduction in normal hair density. “I’m looking at the hairline, their part width, and the length of their hair,” she said. “I also look at the eyebrows and eyelashes, because these can be involved in alopecia areata, frontal fibrosing alopecia, or congenital hair shaft disorders.”

On closeup examination, she looks for scarring versus non-scarring types of hair loss, and for the presence or absence of follicular ostia. “I also look at hair changes,” she said. “Is the texture of their hair different? Are there signs of breakage or fragility? It’s been noted in studies that breakage can be an early sign of central centrifugal cicatricial alopecia.” (For more tips on examining tightly coiled hair among patients with hair loss in race discordant patient-physician interactions, she recommended a 2021 article in JAMA Dermatology)..

Trichoscopy allows for magnified observation of the hair shafts, hair follicle openings, perifollicular dermis, and blood vessels. Normal trichoscopy findings in skin of color reveal a perifollicular pigment network (honeycomb pattern) and pinpoint white dots that are regularly distributed between follicular units.

Common abnormalities seen on trichoscopy include central centrifugal cicatricial alopecia (CCCA), with one or two hairs emerging together, surrounded by a gray halo; lichen planopilaris/frontal fibrosing alopecia, characterized by hair with peripilar casts and absence of vellus hairs; discoid lupus erythematosus, characterized by keratotic plugs; and traction, characterized by hair casts.

Once a diagnosis is confirmed, Dr. Luke provides other general advice for optimal skin health, including a balanced (whole food) diet to ensure adequate nutrition. “I tend to find a lot of nutrient deficiencies that contribute to and compound their condition,” she said. Other recommendations include avoiding excess tension on the hair, such as hair styles with tight ponytails, buns, braids, and weaves; avoiding or limiting chemical treatments with hair color, relaxers, and permanents; and avoiding or limiting excessive heat styling with blow dryers, flat irons, and curling irons.


 

Photoprotection misconceptions

At the meeting, Dr. Luke also discussed three misconceptions of photoprotection in skin of color, drawn from an article on the topic published in 2021.

• Myth No. 1: Endogenous melanin provides complete photoprotection for Fitzpatrick skin types IV-V. Many people with skin of color may believe sunscreen is not needed given the melanin already present in their skin, but research has shown that the epidermis of dark skin has an intrinsic sun protection factor (SPF) of 13.4, compared with an SPF of 3.3 in light skin. “That may not provide them with full protection,” Dr. Luke said. “Many dermatologists are not counseling their skin of color patients about photoprotection.”
• Myth No. 2: Individuals with skin of color have negligible risks associated with skin cancer. Skin cancer prevalence in patients with skin of color is significantly lower compared with those with light skin. However, people with skin of color tend to be diagnosed with cancers at a more advanced stage, and cancers associated with a worse prognosis and poorer survival rate. An analysis of ethnic differences among patients with cutaneous melanoma that drew from the Surveillance, Epidemiology, and End Results (SEER) program found that Hispanic individuals (odds ratio [OR], 3.6), Black individuals (OR, 4.2), and Asian individuals (OR, 2.4), were more likely than were White individuals to have stage IV melanoma at the time of presentation. “For melanoma in skin of color, UV radiation does not seem to be a major risk factor, as melanoma tends to occur on palmar/plantar and subungual skin as well as mucous membranes,” Dr. Luke said. “For squamous cell carcinoma in skin of color, lesions are more likely to be present in areas that are not sun exposed. The risk factors for this tend to be chronic wounds, nonhealing ulcers, and people with chronic inflammatory conditions.” For basal cell carcinoma, she added, UV radiation seems to play more of a role and tends to occur in sun-exposed areas in patients with lighter Fitzpatrick skin types. Patients are more likely to present with pigmented BCCs.

• Myth No. 3: Broad-spectrum sunscreens provide photoprotection against all wavelengths of light that cause skin damage. To be labeled “broad-spectrum” the Food and Drug Administration requires that sunscreens have a critical wavelength of 370 nm or below, but Dr. Luke noted that broad-spectrum sunscreens do not necessarily protect against visible light (VL) and UV-A1. Research has demonstrated that VL exposure induces both transient and long-term cutaneous pigmentation in a dose-dependent manner.

“This induces free radicals and reactive oxygen species, leading to a cascade of events including the induction of pro-inflammatory cytokines, matrix metalloproteinases, and melanogenesis,” she said. “More intense and persistent VL-induced pigmentation occurs in subjects with darker skin. However, there is increasing evidence that antioxidants may help to mitigate these negative effects, so we are starting to see the addition of antioxidants into sunscreens.”

Dr. Luke recommends a broad-spectrum sunscreen with an SPF of 30 or higher for skin of color patients. Tinted sunscreens, which contain iron oxide pigments, are recommended for the prevention and treatment of pigmentary disorders in patients with Fitzpatrick skin types IV-VI skin. “What about adding antioxidants to prevent formation of reactive oxygen species?” she asked. “It’s possible but we don’t have a lot of research yet. You also want a sunscreen that’s aesthetically elegant, meaning it doesn’t leave a white cast.”

Dr. Luke reported having no relevant disclosures.

PORTLAND, ORE. – When individuals with skin of color seek help from dermatologists to optimize the treatment and management of scalp and hair disorders, they expect them to understand their concerns, but sometimes their doctors fall short.

“Many times, you may not have race concordant visits with patients of color,” Janiene Luke, MD, said at the annual meeting of the Pacific Dermatologic Association. She referred to a survey of 200 Black women aged 21-83 years, which found that 28% had visited a physician to discuss hair or scalp issues. Of those, 68% felt like their dermatologists did not understand African American hair.

“I recommend trying the best you can to familiarize yourself with various common cultural hair styling methods and practices in patients of color. It’s important to understand what your patients are engaging in and the types of styles they’re using,” said Dr. Luke, associate professor of dermatology at Loma Linda (Calif.) University. “Approach all patients with cultural humility. We know from studies that patients value dermatologists who take time to listen to their concerns, involve them in the decision-making process, and educate them about their conditions,” she added.

National efforts to educate clinicians on treating skin of color have emerged in recent years, including textbooks, CME courses at dermatology conferences, and the American Academy of Dermatology’s Skin of Color Curriculum, which consists of 15-minute modules that can be viewed online.

At the meeting, Dr. Luke, shared her approach to assessing hair and scalp disorders in skin of color. She begins by taking a thorough history, “because not all things that are associated with hair styling will be the reason why your patient comes in,” she said. “Patients of color can have telogen effluvium and seborrheic dermatitis just like anyone else. I ask about the hair styling practices they use. I also ask how often they wash their hair, because sometimes our recommendations for treatment are not realistic based on their current routine.”

Next, she examines the scalp with her hands – which sometimes surprises patients. “I’ve had so many patients come in and say, ‘the dermatologist never touched my scalp,’ or ‘they never even looked at my hair,’ ” said Dr. Luke, who directs the university’s dermatology residency program. She asks patients to remove any hair extensions or weaves prior to the office visit and to remove wigs prior to the exam itself. The lab tests she customarily orders include CBC, TSH, iron, total iron binding capacity, ferritin, vitamin D, and zinc. If there are signs of androgen excess, she may check testosterone, sex hormone binding globulin, and dehydroepiandrosterone sulfate (DHEA-S). She routinely incorporates a dermoscopy-directed biopsy into the evaluation.

Dr. Luke examines the patient from above, the sides, and the back to assess the pattern/distribution of hair loss. A visible scalp at the vertex indicates a 50% reduction in normal hair density. “I’m looking at the hairline, their part width, and the length of their hair,” she said. “I also look at the eyebrows and eyelashes, because these can be involved in alopecia areata, frontal fibrosing alopecia, or congenital hair shaft disorders.”

On closeup examination, she looks for scarring versus non-scarring types of hair loss, and for the presence or absence of follicular ostia. “I also look at hair changes,” she said. “Is the texture of their hair different? Are there signs of breakage or fragility? It’s been noted in studies that breakage can be an early sign of central centrifugal cicatricial alopecia.” (For more tips on examining tightly coiled hair among patients with hair loss in race discordant patient-physician interactions, she recommended a 2021 article in JAMA Dermatology)..

Trichoscopy allows for magnified observation of the hair shafts, hair follicle openings, perifollicular dermis, and blood vessels. Normal trichoscopy findings in skin of color reveal a perifollicular pigment network (honeycomb pattern) and pinpoint white dots that are regularly distributed between follicular units.

Common abnormalities seen on trichoscopy include central centrifugal cicatricial alopecia (CCCA), with one or two hairs emerging together, surrounded by a gray halo; lichen planopilaris/frontal fibrosing alopecia, characterized by hair with peripilar casts and absence of vellus hairs; discoid lupus erythematosus, characterized by keratotic plugs; and traction, characterized by hair casts.

Once a diagnosis is confirmed, Dr. Luke provides other general advice for optimal skin health, including a balanced (whole food) diet to ensure adequate nutrition. “I tend to find a lot of nutrient deficiencies that contribute to and compound their condition,” she said. Other recommendations include avoiding excess tension on the hair, such as hair styles with tight ponytails, buns, braids, and weaves; avoiding or limiting chemical treatments with hair color, relaxers, and permanents; and avoiding or limiting excessive heat styling with blow dryers, flat irons, and curling irons.


 

Photoprotection misconceptions

At the meeting, Dr. Luke also discussed three misconceptions of photoprotection in skin of color, drawn from an article on the topic published in 2021.

• Myth No. 1: Endogenous melanin provides complete photoprotection for Fitzpatrick skin types IV-V. Many people with skin of color may believe sunscreen is not needed given the melanin already present in their skin, but research has shown that the epidermis of dark skin has an intrinsic sun protection factor (SPF) of 13.4, compared with an SPF of 3.3 in light skin. “That may not provide them with full protection,” Dr. Luke said. “Many dermatologists are not counseling their skin of color patients about photoprotection.”
• Myth No. 2: Individuals with skin of color have negligible risks associated with skin cancer. Skin cancer prevalence in patients with skin of color is significantly lower compared with those with light skin. However, people with skin of color tend to be diagnosed with cancers at a more advanced stage, and cancers associated with a worse prognosis and poorer survival rate. An analysis of ethnic differences among patients with cutaneous melanoma that drew from the Surveillance, Epidemiology, and End Results (SEER) program found that Hispanic individuals (odds ratio [OR], 3.6), Black individuals (OR, 4.2), and Asian individuals (OR, 2.4), were more likely than were White individuals to have stage IV melanoma at the time of presentation. “For melanoma in skin of color, UV radiation does not seem to be a major risk factor, as melanoma tends to occur on palmar/plantar and subungual skin as well as mucous membranes,” Dr. Luke said. “For squamous cell carcinoma in skin of color, lesions are more likely to be present in areas that are not sun exposed. The risk factors for this tend to be chronic wounds, nonhealing ulcers, and people with chronic inflammatory conditions.” For basal cell carcinoma, she added, UV radiation seems to play more of a role and tends to occur in sun-exposed areas in patients with lighter Fitzpatrick skin types. Patients are more likely to present with pigmented BCCs.

• Myth No. 3: Broad-spectrum sunscreens provide photoprotection against all wavelengths of light that cause skin damage. To be labeled “broad-spectrum” the Food and Drug Administration requires that sunscreens have a critical wavelength of 370 nm or below, but Dr. Luke noted that broad-spectrum sunscreens do not necessarily protect against visible light (VL) and UV-A1. Research has demonstrated that VL exposure induces both transient and long-term cutaneous pigmentation in a dose-dependent manner.

“This induces free radicals and reactive oxygen species, leading to a cascade of events including the induction of pro-inflammatory cytokines, matrix metalloproteinases, and melanogenesis,” she said. “More intense and persistent VL-induced pigmentation occurs in subjects with darker skin. However, there is increasing evidence that antioxidants may help to mitigate these negative effects, so we are starting to see the addition of antioxidants into sunscreens.”

Dr. Luke recommends a broad-spectrum sunscreen with an SPF of 30 or higher for skin of color patients. Tinted sunscreens, which contain iron oxide pigments, are recommended for the prevention and treatment of pigmentary disorders in patients with Fitzpatrick skin types IV-VI skin. “What about adding antioxidants to prevent formation of reactive oxygen species?” she asked. “It’s possible but we don’t have a lot of research yet. You also want a sunscreen that’s aesthetically elegant, meaning it doesn’t leave a white cast.”

Dr. Luke reported having no relevant disclosures.

People who use skin-lightening products that contain hydroquinone may be at an increased risk for skin cancers, an analysis of records from a large research database suggests.

In the study, hydroquinone use was associated with an approximately threefold increase for skin cancer risk, coauthor Brittany Miles, a fourth-year medical student at the University of Texas Medical Branch at Galveston’s John Sealy School of Medicine, told this news organization. “The magnitude of the risk was surprising. Increased risk should be disclosed to patients considering hydroquinone treatment.”

courtesy John Sealy School of Medicine

The results of the study were presented in a poster at the annual meeting of the Society for Investigative Dermatology.

Hydroquinone (multiple brand names), a tyrosinase inhibitor used worldwide for skin lightening because of its inhibition of melanin production, was once considered “generally safe and effective” by the Food and Drug Administration, the authors wrote.

The compound’s use in over-the-counter products in the United States has been restricted based on suspicion of carcinogenicity, but few human studies have been conducted. In April, the FDA issued warning letters to 12 companies that sold hydroquinone in concentrations not generally recognized as safe and effective, because of other concerns including rashes, facial swelling, and ochronosis (skin discoloration).

Ms. Miles and her coauthor, Michael Wilkerson, MD, professor and chair of the department of dermatology at UTMB, analyzed data from TriNetX, the medical research database of anonymized medical record information from 61 million patients in 57 large health care organizations, almost all of them in the United States.

LAGUNA DESIGN/Science Photo Library/Getty Images

The researchers created two cohorts of patients aged 15 years and older with no prior diagnosis of skin cancer: one group had been treated with hydroquinone (medication code 5509 in the TriNetX system), and the other had not been exposed to the drug. Using ICD-10 codes for melanoma, nonmelanoma skin cancer, and all skin cancers, they investigated which groups of people were likely to develop these cancers.

They found that hydroquinone exposure was linked with a significant increase in melanoma (relative risk, 3.0; 95% confidence interval, 1.704-5.281; P < .0001), nonmelanoma skin cancers (RR, 3.6; 95%; CI, 2.815-4.561; P < .0001), and all reported skin cancers combined (relative risk, 3.4; 95% CI, 2.731-4.268; P < .0001)

While “the source of the data and the number of patients in the study are significant strengths,” Ms. Miles said, “the inability to determine how long and how consistently the patients used hydroquinone is likely the biggest weakness.”
 

Skin lightening is big business and more research is needed

“The U.S. market for skin-lightening agents was approximately 330 million dollars in 2021, and 330,000 prescriptions containing hydroquinone were dispensed in 2019,” Ms. Miles said.

Valencia D. Thomas, MD, professor in the department of dermatology of the University of Texas MD Anderson Cancer Center, Houston, said in an email that over-the-counter skin-lightening products containing low-concentration hydroquinone are in widespread use and are commonly used in populations of color.

“Hydroquinone preparations in higher concentrations are unfortunately also available in the United States,” added Dr. Thomas, who was not involved in the study and referred to the FDA warning letter issued in April.

Only one hydroquinone-containing medication – Tri-Luma at 4% concentration, used to treat melasma – is currently FDA-approved, she said.

The data in the study do not show an increased risk for skin cancer with hydroquinone exposure, but do show “an increased risk of cancer in the TriNetX medication code 5509 hydroquinone exposure group, which does not prove causation,” Dr. Thomas commented.

“Because ‘hydroquinone exposure’ is not defined, it is unclear how TriNetX identified the hydroquinone exposure cohort,” she noted. “Does ‘exposure’ count prescriptions written and potentially not used, the use of hydroquinone products of high concentration not approved by the FDA, or the use of over-the-counter hydroquinone products?

“The strength of this study is its size,” Dr. Thomas acknowledged. “This study is a wonderful starting point to further investigate the ‘hydroquinone exposure’ cohort to determine if hydroquinone is a driver of cancer, or if hydroquinone is itself a confounder.”

These results highlight the need to examine the social determinants of health that may explain increased risk for cancer, including race, geography, and poverty, she added.

“Given the global consumption of hydroquinone, multinational collaboration investigating hydroquinone and cancer data will likely be needed to provide insight into this continuing question,” Dr. Thomas advised.

Christiane Querfeld, MD, PhD, associate professor of dermatology and dermatopathology at City of Hope in Duarte, Calif., agreed that the occurrence of skin cancer following use of hydroquinone is largely understudied.

Courtesy City of Hope

“The findings have a huge impact on how we counsel and monitor future patients,” Dr. Querfeld, who also was not involved in the study, said in an email. “There may be a trade-off at the start of treatment: Get rid of melasma but develop a skin cancer or melanoma with potentially severe outcomes.

“It remains to be seen if there is a higher incidence of skin cancer following use of hydroquinone or other voluntary bleaching and depigmentation remedies in ethnic groups such as African American or Hispanic patient populations, who have historically been at low risk of developing skin cancer,” she added. “It also remains to be seen if increased risk is due to direct effects or to indirect effects on already-photodamaged skin.

“These data are critical, and I am sure this will open further investigations to study effects in more detail,” Dr. Querfeld said.

The study authors, Dr. Thomas, and Dr. Querfeld reported no relevant financial relationships. The study did not receive external funding.

A version of this article first appeared on Medscape.com.

People who use skin-lightening products that contain hydroquinone may be at an increased risk for skin cancers, an analysis of records from a large research database suggests.

In the study, hydroquinone use was associated with an approximately threefold increase for skin cancer risk, coauthor Brittany Miles, a fourth-year medical student at the University of Texas Medical Branch at Galveston’s John Sealy School of Medicine, told this news organization. “The magnitude of the risk was surprising. Increased risk should be disclosed to patients considering hydroquinone treatment.”

courtesy John Sealy School of Medicine

The results of the study were presented in a poster at the annual meeting of the Society for Investigative Dermatology.

Hydroquinone (multiple brand names), a tyrosinase inhibitor used worldwide for skin lightening because of its inhibition of melanin production, was once considered “generally safe and effective” by the Food and Drug Administration, the authors wrote.

The compound’s use in over-the-counter products in the United States has been restricted based on suspicion of carcinogenicity, but few human studies have been conducted. In April, the FDA issued warning letters to 12 companies that sold hydroquinone in concentrations not generally recognized as safe and effective, because of other concerns including rashes, facial swelling, and ochronosis (skin discoloration).

Ms. Miles and her coauthor, Michael Wilkerson, MD, professor and chair of the department of dermatology at UTMB, analyzed data from TriNetX, the medical research database of anonymized medical record information from 61 million patients in 57 large health care organizations, almost all of them in the United States.

LAGUNA DESIGN/Science Photo Library/Getty Images

The researchers created two cohorts of patients aged 15 years and older with no prior diagnosis of skin cancer: one group had been treated with hydroquinone (medication code 5509 in the TriNetX system), and the other had not been exposed to the drug. Using ICD-10 codes for melanoma, nonmelanoma skin cancer, and all skin cancers, they investigated which groups of people were likely to develop these cancers.

They found that hydroquinone exposure was linked with a significant increase in melanoma (relative risk, 3.0; 95% confidence interval, 1.704-5.281; P < .0001), nonmelanoma skin cancers (RR, 3.6; 95%; CI, 2.815-4.561; P < .0001), and all reported skin cancers combined (relative risk, 3.4; 95% CI, 2.731-4.268; P < .0001)

While “the source of the data and the number of patients in the study are significant strengths,” Ms. Miles said, “the inability to determine how long and how consistently the patients used hydroquinone is likely the biggest weakness.”
 

Skin lightening is big business and more research is needed

“The U.S. market for skin-lightening agents was approximately 330 million dollars in 2021, and 330,000 prescriptions containing hydroquinone were dispensed in 2019,” Ms. Miles said.

Valencia D. Thomas, MD, professor in the department of dermatology of the University of Texas MD Anderson Cancer Center, Houston, said in an email that over-the-counter skin-lightening products containing low-concentration hydroquinone are in widespread use and are commonly used in populations of color.

“Hydroquinone preparations in higher concentrations are unfortunately also available in the United States,” added Dr. Thomas, who was not involved in the study and referred to the FDA warning letter issued in April.

Only one hydroquinone-containing medication – Tri-Luma at 4% concentration, used to treat melasma – is currently FDA-approved, she said.

The data in the study do not show an increased risk for skin cancer with hydroquinone exposure, but do show “an increased risk of cancer in the TriNetX medication code 5509 hydroquinone exposure group, which does not prove causation,” Dr. Thomas commented.

“Because ‘hydroquinone exposure’ is not defined, it is unclear how TriNetX identified the hydroquinone exposure cohort,” she noted. “Does ‘exposure’ count prescriptions written and potentially not used, the use of hydroquinone products of high concentration not approved by the FDA, or the use of over-the-counter hydroquinone products?

“The strength of this study is its size,” Dr. Thomas acknowledged. “This study is a wonderful starting point to further investigate the ‘hydroquinone exposure’ cohort to determine if hydroquinone is a driver of cancer, or if hydroquinone is itself a confounder.”

These results highlight the need to examine the social determinants of health that may explain increased risk for cancer, including race, geography, and poverty, she added.

“Given the global consumption of hydroquinone, multinational collaboration investigating hydroquinone and cancer data will likely be needed to provide insight into this continuing question,” Dr. Thomas advised.

Christiane Querfeld, MD, PhD, associate professor of dermatology and dermatopathology at City of Hope in Duarte, Calif., agreed that the occurrence of skin cancer following use of hydroquinone is largely understudied.

Courtesy City of Hope

“The findings have a huge impact on how we counsel and monitor future patients,” Dr. Querfeld, who also was not involved in the study, said in an email. “There may be a trade-off at the start of treatment: Get rid of melasma but develop a skin cancer or melanoma with potentially severe outcomes.

“It remains to be seen if there is a higher incidence of skin cancer following use of hydroquinone or other voluntary bleaching and depigmentation remedies in ethnic groups such as African American or Hispanic patient populations, who have historically been at low risk of developing skin cancer,” she added. “It also remains to be seen if increased risk is due to direct effects or to indirect effects on already-photodamaged skin.

“These data are critical, and I am sure this will open further investigations to study effects in more detail,” Dr. Querfeld said.

The study authors, Dr. Thomas, and Dr. Querfeld reported no relevant financial relationships. The study did not receive external funding.

A version of this article first appeared on Medscape.com.

People who use skin-lightening products that contain hydroquinone may be at an increased risk for skin cancers, an analysis of records from a large research database suggests.

In the study, hydroquinone use was associated with an approximately threefold increase for skin cancer risk, coauthor Brittany Miles, a fourth-year medical student at the University of Texas Medical Branch at Galveston’s John Sealy School of Medicine, told this news organization. “The magnitude of the risk was surprising. Increased risk should be disclosed to patients considering hydroquinone treatment.”

courtesy John Sealy School of Medicine

The results of the study were presented in a poster at the annual meeting of the Society for Investigative Dermatology.

Hydroquinone (multiple brand names), a tyrosinase inhibitor used worldwide for skin lightening because of its inhibition of melanin production, was once considered “generally safe and effective” by the Food and Drug Administration, the authors wrote.

The compound’s use in over-the-counter products in the United States has been restricted based on suspicion of carcinogenicity, but few human studies have been conducted. In April, the FDA issued warning letters to 12 companies that sold hydroquinone in concentrations not generally recognized as safe and effective, because of other concerns including rashes, facial swelling, and ochronosis (skin discoloration).

Ms. Miles and her coauthor, Michael Wilkerson, MD, professor and chair of the department of dermatology at UTMB, analyzed data from TriNetX, the medical research database of anonymized medical record information from 61 million patients in 57 large health care organizations, almost all of them in the United States.

LAGUNA DESIGN/Science Photo Library/Getty Images

The researchers created two cohorts of patients aged 15 years and older with no prior diagnosis of skin cancer: one group had been treated with hydroquinone (medication code 5509 in the TriNetX system), and the other had not been exposed to the drug. Using ICD-10 codes for melanoma, nonmelanoma skin cancer, and all skin cancers, they investigated which groups of people were likely to develop these cancers.

They found that hydroquinone exposure was linked with a significant increase in melanoma (relative risk, 3.0; 95% confidence interval, 1.704-5.281; P < .0001), nonmelanoma skin cancers (RR, 3.6; 95%; CI, 2.815-4.561; P < .0001), and all reported skin cancers combined (relative risk, 3.4; 95% CI, 2.731-4.268; P < .0001)

While “the source of the data and the number of patients in the study are significant strengths,” Ms. Miles said, “the inability to determine how long and how consistently the patients used hydroquinone is likely the biggest weakness.”
 

Skin lightening is big business and more research is needed

“The U.S. market for skin-lightening agents was approximately 330 million dollars in 2021, and 330,000 prescriptions containing hydroquinone were dispensed in 2019,” Ms. Miles said.

Valencia D. Thomas, MD, professor in the department of dermatology of the University of Texas MD Anderson Cancer Center, Houston, said in an email that over-the-counter skin-lightening products containing low-concentration hydroquinone are in widespread use and are commonly used in populations of color.

“Hydroquinone preparations in higher concentrations are unfortunately also available in the United States,” added Dr. Thomas, who was not involved in the study and referred to the FDA warning letter issued in April.

Only one hydroquinone-containing medication – Tri-Luma at 4% concentration, used to treat melasma – is currently FDA-approved, she said.

The data in the study do not show an increased risk for skin cancer with hydroquinone exposure, but do show “an increased risk of cancer in the TriNetX medication code 5509 hydroquinone exposure group, which does not prove causation,” Dr. Thomas commented.

“Because ‘hydroquinone exposure’ is not defined, it is unclear how TriNetX identified the hydroquinone exposure cohort,” she noted. “Does ‘exposure’ count prescriptions written and potentially not used, the use of hydroquinone products of high concentration not approved by the FDA, or the use of over-the-counter hydroquinone products?

“The strength of this study is its size,” Dr. Thomas acknowledged. “This study is a wonderful starting point to further investigate the ‘hydroquinone exposure’ cohort to determine if hydroquinone is a driver of cancer, or if hydroquinone is itself a confounder.”

These results highlight the need to examine the social determinants of health that may explain increased risk for cancer, including race, geography, and poverty, she added.

“Given the global consumption of hydroquinone, multinational collaboration investigating hydroquinone and cancer data will likely be needed to provide insight into this continuing question,” Dr. Thomas advised.

Christiane Querfeld, MD, PhD, associate professor of dermatology and dermatopathology at City of Hope in Duarte, Calif., agreed that the occurrence of skin cancer following use of hydroquinone is largely understudied.

Courtesy City of Hope

“The findings have a huge impact on how we counsel and monitor future patients,” Dr. Querfeld, who also was not involved in the study, said in an email. “There may be a trade-off at the start of treatment: Get rid of melasma but develop a skin cancer or melanoma with potentially severe outcomes.

“It remains to be seen if there is a higher incidence of skin cancer following use of hydroquinone or other voluntary bleaching and depigmentation remedies in ethnic groups such as African American or Hispanic patient populations, who have historically been at low risk of developing skin cancer,” she added. “It also remains to be seen if increased risk is due to direct effects or to indirect effects on already-photodamaged skin.

“These data are critical, and I am sure this will open further investigations to study effects in more detail,” Dr. Querfeld said.

The study authors, Dr. Thomas, and Dr. Querfeld reported no relevant financial relationships. The study did not receive external funding.

A version of this article first appeared on Medscape.com.

PORTLAND, ORE. – In his nearly 2 decades of dermatology practice, Keith L. Duffy, MD, has seen his share of cases where Mohs surgery was misused or misappropriated.

“Appropriate use criteria in Mohs are near and dear to my heart,” Dr. Duffy, associate professor of dermatology at the University of Utah, Salt Lake City, said at the annual meeting of the Pacific Dermatologic Association. “I want to protect our specialty. I see patients who have dozens of skin cancers. I want to emphasize the long game of management in those patients. You have to think about the tumors in terms of decades.”

In 2012, an ad hoc task force from the American Academy of Dermatology (AAD), the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery developed appropriate use criteria (AUC) for 270 scenarios for which Mohs micrographic surgery (MMS) is frequently considered. The task force used a 9-point scale to rate each indication, as follows:

• A score of 7 to 9: The use of MMS is appropriate for the specific indication and is generally considered acceptable.
• A score of 4 to 6: The use of MMS is uncertain for the specific indication, although its use may be appropriate and acceptable.
• A score of 1 to 3: The use of MMS is inappropriate for the specific indication and is generally not considered acceptable.

These ratings were translated into a free Mohs Surgery Appropriate Use Criteria App developed by the AAD.

Subsequently, Dr. Duffy and colleagues retrospectively examined the University of Utah’s adherence to the Mohs AUC over the course of 3 months. Their analysis, published in 2015, included 1,026 nonmelanoma skin cancers in 724 patients. Of the 1,026 cancers, 350 (34.1%) were treated with MMS. Of these, 339 (96.9%) were deemed appropriate based on the AUC guidelines, 4 (1.1%) were deemed uncertain, and 7 (2%) were deemed inappropriate.

There were also 611 skin cancers that were not treated with Mohs but met criteria for treatment with Mohs. “Most of these were AUC 7 tumors,” Dr. Duffy said. “When I see an AUC 7 tumor, I give high consideration for certain anatomic locations, especially the lower leg, scalp, eyelid, genitalia, ear, hands, and feet. I also think about the patient’s age, the number of skin cancers, and histological characteristics. Consider the long game in management and remember that skin cancer patients can make a near infinite amount of skin cancers, so be conservative when excising skin cancers to preserve precious skin.”

In his opinion, full thickness wounds requiring sutures should be avoided on the scalp and lower leg, if possible. “Most carcinomas in these locations are superficial and not aggressive in immunocompetent patients,” said Dr. Duffy, who said he has had one patient in 12 years who was not a transplant patient who had a metastatic squamous cell carcinoma on the lower leg. “Postop complications can be totally avoided. I don’t worry about these patients bleeding or [about] dehiscence. They can go back and play golf the next day, so you save valuable skin where the real estate is precious. This underscores a practice pearl: Incorporate the Mohs AUC and consideration of anatomic location when considering the most appropriate treatment of skin cancers.”

He also advises dermatologists to consider the histopathologic characteristics of the tumor when treating skin cancers to reduce complications and save tissue, so that patients can resume their lifestyle. “When you read the pathology report, really think about what the dermatopathologist saw under the microscope,” said Dr. Duffy, who is an investigator at the University of Utah’s Huntsman Cancer Institute. He said that he is able to review the slides for 90% of his own cases before surgery. “I’m lucky that way, but if you have any questions, your dermatopathologist should be on speed dial.”

Ultimately, he concluded, proper selection of a treatment modality for a specific tumor and patient rules the day. “Tumors should be thought about in the context of the patient and not as a single or isolated cancer,” he said.

Dr. Duffy reported having no relevant disclosures.

PORTLAND, ORE. – In his nearly 2 decades of dermatology practice, Keith L. Duffy, MD, has seen his share of cases where Mohs surgery was misused or misappropriated.

“Appropriate use criteria in Mohs are near and dear to my heart,” Dr. Duffy, associate professor of dermatology at the University of Utah, Salt Lake City, said at the annual meeting of the Pacific Dermatologic Association. “I want to protect our specialty. I see patients who have dozens of skin cancers. I want to emphasize the long game of management in those patients. You have to think about the tumors in terms of decades.”

In 2012, an ad hoc task force from the American Academy of Dermatology (AAD), the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery developed appropriate use criteria (AUC) for 270 scenarios for which Mohs micrographic surgery (MMS) is frequently considered. The task force used a 9-point scale to rate each indication, as follows:

• A score of 7 to 9: The use of MMS is appropriate for the specific indication and is generally considered acceptable.
• A score of 4 to 6: The use of MMS is uncertain for the specific indication, although its use may be appropriate and acceptable.
• A score of 1 to 3: The use of MMS is inappropriate for the specific indication and is generally not considered acceptable.

These ratings were translated into a free Mohs Surgery Appropriate Use Criteria App developed by the AAD.

Subsequently, Dr. Duffy and colleagues retrospectively examined the University of Utah’s adherence to the Mohs AUC over the course of 3 months. Their analysis, published in 2015, included 1,026 nonmelanoma skin cancers in 724 patients. Of the 1,026 cancers, 350 (34.1%) were treated with MMS. Of these, 339 (96.9%) were deemed appropriate based on the AUC guidelines, 4 (1.1%) were deemed uncertain, and 7 (2%) were deemed inappropriate.

There were also 611 skin cancers that were not treated with Mohs but met criteria for treatment with Mohs. “Most of these were AUC 7 tumors,” Dr. Duffy said. “When I see an AUC 7 tumor, I give high consideration for certain anatomic locations, especially the lower leg, scalp, eyelid, genitalia, ear, hands, and feet. I also think about the patient’s age, the number of skin cancers, and histological characteristics. Consider the long game in management and remember that skin cancer patients can make a near infinite amount of skin cancers, so be conservative when excising skin cancers to preserve precious skin.”

In his opinion, full thickness wounds requiring sutures should be avoided on the scalp and lower leg, if possible. “Most carcinomas in these locations are superficial and not aggressive in immunocompetent patients,” said Dr. Duffy, who said he has had one patient in 12 years who was not a transplant patient who had a metastatic squamous cell carcinoma on the lower leg. “Postop complications can be totally avoided. I don’t worry about these patients bleeding or [about] dehiscence. They can go back and play golf the next day, so you save valuable skin where the real estate is precious. This underscores a practice pearl: Incorporate the Mohs AUC and consideration of anatomic location when considering the most appropriate treatment of skin cancers.”

He also advises dermatologists to consider the histopathologic characteristics of the tumor when treating skin cancers to reduce complications and save tissue, so that patients can resume their lifestyle. “When you read the pathology report, really think about what the dermatopathologist saw under the microscope,” said Dr. Duffy, who is an investigator at the University of Utah’s Huntsman Cancer Institute. He said that he is able to review the slides for 90% of his own cases before surgery. “I’m lucky that way, but if you have any questions, your dermatopathologist should be on speed dial.”

Ultimately, he concluded, proper selection of a treatment modality for a specific tumor and patient rules the day. “Tumors should be thought about in the context of the patient and not as a single or isolated cancer,” he said.

Dr. Duffy reported having no relevant disclosures.

PORTLAND, ORE. – In his nearly 2 decades of dermatology practice, Keith L. Duffy, MD, has seen his share of cases where Mohs surgery was misused or misappropriated.

“Appropriate use criteria in Mohs are near and dear to my heart,” Dr. Duffy, associate professor of dermatology at the University of Utah, Salt Lake City, said at the annual meeting of the Pacific Dermatologic Association. “I want to protect our specialty. I see patients who have dozens of skin cancers. I want to emphasize the long game of management in those patients. You have to think about the tumors in terms of decades.”

In 2012, an ad hoc task force from the American Academy of Dermatology (AAD), the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery developed appropriate use criteria (AUC) for 270 scenarios for which Mohs micrographic surgery (MMS) is frequently considered. The task force used a 9-point scale to rate each indication, as follows:

• A score of 7 to 9: The use of MMS is appropriate for the specific indication and is generally considered acceptable.
• A score of 4 to 6: The use of MMS is uncertain for the specific indication, although its use may be appropriate and acceptable.
• A score of 1 to 3: The use of MMS is inappropriate for the specific indication and is generally not considered acceptable.

These ratings were translated into a free Mohs Surgery Appropriate Use Criteria App developed by the AAD.

Subsequently, Dr. Duffy and colleagues retrospectively examined the University of Utah’s adherence to the Mohs AUC over the course of 3 months. Their analysis, published in 2015, included 1,026 nonmelanoma skin cancers in 724 patients. Of the 1,026 cancers, 350 (34.1%) were treated with MMS. Of these, 339 (96.9%) were deemed appropriate based on the AUC guidelines, 4 (1.1%) were deemed uncertain, and 7 (2%) were deemed inappropriate.

There were also 611 skin cancers that were not treated with Mohs but met criteria for treatment with Mohs. “Most of these were AUC 7 tumors,” Dr. Duffy said. “When I see an AUC 7 tumor, I give high consideration for certain anatomic locations, especially the lower leg, scalp, eyelid, genitalia, ear, hands, and feet. I also think about the patient’s age, the number of skin cancers, and histological characteristics. Consider the long game in management and remember that skin cancer patients can make a near infinite amount of skin cancers, so be conservative when excising skin cancers to preserve precious skin.”

In his opinion, full thickness wounds requiring sutures should be avoided on the scalp and lower leg, if possible. “Most carcinomas in these locations are superficial and not aggressive in immunocompetent patients,” said Dr. Duffy, who said he has had one patient in 12 years who was not a transplant patient who had a metastatic squamous cell carcinoma on the lower leg. “Postop complications can be totally avoided. I don’t worry about these patients bleeding or [about] dehiscence. They can go back and play golf the next day, so you save valuable skin where the real estate is precious. This underscores a practice pearl: Incorporate the Mohs AUC and consideration of anatomic location when considering the most appropriate treatment of skin cancers.”

He also advises dermatologists to consider the histopathologic characteristics of the tumor when treating skin cancers to reduce complications and save tissue, so that patients can resume their lifestyle. “When you read the pathology report, really think about what the dermatopathologist saw under the microscope,” said Dr. Duffy, who is an investigator at the University of Utah’s Huntsman Cancer Institute. He said that he is able to review the slides for 90% of his own cases before surgery. “I’m lucky that way, but if you have any questions, your dermatopathologist should be on speed dial.”

Ultimately, he concluded, proper selection of a treatment modality for a specific tumor and patient rules the day. “Tumors should be thought about in the context of the patient and not as a single or isolated cancer,” he said.

Dr. Duffy reported having no relevant disclosures.

Many dermatopathologists offering a second opinion about melanocytic skin lesions prefer to have access to the first diagnostic report, but a controlled trial demonstrates that this has a powerful influence on perception, diminishing the value and accuracy of an independent analysis.

In a novel effort to determine whether previous interpretations sway second opinions, 149 dermatopathologists were asked to read melanocytic skin biopsy specimens without access to the initial pathology report. A year or more later they read them again but now with access to the initial reading.

The study showed that the participants, independent of many variables, such as years of experience or frequency with which they offered second options, were more likely to upgrade or downgrade the severity of the specimens in accordance with the initial report even if their original reading was correct.

If the goal of a second dermatopathologist opinion is to obtain an independent diagnostic opinion, the message from this study is that they “should be blinded to first opinions,” according to the authors of this study, led by Joann G. Elmore, MD, professor of medicine, University of California, Los Angeles. The study was published online in JAMA Dermatology.
 

Two-phase study has 1-year washout

The study was conducted in two phases. In phase 1, a nationally representative sample of volunteer dermatopathologists performed 878 interpretations. In phase 2, conducted after a washout period of 12 months or more, the dermatopathologists read a random subset of the same cases evaluated in phase 1, but this time, unlike the first, they were first exposed to prior pathology reports.

Ultimately, “the dermatologists provided more than 5,000 interpretations of study cases, which was a big contribution of time,” Dr. Elmore said in an interview. Grateful for their critical contribution, she speculated that they were driven by the importance of the question being asked.

When categorized by the Melanocytic Pathology Assessment Tool (MPAT), which rates specimens from benign (class 1) to pT1b invasive melanoma (class 4), the influence of the prior report went in both directions, so that the likelihood of upgrading or downgrading went in accordance with the grading in the original dermatopathology report.

As a result, the risk of a less severe interpretation on the second relative to the first reading was 38% greater if the initial dermatopathology report had a lower grade (relative risk, 1.38; 95% confidence interval [CI], 1.19-1.59). The risk of upgrading the second report if the initial pathology report had a higher grade was increased by more than 50% (RR, 1.52; 95% CI, 1.34-1.73).

The greater likelihood of upgrading than downgrading is “understandable,” Dr. Elmore said. “I think this is consistent with the concern about missing something,” she explained.

According to Dr. Elmore, one of the greatest concerns regarding the bias imposed by the original pathology report is that the switch of opinions often went from one that was accurate to one that was inaccurate.

If the phase 1 diagnosis was accurate but upgraded in the phase 2 diagnosis, the risk of inaccuracy was almost doubled (RR, 1.96; 95% CI, 1.31-2.93). If the phase 1 report was inaccurate, the relative risk of changing the phase 2 diagnosis was still high but lower than if it was accurate (RR, 1.46; 95% CI, 1.27-1.68).

“That is, even when the phase 1 diagnoses agreed with the consensus reference diagnosis, they were swayed away from the correct diagnosis in phase 2 [when the initial pathology report characterized the specimen as higher grade],” Dr. Elmore reported.

Conversely, the risk of downgrading was about the same whether the phase 1 evaluation was accurate (RR, 1.37; 95% CI, 1.14-1.64) or inaccurate (RR 1.32; 95% CI, 1.07-1.64).

Downward and upward shifts in severity from an accurate diagnosis are concerning because of the likelihood they will lead to overtreatment or undertreatment. The problem, according to data from this study, is that dermatologists making a second opinion cannot judge their own susceptibility to being swayed by the original report.
 

Pathologists might be unaware of bias

At baseline, the participants were asked whether they thought they were influenced by the first interpretation when providing a second opinion. Although 69% acknowledged that they might be “somewhat influenced,” 31% maintained that they do not take initial reports into consideration. When the two groups were compared, the risk of downgrading was nearly identical. The risk of upgrading was lower in those claiming to disregard initial reports (RR, 1.29) relative to those who said they were “somewhat influenced” by a previous diagnosis (RR, 1.64), but the difference was not significant.

The actual risk of bias incurred by prior pathology reports might be greater than that captured in this study for several reasons, according to the investigators. They pointed out that all participants were experienced and board-certified and might therefore be expected to be more confident in their interpretations than an unselected group of dermatopathologists. In addition, participants might have been more careful in their interpretations knowing they were participating in a study.

“There are a lot of data to support the value of second opinions [in dermatopathology and other areas], but we need to consider the process of how they are being obtained,” Dr. Elmore said. “There needs to be a greater emphasis on providing an independent analysis.”

More than 60% of the dermatologists participating in this study reported that they agreed or strongly agreed with the premise that they prefer to have the original dermatopathology report when they offer a second opinion. Dr. Elmore said that the desire of those offering a second opinion to have as much information in front of them as possible is understandable, but the bias imposed by the original report weakens the value of the second opinion.
 

Blind reading of pathology reports needed

“These data suggest that seeing the original report sways opinions and that includes swaying opinions away from an accurate reading,” Dr. Elmore said. She thinks that for dermatopathologists to render a valuable and independent second opinion, the specimens should be examined “at least initially” without access to the first report.

The results of this study were not surprising to Vishal Anil Patel, MD, director of the Cutaneous Oncology Program, George Washington University Cancer Center, Washington. He made the point that physicians “are human first and foremost and not perfect machines.” As a result, he suggested bias and error are inevitable.

Although strategies to avoid bias are likely to offer some protection against inaccuracy, he said that diagnostic support tools such as artificial intelligence might be the right direction for improving inter- and intra-rater reliability.

Ruifeng Guo, MD, PhD, a consultant in the division of anatomic pathology at the Mayo Clinic, Rochester, Minn., agreed with the basic premise of the study, but he cautioned that restricting access to the initial pathology report might not always be the right approach.

It is true that “dermatopathologists providing a second opinion in diagnosing cutaneous melanoma are mostly unaware of the risk of bias if they read the initial pathology report,” said Dr. Guo, but restricting access comes with risks.

“There are also times critical information may be contained in the initial pathology report that needs to be considered when providing a second opinion consultation,” he noted. Ultimately, the decision to read or not read the initial report should be decided “on an individual basis.”

The study was funded by grants from the National Cancer Institute. Dr. Elmore, Dr. Patel, and Dr. Guo reported no relevant financial relationships. 

A version of this article first appeared on Medscape.com.

Many dermatopathologists offering a second opinion about melanocytic skin lesions prefer to have access to the first diagnostic report, but a controlled trial demonstrates that this has a powerful influence on perception, diminishing the value and accuracy of an independent analysis.

In a novel effort to determine whether previous interpretations sway second opinions, 149 dermatopathologists were asked to read melanocytic skin biopsy specimens without access to the initial pathology report. A year or more later they read them again but now with access to the initial reading.

The study showed that the participants, independent of many variables, such as years of experience or frequency with which they offered second options, were more likely to upgrade or downgrade the severity of the specimens in accordance with the initial report even if their original reading was correct.

If the goal of a second dermatopathologist opinion is to obtain an independent diagnostic opinion, the message from this study is that they “should be blinded to first opinions,” according to the authors of this study, led by Joann G. Elmore, MD, professor of medicine, University of California, Los Angeles. The study was published online in JAMA Dermatology.
 

Two-phase study has 1-year washout

The study was conducted in two phases. In phase 1, a nationally representative sample of volunteer dermatopathologists performed 878 interpretations. In phase 2, conducted after a washout period of 12 months or more, the dermatopathologists read a random subset of the same cases evaluated in phase 1, but this time, unlike the first, they were first exposed to prior pathology reports.

Ultimately, “the dermatologists provided more than 5,000 interpretations of study cases, which was a big contribution of time,” Dr. Elmore said in an interview. Grateful for their critical contribution, she speculated that they were driven by the importance of the question being asked.

When categorized by the Melanocytic Pathology Assessment Tool (MPAT), which rates specimens from benign (class 1) to pT1b invasive melanoma (class 4), the influence of the prior report went in both directions, so that the likelihood of upgrading or downgrading went in accordance with the grading in the original dermatopathology report.

As a result, the risk of a less severe interpretation on the second relative to the first reading was 38% greater if the initial dermatopathology report had a lower grade (relative risk, 1.38; 95% confidence interval [CI], 1.19-1.59). The risk of upgrading the second report if the initial pathology report had a higher grade was increased by more than 50% (RR, 1.52; 95% CI, 1.34-1.73).

The greater likelihood of upgrading than downgrading is “understandable,” Dr. Elmore said. “I think this is consistent with the concern about missing something,” she explained.

According to Dr. Elmore, one of the greatest concerns regarding the bias imposed by the original pathology report is that the switch of opinions often went from one that was accurate to one that was inaccurate.

If the phase 1 diagnosis was accurate but upgraded in the phase 2 diagnosis, the risk of inaccuracy was almost doubled (RR, 1.96; 95% CI, 1.31-2.93). If the phase 1 report was inaccurate, the relative risk of changing the phase 2 diagnosis was still high but lower than if it was accurate (RR, 1.46; 95% CI, 1.27-1.68).

“That is, even when the phase 1 diagnoses agreed with the consensus reference diagnosis, they were swayed away from the correct diagnosis in phase 2 [when the initial pathology report characterized the specimen as higher grade],” Dr. Elmore reported.

Conversely, the risk of downgrading was about the same whether the phase 1 evaluation was accurate (RR, 1.37; 95% CI, 1.14-1.64) or inaccurate (RR 1.32; 95% CI, 1.07-1.64).

Downward and upward shifts in severity from an accurate diagnosis are concerning because of the likelihood they will lead to overtreatment or undertreatment. The problem, according to data from this study, is that dermatologists making a second opinion cannot judge their own susceptibility to being swayed by the original report.
 

Pathologists might be unaware of bias

At baseline, the participants were asked whether they thought they were influenced by the first interpretation when providing a second opinion. Although 69% acknowledged that they might be “somewhat influenced,” 31% maintained that they do not take initial reports into consideration. When the two groups were compared, the risk of downgrading was nearly identical. The risk of upgrading was lower in those claiming to disregard initial reports (RR, 1.29) relative to those who said they were “somewhat influenced” by a previous diagnosis (RR, 1.64), but the difference was not significant.

The actual risk of bias incurred by prior pathology reports might be greater than that captured in this study for several reasons, according to the investigators. They pointed out that all participants were experienced and board-certified and might therefore be expected to be more confident in their interpretations than an unselected group of dermatopathologists. In addition, participants might have been more careful in their interpretations knowing they were participating in a study.

“There are a lot of data to support the value of second opinions [in dermatopathology and other areas], but we need to consider the process of how they are being obtained,” Dr. Elmore said. “There needs to be a greater emphasis on providing an independent analysis.”

More than 60% of the dermatologists participating in this study reported that they agreed or strongly agreed with the premise that they prefer to have the original dermatopathology report when they offer a second opinion. Dr. Elmore said that the desire of those offering a second opinion to have as much information in front of them as possible is understandable, but the bias imposed by the original report weakens the value of the second opinion.
 

Blind reading of pathology reports needed

“These data suggest that seeing the original report sways opinions and that includes swaying opinions away from an accurate reading,” Dr. Elmore said. She thinks that for dermatopathologists to render a valuable and independent second opinion, the specimens should be examined “at least initially” without access to the first report.

The results of this study were not surprising to Vishal Anil Patel, MD, director of the Cutaneous Oncology Program, George Washington University Cancer Center, Washington. He made the point that physicians “are human first and foremost and not perfect machines.” As a result, he suggested bias and error are inevitable.

Although strategies to avoid bias are likely to offer some protection against inaccuracy, he said that diagnostic support tools such as artificial intelligence might be the right direction for improving inter- and intra-rater reliability.

Ruifeng Guo, MD, PhD, a consultant in the division of anatomic pathology at the Mayo Clinic, Rochester, Minn., agreed with the basic premise of the study, but he cautioned that restricting access to the initial pathology report might not always be the right approach.

It is true that “dermatopathologists providing a second opinion in diagnosing cutaneous melanoma are mostly unaware of the risk of bias if they read the initial pathology report,” said Dr. Guo, but restricting access comes with risks.

“There are also times critical information may be contained in the initial pathology report that needs to be considered when providing a second opinion consultation,” he noted. Ultimately, the decision to read or not read the initial report should be decided “on an individual basis.”

The study was funded by grants from the National Cancer Institute. Dr. Elmore, Dr. Patel, and Dr. Guo reported no relevant financial relationships. 

A version of this article first appeared on Medscape.com.

Many dermatopathologists offering a second opinion about melanocytic skin lesions prefer to have access to the first diagnostic report, but a controlled trial demonstrates that this has a powerful influence on perception, diminishing the value and accuracy of an independent analysis.

In a novel effort to determine whether previous interpretations sway second opinions, 149 dermatopathologists were asked to read melanocytic skin biopsy specimens without access to the initial pathology report. A year or more later they read them again but now with access to the initial reading.

The study showed that the participants, independent of many variables, such as years of experience or frequency with which they offered second options, were more likely to upgrade or downgrade the severity of the specimens in accordance with the initial report even if their original reading was correct.

If the goal of a second dermatopathologist opinion is to obtain an independent diagnostic opinion, the message from this study is that they “should be blinded to first opinions,” according to the authors of this study, led by Joann G. Elmore, MD, professor of medicine, University of California, Los Angeles. The study was published online in JAMA Dermatology.
 

Two-phase study has 1-year washout

The study was conducted in two phases. In phase 1, a nationally representative sample of volunteer dermatopathologists performed 878 interpretations. In phase 2, conducted after a washout period of 12 months or more, the dermatopathologists read a random subset of the same cases evaluated in phase 1, but this time, unlike the first, they were first exposed to prior pathology reports.

Ultimately, “the dermatologists provided more than 5,000 interpretations of study cases, which was a big contribution of time,” Dr. Elmore said in an interview. Grateful for their critical contribution, she speculated that they were driven by the importance of the question being asked.

When categorized by the Melanocytic Pathology Assessment Tool (MPAT), which rates specimens from benign (class 1) to pT1b invasive melanoma (class 4), the influence of the prior report went in both directions, so that the likelihood of upgrading or downgrading went in accordance with the grading in the original dermatopathology report.

As a result, the risk of a less severe interpretation on the second relative to the first reading was 38% greater if the initial dermatopathology report had a lower grade (relative risk, 1.38; 95% confidence interval [CI], 1.19-1.59). The risk of upgrading the second report if the initial pathology report had a higher grade was increased by more than 50% (RR, 1.52; 95% CI, 1.34-1.73).

The greater likelihood of upgrading than downgrading is “understandable,” Dr. Elmore said. “I think this is consistent with the concern about missing something,” she explained.

According to Dr. Elmore, one of the greatest concerns regarding the bias imposed by the original pathology report is that the switch of opinions often went from one that was accurate to one that was inaccurate.

If the phase 1 diagnosis was accurate but upgraded in the phase 2 diagnosis, the risk of inaccuracy was almost doubled (RR, 1.96; 95% CI, 1.31-2.93). If the phase 1 report was inaccurate, the relative risk of changing the phase 2 diagnosis was still high but lower than if it was accurate (RR, 1.46; 95% CI, 1.27-1.68).

“That is, even when the phase 1 diagnoses agreed with the consensus reference diagnosis, they were swayed away from the correct diagnosis in phase 2 [when the initial pathology report characterized the specimen as higher grade],” Dr. Elmore reported.

Conversely, the risk of downgrading was about the same whether the phase 1 evaluation was accurate (RR, 1.37; 95% CI, 1.14-1.64) or inaccurate (RR 1.32; 95% CI, 1.07-1.64).

Downward and upward shifts in severity from an accurate diagnosis are concerning because of the likelihood they will lead to overtreatment or undertreatment. The problem, according to data from this study, is that dermatologists making a second opinion cannot judge their own susceptibility to being swayed by the original report.
 

Pathologists might be unaware of bias

At baseline, the participants were asked whether they thought they were influenced by the first interpretation when providing a second opinion. Although 69% acknowledged that they might be “somewhat influenced,” 31% maintained that they do not take initial reports into consideration. When the two groups were compared, the risk of downgrading was nearly identical. The risk of upgrading was lower in those claiming to disregard initial reports (RR, 1.29) relative to those who said they were “somewhat influenced” by a previous diagnosis (RR, 1.64), but the difference was not significant.

The actual risk of bias incurred by prior pathology reports might be greater than that captured in this study for several reasons, according to the investigators. They pointed out that all participants were experienced and board-certified and might therefore be expected to be more confident in their interpretations than an unselected group of dermatopathologists. In addition, participants might have been more careful in their interpretations knowing they were participating in a study.

“There are a lot of data to support the value of second opinions [in dermatopathology and other areas], but we need to consider the process of how they are being obtained,” Dr. Elmore said. “There needs to be a greater emphasis on providing an independent analysis.”

More than 60% of the dermatologists participating in this study reported that they agreed or strongly agreed with the premise that they prefer to have the original dermatopathology report when they offer a second opinion. Dr. Elmore said that the desire of those offering a second opinion to have as much information in front of them as possible is understandable, but the bias imposed by the original report weakens the value of the second opinion.
 

Blind reading of pathology reports needed

“These data suggest that seeing the original report sways opinions and that includes swaying opinions away from an accurate reading,” Dr. Elmore said. She thinks that for dermatopathologists to render a valuable and independent second opinion, the specimens should be examined “at least initially” without access to the first report.

The results of this study were not surprising to Vishal Anil Patel, MD, director of the Cutaneous Oncology Program, George Washington University Cancer Center, Washington. He made the point that physicians “are human first and foremost and not perfect machines.” As a result, he suggested bias and error are inevitable.

Although strategies to avoid bias are likely to offer some protection against inaccuracy, he said that diagnostic support tools such as artificial intelligence might be the right direction for improving inter- and intra-rater reliability.

Ruifeng Guo, MD, PhD, a consultant in the division of anatomic pathology at the Mayo Clinic, Rochester, Minn., agreed with the basic premise of the study, but he cautioned that restricting access to the initial pathology report might not always be the right approach.

It is true that “dermatopathologists providing a second opinion in diagnosing cutaneous melanoma are mostly unaware of the risk of bias if they read the initial pathology report,” said Dr. Guo, but restricting access comes with risks.

“There are also times critical information may be contained in the initial pathology report that needs to be considered when providing a second opinion consultation,” he noted. Ultimately, the decision to read or not read the initial report should be decided “on an individual basis.”

The study was funded by grants from the National Cancer Institute. Dr. Elmore, Dr. Patel, and Dr. Guo reported no relevant financial relationships. 

A version of this article first appeared on Medscape.com.